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    Clinical Trial Results:
    A MULTICENTER, PHASE III, RANDOMIZED, PLACEBO-CONTROLLED TRIAL EVALUATING THE EFFICACY AND SAFETY OF BEVACIZUMAB IN COMBINATION WITH CHEMOTHERAPY REGIMENS IN SUBJECTS WITH PREVIOUSLY UNTREATED METASTATIC BREAST CANCER

    Summary
    EudraCT number
    2006-000378-61
    Trial protocol
    ES   GB   NL   SE   GR  
    Global end of trial date
    08 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Nov 2016
    First version publication date
    27 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AVF3694g
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00262067
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the clinical benefit of the addition of bevacizumab to standard chemotherapy regimens (taxane or anthracycline based and capecitabine) for previously untreated metastatic breast cancer, as measured by progression-free survival based on investigator tumor assessment.
    Protection of trial subjects
    Participants were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the participant and considering the local culture. The participants were provided an emergency medical call center help desk in the case of emergency during the study to ensure the safety.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Dec 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 610
    Country: Number of subjects enrolled
    Ukraine: 82
    Country: Number of subjects enrolled
    Australia: 55
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 31
    Country: Number of subjects enrolled
    Philippines: 25
    Country: Number of subjects enrolled
    Brazil: 35
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    Singapore: 26
    Country: Number of subjects enrolled
    Mexico: 11
    Country: Number of subjects enrolled
    Panama: 4
    Country: Number of subjects enrolled
    Russian Federation: 126
    Country: Number of subjects enrolled
    Netherlands: 15
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    United Kingdom: 42
    Country: Number of subjects enrolled
    France: 60
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Guatemala: 20
    Country: Number of subjects enrolled
    Uruguay: 6
    Country: Number of subjects enrolled
    Peru: 5
    Country: Number of subjects enrolled
    Greece: 4
    Worldwide total number of subjects
    1237
    EEA total number of subjects
    161
    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)
    960
    From 65 to 84 years
    277
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted from 15 December 2005 to 8 January 2015 in the United States, Europe, and the rest of the world.

    Pre-assignment
    Screening details
    A total of 1237 participants were enrolled in the United States, Europe, and the rest of the world. Eligible participants were randomized in a 2:1 ratio to receive either chemotherapy plus bevacizumab or chemotherapy plus placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bevacizumab + Taxane or Anthracycline
    Arm description
    Eligible participants were administered Avastin® (bevacizumab) 15 milligrams (mg)/kilogram (kg) intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline (minimum 6 cycles and maximum 8 cycles of anthracycline)-based standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was packaged in either 5 milliliter (mL) (100 mg) or 20 mL (400 mg) glass vials containing 4 mL or 16 mL of bevacizumab, respectively (25 mg/mL for either vial).

    Arm title
    Placebo + Taxane or Anthracycline
    Arm description
    Eligible participants were administered bevacizumab matching placebo IV on Day 1 of every 21-day cycle + either a taxane or anthracycline (minimum 6 cycles and maximum 8 cycles of anthracycline)-based standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was a clear to slightly opalescent and sterile liquid ready for intravenous administration.

    Arm title
    Bevacizumab + Capecitabine
    Arm description
    Eligible participants were administered bevacizumab 15 mg/kg IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was packaged in either 5 mL (100 mg) or 20 mL (400 mg) glass vials containing 4 mL or 16 mL of bevacizumab, respectively (25 mg/mL for either vial).

    Arm title
    Placebo + Capecitabine
    Arm description
    Eligible participants were administered bevacizumab matching placebo IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was a clear to slightly opalescent and sterile liquid ready for intravenous administration.

