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    Clinical Trial Results:
    Capecitabine and bevacizumab ± vinorelbine as 1st line treatment in HER2/neu-negative metastatic or locally advanced inoperable breast cancer patients

    Summary
    EudraCT number
    		 2008-003779-37
    Trial protocol
    		 DE  
    Global end of trial date
    15 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Aug 2021
    First version publication date
    04 Aug 2021
    Other versions
    Summary report(s)
    		 CARIN Study Results

    Trial information

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    Trial identification
    Sponsor protocol code
    IOM-080-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00868634
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    iOMEDICO AG
    Sponsor organisation address
    Ellen-Gottlieb-Str. 19, Freiburg, Germany, 79106
    Public contact
    Clinical Trials Information, iOMEDICO AG, 0049 761152420, info@iomedico.com
    Scientific contact
    Clinical Trials Information, iOMEDICO AG, 0049 761152420, info@iomedico.com
    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
    08 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To verify the superiority of the combination capecitabine, bevacizumab and vinorelbin compared to the combination of capecitabine and bevacizumab. Primary endpoint: Progression free survival
    Protection of trial subjects
    Independent ethics committees at all participating sites approved the protocol and all modifications. All patients provided written informed consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Feb 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 592
    Worldwide total number of subjects
    592
    EEA total number of subjects
    592
    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)
    355
    From 65 to 84 years
    237
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment 1:1

    Pre-assignment
    Screening details
    		 After a patient had signed informed consent form, screening procedures for study enrollment were completed.

    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
    Yes

    Arm title
    		 Arm A - CAP/BEV
    Arm description
    		 Capecitabine + bevacizumab
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 (twice daily, days 1-14, q3w)

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg (day 1, q3w)

    Arm title
    		 Arm B - CAP/BEV/VIN
    Arm description
    		 Capecitabine + bevacizumab + vinorelbine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m2 (twice daily, days 1-14, q3w)

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mg/kg (day 1, q3w)

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 mg/m2 (days 1+8, q3w)

    Number of subjects in period 1
    		Arm A - CAP/BEV Arm B - CAP/BEV/VIN
    Started
    297
    295
    Completed
    297
    295

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - CAP/BEV
    Reporting group description
    		 Capecitabine + bevacizumab

    Reporting group title
    Arm B - CAP/BEV/VIN
    Reporting group description
    		 Capecitabine + bevacizumab + vinorelbine

    Reporting group values
    		 Arm A - CAP/BEV Arm B - CAP/BEV/VIN Total
    Number of subjects
    		 297 295 592
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        < 65 years
    		 192 163 355
        >= 65 years
    		 105 132 237
    Gender categorical
    Units: Subjects
        Female
    		 297 295 592

    End points

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    End points reporting groups
    Reporting group title
    Arm A - CAP/BEV
    Reporting group description
    		 Capecitabine + bevacizumab

    Reporting group title
    Arm B - CAP/BEV/VIN
    Reporting group description
    		 Capecitabine + bevacizumab + vinorelbine

    Primary: PFS - Progression Free Survival

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    End point title
    		 PFS - Progression Free Survival
    End point description
    End point type
    Primary
    End point timeframe
    Time from first randomizaton until first signs of tumor progression or death from any cause.
    End point values
    		 Arm A - CAP/BEV Arm B - CAP/BEV/VIN
    Number of subjects analysed
    297
    295
    Units: months
        median (inter-quartile range (Q1-Q3))
    8.8 (8.15 to 9.79)
    9.6 (8.8 to 11.2)
    Statistical analysis title
    		 Kaplan Meier Estimates
    Comparison groups
    Arm A - CAP/BEV v Arm B - CAP/BEV/VIN
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.01
    Variability estimate
    Standard deviation

