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    Clinical Trial Results:
    A prospective, randomized Phase III trial of carboplatin/gemcitabine/bevacizumab vs. carboplatin/pegylated liposomal doxorubicin/bevacizumab in patients with platinum-sensitive recurrent ovarian cancer.

    Summary
    EudraCT number
    2012-004125-24
    Trial protocol
    DE   AT   BE   GB  
    Global end of trial date
    19 Jan 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jul 2022
    First version publication date
    30 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AGO-OVAR2.21
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01837251
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AGO Research GmbH
    Sponsor organisation address
    Kaiser-Friedrich-Ring 71, Wiesbaden, Germany, 65185
    Public contact
    Study Office, AGO Research GmbH, 0049 6118804670, office-wiesbaden@ago-ovar.de
    Scientific contact
    Study Office, AGO Research GmbH, 0049 6118804670, office-wiesbaden@ago-ovar.de
    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
    01 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy outcome measure is investigator-determined progression-free survival (PFS)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Austria: 19
    Country: Number of subjects enrolled
    France: 107
    Country: Number of subjects enrolled
    Germany: 473
    Country: Number of subjects enrolled
    Australia: 76
    Worldwide total number of subjects
    682
    EEA total number of subjects
    599
    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)
    394
    From 65 to 84 years
    287
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    FPFV: 21-AUG-2013, LPLV: 14-JAN-2019

    Pre-assignment
    Screening details
    The study consisted of a screening/baseline period, a treatment period and a posttreatment or follow-up period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm 2 (experimental group)
    Arm description
    Bevacizumab, Peylated Liposomal Doxorubicin, Carboplatin
    Arm type
    Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15mg/kg/body weight

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10mg/kg/body weight

    Arm title
    Arm 1 (standard group)
    Arm description
    Bevacizumab, Gemcitabine, Carboplatin
    Arm type
    Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15mg/kg/body weight

    Number of subjects in period 1
    Arm 2 (experimental group) Arm 1 (standard group)
    Started
    345
    337
    Completed
    332
    329
    Not completed
    13
    8
         did not receive allocated intervention
    8
    5
         received only chemotherapy
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 2 (experimental group)
    Reporting group description
    Bevacizumab, Peylated Liposomal Doxorubicin, Carboplatin

    Reporting group title
    Arm 1 (standard group)
    Reporting group description
    Bevacizumab, Gemcitabine, Carboplatin

    Reporting group values
    Arm 2 (experimental group) Arm 1 (standard group) Total
    Number of subjects
    345 337 682
    Age categorical
    female patients 18 years and older.
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    202 192 394
        From 65-84 years
    143 144 287
        85 years and over
    0 1 1
    Gender categorical
    Units: Subjects
        Female
    345 337 682
        Male
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Arm 2 (experimental group)
    Reporting group description
    Bevacizumab, Peylated Liposomal Doxorubicin, Carboplatin

    Reporting group title
    Arm 1 (standard group)
    Reporting group description
    Bevacizumab, Gemcitabine, Carboplatin

    Primary: Progression free survival

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    End point title
    Progression free survival
    End point description
    End point type
    Primary
    End point timeframe
    PFS defined as the interval between randomisation and first documented disease progression or death, whichever occurred first
    End point values
    Arm 2 (experimental group) Arm 1 (standard group)
    Number of subjects analysed
    332
    329
    Units: months
        number (not applicable)
    13.3
    11.6
    Statistical analysis title
    Primary statistical analysis
    Statistical analysis description
    Efficacy outcomes were analysed in the intention-to-treat population, defined as all randomly assigned patients irrespective of whether they actually received treatment. Progression-free survival were compared between the two treatment groups using a stratified log-rank test at a two-sided 5% significance level, stratified by the factors used for randomisation. Median progression-free survival were estimated using Kaplan-Meier estimates with corresponding 95% CIs.
    Comparison groups
    Arm 2 (experimental group) v Arm 1 (standard group)
    Number of subjects included in analysis
    661
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.012
    Method
    Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Events occurring during the clinical trial or within 30 days after treatment discontinuation
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Arm 2
    Reporting group description
    Experimental group: Bevacizumab, Peylated Liposomal Doxorubicin, Carboplatin

    Reporting group title
    Arm 1
    Reporting group description
    Standard group: Bevacizumab, Gemcitabine, Carboplatin