    Number of subjects in period 1
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Started
    415
    207
    409
    206
    Completed
    0
    0
    0
    0
    Not completed
    415
    207
    409
    206
         Consent withdrawn by subject
    45
    14
    25
    5
         Physician decision
    46
    12
    17
    6
         Disease progression
    187
    146
    245
    145
         >60 days since last administration of BV
    6
    -
    -
    -
         > 60 days since last administration of BV
    -
    1
    8
    1
         Death
    14
    7
    11
    6
         Other
    12
    6
    5
    5
         Treatment completion
    -
    -
    1
    -
         Adverse event
    63
    10
    37
    11
         Lost to follow-up
    -
    3
    -
    -
         Not known to have discontinued protocol therapy
    36
    7
    55
    22
         Not treated
    6
    1
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bevacizumab + Taxane or Anthracycline
    Reporting group description
    Eligible participants were administered Avastin® (bevacizumab) 15 milligrams (mg)/kilogram (kg) intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline (minimum 6 cycles and maximum 8 cycles of anthracycline)-based standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Placebo + Taxane or Anthracycline
    Reporting group description
    Eligible participants were administered bevacizumab matching placebo IV on Day 1 of every 21-day cycle + either a taxane or anthracycline (minimum 6 cycles and maximum 8 cycles of anthracycline)-based standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Bevacizumab + Capecitabine
    Reporting group description
    Eligible participants were administered bevacizumab 15 mg/kg IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Placebo + Capecitabine
    Reporting group description
    Eligible participants were administered bevacizumab matching placebo IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group values
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine Total
    Number of subjects
    415 207 409 206 1237
    Age categorical
    Units: Subjects
        < 40 years
    29 14 21 15 79
        40-64 years
    295 160 289 137 881
        ≥ 65 years
    91 33 99 54 277
    Gender categorical
    Units: Subjects
        Female
    413 207 408 204 1232
        Male
    2 0 1 2 5

    End points

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    End points reporting groups
    Reporting group title
    Bevacizumab + Taxane or Anthracycline
    Reporting group description
    Eligible participants were administered Avastin® (bevacizumab) 15 milligrams (mg)/kilogram (kg) intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline (minimum 6 cycles and maximum 8 cycles of anthracycline)-based standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Placebo + Taxane or Anthracycline
    Reporting group description
    Eligible participants were administered bevacizumab matching placebo IV on Day 1 of every 21-day cycle + either a taxane or anthracycline (minimum 6 cycles and maximum 8 cycles of anthracycline)-based standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Bevacizumab + Capecitabine
    Reporting group description
    Eligible participants were administered bevacizumab 15 mg/kg IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Placebo + Capecitabine
    Reporting group description
    Eligible participants were administered bevacizumab matching placebo IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Subject analysis set title
    Intent-to-treat population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intent-to-treat (ITT) population included all participants who were randomized, regardless of whether they received any study medication or completed the full course of treatment.

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety population included all randomized participants who received any study treatment (at least one full or partial dose of either study medication or chemotherapy).

    Primary: Progression-free Survival as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors

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    End point title
    Progression-free Survival as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors
    End point description
    Progression-free Survival (PFS) was defined as time from randomization to first documented disease progression (PD). It was determined by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 or death due to any cause, whichever occurred first. For target lesions, PD was defined as at least 20% increase in sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or appearance of one or more new lesions. For non-target lesions, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. ITT population was considered for this end point.
    End point type
    Primary
    End point timeframe
    From first participant in (15 December 2005) till PFS analysis cut-off (31 July 2008) (Up to 2 years, 7 months)
    End point values
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    415
    207
    409
    206
    Units: Months
        median (confidence interval 95%)
    9.2 (8.6 to 10.1)
    8 (6.7 to 8.4)
    8.6 (8.1 to 9.5)
    5.7 (4.3 to 6.2)
    Statistical analysis title
    T/Anth+Placebo VS T/Anth+BV
    Comparison groups
    Bevacizumab + Taxane or Anthracycline v Placebo + Taxane or Anthracycline
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.644
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.522
         upper limit
    0.795
    Statistical analysis title
    Cap+Placebo VS Cap+BV
    Comparison groups
    Bevacizumab + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0002
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.688
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.564
         upper limit
    0.84