    Secondary: ORR - Overall Response Rate

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    End point title
    		 ORR - Overall Response Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Patients were considered evaluable for response if they had measurable disease at baseline
    End point values
    		 Arm A - CAP/BEV Arm B - CAP/BEV/VIN
    Number of subjects analysed
    179 [1]
    162 [2]
    Units: Number of patients
    65
    77
    Notes
    [1] - Only patients with measurable disease at baseline were evaluable
    [2] - Only patients with measurable disease at baseline were evaluable
    Statistical analysis title
    		 ORR Analysis
    Comparison groups
    Arm A - CAP/BEV v Arm B - CAP/BEV/VIN
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3986
         upper limit
    		 0.9936
    Variability estimate
    Standard deviation

    Secondary: OS - Overall Survival

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    End point title
    		 OS - Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Time from randomization until death
    End point values
    		 Arm A - CAP/BEV Arm B - CAP/BEV/VIN
    Number of subjects analysed
    297
    295
    Units: months
        median (inter-quartile range (Q1-Q3))
    25.1 (23.06 to 28.98)
    27.2 (23.46 to 29.67)
    Statistical analysis title
    		 Kaplan Meier Estimates
    Comparison groups
    Arm A - CAP/BEV v Arm B - CAP/BEV/VIN
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Logrank
    Parameter type
    		 Average Hazard Ratio
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.03
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE assessment started with randomization until end of treatment plus 30 days safety follow-up (=treatment emergent period)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Arm A - CAP/BEV
    Reporting group description
    		 -