    Secondary: Objective Response Rate as Assessed by Investigator Using RECIST

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    End point title
    Objective Response Rate as Assessed by Investigator Using RECIST
    End point description
    An objective response was defined as a complete response or a partial response determined on two consecutive occasions >= 4 weeks apart as determined by the investigator using RECIST 1.0. Objective response rate (ORR) was defined as the percentage of participants who had an objective response. For target lesions, a complete response was defined as the disappearance of all target lesions and a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions and a partial response was defined as the persistence of one or more non-target lesions. Analysis population consisted of randomized participants (ITT population) who had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    From first participant in (15 December 2005) till ORR analysis cut-off (31 July 2008) (Up to 2 years, 7 months)
    End point values
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    345 [1]
    177 [2]
    325 [3]
    161 [4]
    Units: Percentage of participants
        number (confidence interval 95%)
    51.3 (45.9 to 56.7)
    37.9 (30.7 to 45.2)
    35.4 (30.2 to 40.6)
    23.6 (17.6 to 30.7)
    Notes
    [1] - Only participants with measurable disease at baseline were included in the analysis.
    [2] - Only participants with measurable disease at baseline were included in the analysis.
    [3] - Only participants with measurable disease at baseline were included in the analysis.
    [4] - Only participants with measurable disease at baseline were included in the analysis.
    Statistical analysis title
    T/Anth+Placebo vs T/Anth+BV
    Comparison groups
    Placebo + Taxane or Anthracycline v Bevacizumab + Taxane or Anthracycline
    Number of subjects included in analysis
    522
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0054
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference in ORR
    Point estimate
    13.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.6
         upper limit
    22.3
    Statistical analysis title
    Cap+Placebo VS Cap+BV
    Comparison groups
    Bevacizumab + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    486
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0097
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Percentage difference in ORR
    Point estimate
    11.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.4
         upper limit
    20.2

    Secondary: Duration of Objective Response as Determined by the Investigator Using RECIST

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    End point title
    Duration of Objective Response as Determined by the Investigator Using RECIST
    End point description
    Duration of objective response was defined as the time from the first tumor assessment that led to a determination of an objective response to the time of disease progression or death due to any cause, whichever occurred first. Analysis population consisted of randomized participants (ITT population) who had measurable disease at baseline and achieved an objective response.
    End point type
    Secondary
    End point timeframe
    From first participant in (15 December 2005) till objective response analysis cut-off (31 July 2008) (Up to 2 years, 7 months)
    End point values
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    177 [5]
    67 [6]
    115 [7]
    38 [8]
    Units: Months
        median (confidence interval 95%)
    8.3 (7.2 to 10.7)
    7.1 (6.2 to 8.8)
    9.2 (8.5 to 10.4)
    7.2 (5.1 to 9.3)
    Notes
    [5] - Only participants with measurable disease at baseline and who had objective response were included.
    [6] - Only participants with measurable disease at baseline and who had objective response were included.
    [7] - Only participants with measurable disease at baseline and who had objective response were included.
    [8] - Only participants with measurable disease at baseline and who had objective response were included.
    Statistical analysis title
    T/Anth+Placebo VS T/Anth+BV
    Comparison groups
    Bevacizumab + Taxane or Anthracycline v Placebo + Taxane or Anthracycline
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0064
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.627
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.447
         upper limit
    0.88
    Statistical analysis title
    Cap+Placebo VS Cap+BV
    Comparison groups
    Bevacizumab + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0326
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.612
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.388
         upper limit
    0.964

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival was defined as the time from randomization until death from any cause. ITT population was considered for this end point. The median value and value of upper limit of confidence interval for Placebo + Taxane or Anthracycline was 'not reached' and 'not estimable', respectively. However, the EudraCT portal does not accept blank field or have free text option for the explanation; therefore, we have presented an arbitrary value (99999) for the same.
    End point type
    Secondary
    End point timeframe
    From first participant in (15 December 2005) till overall survival analysis cut-off (24 February 2009) (Up to 3 years, 2 months)
    End point values
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    415
    207
    409
    206
    Units: Months
        median (confidence interval 95%)
    27.5 (25.6 to 31.4)
    99999 (23.6 to 99999)
    25.7 (22 to 28.4)
    22.8 (20.5 to 28.4)
    Statistical analysis title
    T/Anth+Placebo VS T/Anth+BV
    Comparison groups
    Bevacizumab + Taxane or Anthracycline v Placebo + Taxane or Anthracycline
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.44
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.43
    Statistical analysis title
    Cap+Placebo VS Cap+BV
    Comparison groups
    Bevacizumab + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.33
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.13

    Secondary: One-year Survival Rate

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    End point title
    One-year Survival Rate
    End point description
    One-year survival rate was defined as the percentage of participants who were alive one-year after randomization. The percentage of participants alive at one-year was determined using Kaplan-Meier analyses and the 95% confidence intervals were computed using the Greenwood’s formula. ITT population was considered for this end point.
    End point type
    Secondary
    End point timeframe
    One year after randomization for each participant
    End point values
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    415
    207
    409
    206
    Units: Percentage of participants
        number (confidence interval 95%)
    80.7 (76.8 to 84.5)
    83.2 (78.1 to 88.4)
    81 (77.1 to 84.8)
    74.8 (68.7 to 80.8)
    Statistical analysis title
    T/Anth+Placebo vs T/Anth+BV
    Comparison groups
    Bevacizumab + Taxane or Anthracycline v Placebo + Taxane or Anthracycline
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.436
    Method
    Normal approximation
    Parameter type
    % difference in one−year survival rate
    Point estimate
    -2.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9
         upper limit
    3.9
    Statistical analysis title
    Cap+Placebo VS Cap+BV
    Comparison groups
    Bevacizumab + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.092
    Method
    Normal approximation
    Parameter type
    % difference in one−year survival rate
    Point estimate
    6.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    13.4

    Secondary: PFS as Determined by the Independent Review Committee Using RECIST

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    End point title
    PFS as Determined by the Independent Review Committee Using RECIST
    End point description
    PFS was defined as time from randomization to first documented PD. It was determined by independent review committee using RECIST 1.0 or death due to any cause, whichever occurred first. For target lesions, PD was defined as at least 20% increase in sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or appearance of one or more new lesions. For non-target lesions, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. ITT population was considered for this end point.
    End point type
    Secondary
    End point timeframe
    From first participant in (15 December 2005) till PFS analysis cut-off (31 July 2008) (Up to 2 years, 7 months)
    End point values
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Number of subjects analysed
    415
    207
    409
    206
    Units: Months
        median (confidence interval 95%)
    10.7 (9.9 to 12.1)
    8.3 (8 to 9.9)
    9.8 (8.4 to 10.4)
    6.2 (4.7 to 7.8)
    Statistical analysis title
    T/Anth+Placebo VS T/Anth+BV
    Comparison groups
    Bevacizumab + Taxane or Anthracycline v Placebo + Taxane or Anthracycline
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.04
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.601
         upper limit
    0.988
    Statistical analysis title
    Cap+Placebo VS Cap+BV
    Comparison groups
    Bevacizumab + Capecitabine v Placebo + Capecitabine
    Number of subjects included in analysis
    615
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0011
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.681
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    0.858

    Secondary: Number of Participants With Serious Adverse Events after final overall survival analysis (24 February 2009) till end of study (8 January 2015)

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    End point title
    Number of Participants With Serious Adverse Events after final overall survival analysis (24 February 2009) till end of study (8 January 2015)
    End point description
    A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in death, is life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. The SAEs presented here were collected from 24 February 2009 to 8 January 2015. Safety population was considered for this end point.
    End point type
    Secondary
    End point timeframe
    Post final overall survival analysis (24 February 2009) till end of study (8 January 2015) (Approximately 6 years)
    End point values
    Safety population
    Number of subjects analysed
    1220
    Units: Number
    21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 3 years, 2 months (First participant enrolment [15 December 2005] to data cut-off date [24 February 2009])
    Adverse event reporting additional description
    Adverse event is reported for safety population which included all randomized participants who received any study treatment, defined as at least one full or partial dose of either study drug or chemotherapy.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Bevacizumab + Taxane or Anthracycline
    Reporting group description
    Participants received bevacizumab 15 mg/kg IV on Day 1 of every 21-day cycle + either a taxane or anthracycline (minimum 6 cycles and maximum 8 cycles of anthracycline)-based standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Placebo + Taxane or Anthracycline
    Reporting group description
    Participants received bevacizumab matching placebo IV on Day 1 of every 21-day cycle + either a taxane or anthracycline (minimum 6 cycles and maximum 8 cycles of anthracycline)-based standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Bevacizumab + Capecitabine
    Reporting group description
    Participants received bevacizumab 15 mg/kg IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Reporting group title
    Placebo + Capecitabine
    Reporting group description
    Participants received bevacizumab matching placebo IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer until disease progression, treatment-limiting toxicity, or death due to any cause.