    Reporting group title
    Arm B - CAP/BEV/VIN
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A - CAP/BEV Arm B - CAP/BEV/VIN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    112 / 297 (37.71%)
    150 / 295 (50.85%)
         number of deaths (all causes)
    219
    205
         number of deaths resulting from adverse events
    18
    25
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    2 / 297 (0.67%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastases to bone marrow
         subjects affected / exposed
    2 / 297 (0.67%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to meninges
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to peritoneum
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    2 / 297 (0.67%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Tumour pain
         subjects affected / exposed
    2 / 297 (0.67%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 297 (0.34%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 297 (0.67%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    3 / 297 (1.01%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebosclerosis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 297 (0.67%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 297 (0.00%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter management
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemotherapy
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiofrequency ablation of oesophagus
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 297 (0.34%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Chest pain
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    6 / 297 (2.02%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 4
    1 / 3
    Fatigue
         subjects affected / exposed
    0 / 297 (0.00%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    6 / 297 (2.02%)
    14 / 295 (4.75%)
         occurrences causally related to treatment / all
    2 / 6
    7 / 15
         deaths causally related to treatment / all
    0 / 1
    1 / 4
    Impaired healing
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multi-organ failure
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pain
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 297 (0.67%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ulcer
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    2 / 297 (0.67%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 297 (2.02%)
    5 / 295 (1.69%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 297 (0.67%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 297 (0.34%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 297 (1.35%)
    16 / 295 (5.42%)
         occurrences causally related to treatment / all
    3 / 4
    11 / 16
         deaths causally related to treatment / all
    1 / 1
    1 / 4
    Respiratory failure
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 297 (0.34%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine increased
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure orthostatic abnormal
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granulocyte count decreased
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein total decreased
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury corneal
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mitral valve incompetence
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cauda equina syndrome
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic coma
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    2 / 297 (0.67%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 297 (0.67%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 297 (0.00%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diplegia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 297 (0.34%)
    5 / 295 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematotoxicity
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 297 (0.34%)
    20 / 295 (6.78%)
         occurrences causally related to treatment / all
    1 / 1
    26 / 26
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lymphadenopathy
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 297 (0.00%)
    19 / 295 (6.44%)
         occurrences causally related to treatment / all
    0 / 0
    22 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    4 / 297 (1.35%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 297 (0.67%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 297 (0.34%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 297 (0.67%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 297 (0.00%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colitis
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 297 (0.67%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 297 (2.36%)
    5 / 295 (1.69%)
         occurrences causally related to treatment / all
    4 / 7
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enteritis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 297 (0.67%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 297 (0.34%)
    5 / 295 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 297 (0.67%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 297 (1.01%)
    6 / 295 (2.03%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 297 (1.01%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity vasculitis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin fissures
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    2 / 297 (0.67%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 297 (0.00%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 297 (0.00%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Ureteric stenosis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 297 (0.34%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Actinomycosis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amoebic dysentery
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial disease carrier
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    2 / 297 (0.67%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 297 (0.34%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 297 (0.67%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 297 (1.68%)
    7 / 295 (2.37%)
         occurrences causally related to treatment / all
    2 / 5
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 297 (0.34%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 297 (1.01%)
    4 / 295 (1.36%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 297 (0.00%)
    2 / 295 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 297 (1.35%)
    3 / 295 (1.02%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 295 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 295 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A - CAP/BEV Arm B - CAP/BEV/VIN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    292 / 297 (98.32%)
    291 / 295 (98.64%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    85 / 297 (28.62%)
    66 / 295 (22.37%)
         occurrences all number
    112
    83
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    89 / 297 (29.97%)