    Serious adverse events
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    146 / 413 (35.35%)
    57 / 202 (28.22%)
    132 / 404 (32.67%)
    64 / 201 (31.84%)
         number of deaths (all causes)
    18
    9
    15
    11
         number of deaths resulting from adverse events
    6
    4
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Breast cancer metastatic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Metastases to meninges
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Tumour pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour ulceration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    1 / 202 (0.50%)
    3 / 404 (0.74%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 413 (1.21%)
    0 / 202 (0.00%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 413 (0.73%)
    1 / 202 (0.50%)
    2 / 404 (0.50%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    6 / 404 (1.49%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 413 (0.73%)
    2 / 202 (0.99%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 413 (0.97%)
    1 / 202 (0.50%)
    7 / 404 (1.73%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Immune system disorders
    Hypersensitivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diaphragmatic hernia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 413 (1.21%)
    2 / 202 (0.99%)
    6 / 404 (1.49%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    1 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Dyspnoea exertional
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    1 / 202 (0.50%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hypoxia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 413 (1.21%)
    3 / 202 (1.49%)
    5 / 404 (1.24%)
    5 / 201 (2.49%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 8
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    Pleuritic pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    1 / 202 (0.50%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 413 (0.73%)
    3 / 202 (1.49%)
    8 / 404 (1.98%)
    5 / 201 (2.49%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 3
    6 / 8
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    2 / 2
    Pulmonary haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    Tracheomalacia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Confusional state
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    3 / 404 (0.74%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 202 (0.50%)
    3 / 404 (0.74%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood potassium increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotavirus test positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug toxicity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    3 / 404 (0.74%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation oesophagitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 413 (0.48%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 413 (0.24%)
    2 / 202 (0.99%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    6 / 404 (1.49%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    1 / 404 (0.25%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular dysfunction
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid sinus syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cerebrovascular accident
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma hepatic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Convulsion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial palsy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 413 (0.73%)
    1 / 202 (0.50%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reversible posterior leukoencephalopathy syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 413 (0.73%)
    1 / 202 (0.50%)
    3 / 404 (0.74%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphasia
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 413 (0.73%)
    0 / 202 (0.00%)
    3 / 404 (0.74%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    26 / 413 (6.30%)
    11 / 202 (5.45%)
    3 / 404 (0.74%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    2 / 29
    0 / 11
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    10 / 413 (2.42%)
    5 / 202 (2.48%)
    3 / 404 (0.74%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    2 / 15
    0 / 5
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macular hole
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 413 (0.97%)
    1 / 202 (0.50%)
    4 / 404 (0.99%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 413 (1.94%)
    0 / 202 (0.00%)
    6 / 404 (1.49%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 0
    0 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 413 (1.21%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal toxicity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Haemorrhoids
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileal ulcer perforation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Ileus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jejunitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 413 (1.45%)
    1 / 202 (0.50%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    2 / 404 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 413 (1.45%)
    3 / 202 (1.49%)
    4 / 404 (0.99%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 3
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatic function abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pain of skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palmar−plantar erythrodysaesthesia syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 413 (0.73%)
    1 / 202 (0.50%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 202 (0.50%)
    5 / 404 (1.24%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal deformity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Abscess intestinal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess jaw
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Catheter related infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    3 / 404 (0.74%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 413 (1.69%)
    1 / 202 (0.50%)
    2 / 404 (0.50%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central line infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    2 / 404 (0.50%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes oesophagitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 413 (0.97%)
    1 / 202 (0.50%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella bacteraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    2 / 202 (0.99%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Osteomyelitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 413 (0.73%)
    5 / 202 (2.48%)
    6 / 404 (1.49%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophoritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 413 (1.45%)
    1 / 202 (0.50%)
    3 / 404 (0.74%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 0
    Sinusitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sweat gland infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    2 / 202 (0.99%)
    2 / 404 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 413 (1.69%)
    1 / 202 (0.50%)
    5 / 404 (1.24%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    0 / 404 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 413 (0.00%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 413 (0.48%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    1 / 413 (0.24%)
    0 / 202 (0.00%)
    1 / 404 (0.25%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bevacizumab + Taxane or Anthracycline Placebo + Taxane or Anthracycline Bevacizumab + Capecitabine Placebo + Capecitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 413 (23.24%)
    28 / 202 (13.86%)
    80 / 404 (19.80%)
    20 / 201 (9.95%)
    Vascular disorders
    Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    43 / 413 (10.41%)
    8 / 202 (3.96%)
    51 / 404 (12.62%)
    8 / 201 (3.98%)
         occurrences all number
    122
    14
    149
    11
    Cardiac disorders
    Left ventricular dysfunction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    19 / 413 (4.60%)
    8 / 202 (3.96%)
    3 / 404 (0.74%)
    2 / 201 (1.00%)
         occurrences all number
    53
    17
    6
    7
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    21 / 413 (5.08%)
    10 / 202 (4.95%)
    18 / 404 (4.46%)
    5 / 201 (2.49%)
         occurrences all number
    49
    26
    37
    7
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    25 / 413 (6.05%)
    6 / 202 (2.97%)
    18 / 404 (4.46%)
    5 / 201 (2.49%)
         occurrences all number
    137
    13
    59
    12

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2006
    Study AVF3694g was amended to provide more clarity and rigorous guidelines for study therapy in both the blinded treatment and post-progression phases. Safety information was also updated to be consistent with current standard bevacizumab dose modification guidelines. Protocol-specified selected adverse events and special reporting for nonserious cardiac adverse events were further defined. For this study, all intracranial hemorrhages were reported as serious and were therefore subject to serious adverse event reporting requirements. Safety monitoring of left ventricular function during initial screening was added for subjects with prior exposure to anthracycline-based therapy, rather than only for subjects entering the anthracycline cohort. All Grade >= 2 left ventricular systolic dysfunction events were reported immediately to the Sponsor to allow for a timely and thorough review of cardiotoxicity events by the Data Monitoring Committee.
    22 Nov 2006
    Study AVF3694g was amended to better fit the practice patterns of oncologists treating first-line metastatic breast cancer with chemotherapy. Major changes to the protocol are described below: • Secondary objectives and outcome measures were amended to include 1-year survival. • Modifications were made to the exclusion criteria, including allowing subjects who had unknown HER2 status and for whom the determination of HER2 status was not possible and disallowing subjects who had received radiotherapy within 2 weeks prior to Day 0. • Subjects with a history of anaphylactic reaction to monoclonal antibody therapy not controlled with treatment premedication were excluded from receiving bevacizumab. • Optional unblinding was allowed when a subject had documented progressive disease and if such information was instrumental in determining the next course of treatment. • For subjects who received prior anthracycline therapy or who were to be enrolled to the anthracycline cohort, an echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan was required (may be performed within 12 weeks prior to Day 0 if no cardiotoxic treatments or events occur within that period). Subjects who were to be enrolled into the anthracycline cohort should have had left ventricular ejection fraction (LVEF) >= 50%. Subjects who had received prior anthracycline therapy and were to be enrolled into the taxane or capecitabine cohort could not have New York Heart Association (NYHA) Grade II or higher CHF. • Subjects who had alkaline phosphatase > 2× the upper limit of normal (ULN; > 7× ULN in subjects with known bone involvement) were excluded from study entry.
    20 Feb 2007
    Study AVF3694g was amended to detect, statistically, the clinical benefit of the addition of bevacizumab to capecitabine therapy compared with capecitabine alone for first-line metastatic breast cancer participants. This study design allowed detection of the clinical benefit of the addition of bevacizumab to taxane therapy and anthracycline-based therapy in a parallel analysis.
    24 Jul 2007
    Study AVF3694g was amended to provide more information in support of the primary endpoint of progression free survival (PFS) and secondary endpoint of overall survival. An Independent Review Committee (IRC) assessment was added to meet study design guidelines and provide a sensitivity analysis for the investigator assessment−based primary endpoint. Additional subsequent anti-cancer therapy during the survival follow-up phase for all subjects were captured to provide information on therapies that may contribute to overall survival of participants after they had discontinued from the blinded phase of the study. The definition of PFS was updated, to be well characterized and accepted by the regulatory and research communities.
    27 Mar 2008
    Study AVF3694g was amended to provide bevacizumab in an optional extended treatment phase to all subjects receiving study treatment when the study analysis was complete if the primary efficacy analysis showed significant improvement with bevacizumab without a detrimental effect on subject safety. The maximum duration of treatment with bevacizumab (blinded treatment phase plus optional open-label post-progression phase and/or extended treatment phase) was increased to 48 months; this allowed subjects who were benefiting from bevacizumab treatment to continue to receive it.
    12 May 2011
    Study AVF3694g was amended to remove the maximum duration of treatment with bevacizumab (blinded treatment phase plus optional open-label post-progression phase and/or extended treatment phase) to all participants receiving study treatment when the study analysis was complete, if the primary efficacy analysis shows significant improvement with bevacizumab without a detrimental effect on subject safety. This was allow participants who are benefiting from bevacizumab treatment to continue to receive it. Other significant changes to the protocol has been described below: • Study treatment information and the study assessment schedule have been updated to reflect the amended duration of treatment of the optional extended treatment phase. • Only serious adverse event data was continue to be collected and reported as currently required by the protocol. Participants who were no longer receiving bevacizumab through the study have completed the study, and no further data need to be recorded. • Bevacizumab safety information was updated. • The sample Informed Consent Form was revised to reflect the changes to the protocol and the updated risk section.

    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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