    125 / 295 (42.37%)
         occurrences all number
    102
    155
    General physical health deterioration
         subjects affected / exposed
    17 / 297 (5.72%)
    19 / 295 (6.44%)
         occurrences all number
    17
    22
    Mucosal inflammation
         subjects affected / exposed
    57 / 297 (19.19%)
    67 / 295 (22.71%)
         occurrences all number
    73
    88
    Oedema peripheral
         subjects affected / exposed
    16 / 297 (5.39%)
    15 / 295 (5.08%)
         occurrences all number
    17
    16
    Pain
         subjects affected / exposed
    24 / 297 (8.08%)
    32 / 295 (10.85%)
         occurrences all number
    26
    36
    Pyrexia
         subjects affected / exposed
    13 / 297 (4.38%)
    28 / 295 (9.49%)
         occurrences all number
    14
    38
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 297 (10.10%)
    27 / 295 (9.15%)
         occurrences all number
    32
    28
    Dysphonia
         subjects affected / exposed
    11 / 297 (3.70%)
    18 / 295 (6.10%)
         occurrences all number
    12
    20
    Dyspnoea
         subjects affected / exposed
    34 / 297 (11.45%)
    43 / 295 (14.58%)
         occurrences all number
    35
    49
    Epistaxis
         subjects affected / exposed
    34 / 297 (11.45%)
    59 / 295 (20.00%)
         occurrences all number
    39
    68
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    19 / 297 (6.40%)
    23 / 295 (7.80%)
         occurrences all number
    20
    23
    Investigations
    Weight decreased
         subjects affected / exposed
    23 / 297 (7.74%)
    36 / 295 (12.20%)
         occurrences all number
    23
    37
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 297 (7.07%)
    27 / 295 (9.15%)
         occurrences all number
    25
    35
    Dysgeusia
         subjects affected / exposed
    28 / 297 (9.43%)
    26 / 295 (8.81%)
         occurrences all number
    28
    28
    Headache
         subjects affected / exposed
    41 / 297 (13.80%)
    49 / 295 (16.61%)
         occurrences all number
    48
    63
    Paraesthesia
         subjects affected / exposed
    18 / 297 (6.06%)
    17 / 295 (5.76%)
         occurrences all number
    22
    21
    Polyneuropathy
         subjects affected / exposed
    22 / 297 (7.41%)
    45 / 295 (15.25%)
         occurrences all number
    24
    48
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 297 (4.04%)
    45 / 295 (15.25%)
         occurrences all number
    16
    58
    Leukopenia
         subjects affected / exposed
    8 / 297 (2.69%)
    83 / 295 (28.14%)
         occurrences all number
    9
    171
    Neutropenia
         subjects affected / exposed
    10 / 297 (3.37%)
    80 / 295 (27.12%)
         occurrences all number
    13
    155
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    7 / 297 (2.36%)
    15 / 295 (5.08%)
         occurrences all number
    7
    16
    Abdominal pain upper
         subjects affected / exposed
    26 / 297 (8.75%)
    43 / 295 (14.58%)
         occurrences all number
    31
    53
    Constipation
         subjects affected / exposed
    43 / 297 (14.48%)
    67 / 295 (22.71%)
         occurrences all number
    52
    82
    Diarrhoea
         subjects affected / exposed
    92 / 297 (30.98%)
    83 / 295 (28.14%)
         occurrences all number
    140
    117
    Dyspepsia
         subjects affected / exposed
    16 / 297 (5.39%)
    26 / 295 (8.81%)
         occurrences all number
    17
    27
    Nausea
         subjects affected / exposed
    96 / 297 (32.32%)
    129 / 295 (43.73%)
         occurrences all number
    119
    179
    Stomatitis
         subjects affected / exposed
    22 / 297 (7.41%)
    25 / 295 (8.47%)
         occurrences all number
    24
    35
    Vomiting
         subjects affected / exposed
    39 / 297 (13.13%)
    51 / 295 (17.29%)
         occurrences all number
    50
    64
    Abdominal pain
         subjects affected / exposed
    16 / 297 (5.39%)
    14 / 295 (4.75%)
         occurrences all number
    20
    18
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    20 / 297 (6.73%)
    59 / 295 (20.00%)
         occurrences all number
    22
    61
    Erythema
         subjects affected / exposed
    18 / 297 (6.06%)
    8 / 295 (2.71%)
         occurrences all number
    18
    9
    Nail disorder
         subjects affected / exposed
    17 / 297 (5.72%)
    11 / 295 (3.73%)
         occurrences all number
    17
    12
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    195 / 297 (65.66%)
    119 / 295 (40.34%)
         occurrences all number
    305
    174
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    23 / 297 (7.74%)
    19 / 295 (6.44%)
         occurrences all number
    38
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 297 (7.41%)
    29 / 295 (9.83%)
         occurrences all number
    24
    30
    Back pain
         subjects affected / exposed
    20 / 297 (6.73%)
    28 / 295 (9.49%)
         occurrences all number
    21
    29
    Bone pain
         subjects affected / exposed
    26 / 297 (8.75%)
    24 / 295 (8.14%)
         occurrences all number
    28
    27
    Muscle spasms
         subjects affected / exposed
    7 / 297 (2.36%)
    16 / 295 (5.42%)
         occurrences all number
    7
    19
    Pain in extremity
         subjects affected / exposed
    20 / 297 (6.73%)
    26 / 295 (8.81%)
         occurrences all number
    22
    29
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    27 / 297 (9.09%)
    32 / 295 (10.85%)
         occurrences all number
    32
    47
    Urinary tract infection
         subjects affected / exposed
    28 / 297 (9.43%)
    29 / 295 (9.83%)
         occurrences all number
    35
    33
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    39 / 297 (13.13%)
    45 / 295 (15.25%)
         occurrences all number
    41
    57

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2009
    A first revision of the initial study protocol introduced the project “Translational research”
    23 Sep 2009
    The substantial amendment 1 introduced the project “Epigenetic Profiling of Plasma DNA in Response to Chemotherapy Treatment”
    14 Mar 2011
    The substantial amendment 2 included the capture of laboratory values extended even to laboratory values considered non-pathological, and the capture of tumor evaluations independent of individual treatment cycles.
    09 Aug 2011
    The substantial amendment 3 included the increase of the patient number from initial 400 to 600, and the changeover of capecitabine and bevacizumab to articles of trade.
    21 Oct 2014
    The substantial amendment 4 issued the classification of the trial. The trial phase was changed from IIb to phase III. Further, the number of events for the primary endpoint analysis was reduced due to the unexpected high drop-out rate. The original sample size calculation assumed 494 events, the amended sample size included at least 441 events, yielding 75% power to detect a PFS difference between treatment arms.

    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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