    Serious adverse events
    Arm 2 Arm 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 332 (9.94%)
    28 / 329 (8.51%)
         number of deaths (all causes)
    207
    232
         number of deaths resulting from adverse events
    13
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thyroid cancer
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial stenosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    11 / 332 (3.31%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    13 / 13
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    4 / 332 (1.20%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter management
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheterisation venous
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implantable pleural catheter insertion
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenectomy
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrostomy
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 332 (0.90%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    14 / 332 (4.22%)
    16 / 329 (4.86%)
         occurrences causally related to treatment / all
    3 / 20
    4 / 20
         deaths causally related to treatment / all
    2 / 2
    2 / 2
    Impaired healing
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    1 / 117
    1 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 332 (0.00%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 332 (1.20%)
    7 / 329 (2.13%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 332 (0.00%)
    9 / 329 (2.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 332 (1.51%)
    5 / 329 (1.52%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 332 (0.60%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    9 / 332 (2.71%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 332 (1.51%)
    5 / 329 (1.52%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood altered
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematology test abnormal
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    8 / 332 (2.41%)
    10 / 329 (3.04%)
         occurrences causally related to treatment / all
    6 / 9
    3 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal anastomosis complication
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urostomy complication
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 332 (0.90%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiotoxicity
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 332 (0.60%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osmotic demyelination syndrome
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Parkinsonism
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    4 / 332 (1.20%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 332 (2.71%)
    8 / 329 (2.43%)
         occurrences causally related to treatment / all
    3 / 12
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood disorder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematotoxicity
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 332 (0.30%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    4 / 332 (1.20%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    7 / 332 (2.11%)
    25 / 329 (7.60%)
         occurrences causally related to treatment / all
    5 / 10
    8 / 32
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    13 / 332 (3.92%)
    12 / 329 (3.65%)
         occurrences causally related to treatment / all
    4 / 13
    6 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 332 (0.90%)
    8 / 329 (2.43%)
         occurrences causally related to treatment / all
    1 / 4
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 332 (1.51%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    8 / 332 (2.41%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    4 / 9
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 332 (1.20%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal perforation
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    9 / 332 (2.71%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    3 / 9
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    13 / 332 (3.92%)
    8 / 329 (2.43%)
         occurrences causally related to treatment / all
    4 / 18
    4 / 10
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Vomiting
         subjects affected / exposed
    9 / 332 (2.71%)
    8 / 329 (2.43%)
         occurrences causally related to treatment / all
    6 / 11
    0 / 9
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Haemorrhage subcutaneous
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    5 / 332 (1.51%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Renal failure acute
         subjects affected / exposed
    3 / 332 (0.90%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary fistula
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 332 (0.90%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fascioliasis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    6 / 332 (1.81%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharingitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    5 / 332 (1.51%)
    9 / 329 (2.74%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 332 (0.60%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Malnutrition
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm 2 Arm 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    327 / 332 (98.49%)
    319 / 329 (96.96%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    144 / 332 (43.37%)
    121 / 329 (36.78%)
         occurrences all number
    502
    399
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    23 / 332 (6.93%)
    31 / 329 (9.42%)
         occurrences all number
    69
    59
    Fatigue
         subjects affected / exposed
    163 / 332 (49.10%)
    147 / 329 (44.68%)
         occurrences all number
    343
    281
    Mucosal inflammation
         subjects affected / exposed
    59 / 332 (17.77%)
    38 / 329 (11.55%)
         occurrences all number
    117
    57
    Oedema
         subjects affected / exposed
    18 / 332 (5.42%)
    0 / 329 (0.00%)
         occurrences all number
    31
    0
    Oedema peripheral
         subjects affected / exposed
    30 / 332 (9.04%)
    27 / 329 (8.21%)
         occurrences all number
    38
    40
    Pain
         subjects affected / exposed
    22 / 332 (6.63%)
    0 / 329 (0.00%)
         occurrences all number
    47
    0
    Pyrexia
         subjects affected / exposed
    23 / 332 (6.93%)
    22 / 329 (6.69%)
         occurrences all number
    32
    26
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 332 (7.83%)
    23 / 329 (6.99%)
         occurrences all number
    32
    27
    Dysphonia
         subjects affected / exposed
    17 / 332 (5.12%)
    0 / 329 (0.00%)
         occurrences all number
    22
    0
    Dyspnoea
         subjects affected / exposed
    71 / 332 (21.39%)
    61 / 329 (18.54%)
         occurrences all number
    114
    90
    Epistaxis
         subjects affected / exposed
    80 / 332 (24.10%)
    82 / 329 (24.92%)
         occurrences all number
    112
    113
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 332 (0.00%)
    19 / 329 (5.78%)
         occurrences all number
    0
    21
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    34 / 332 (10.24%)
    50 / 329 (15.20%)
         occurrences all number
    131
    168
    Platelet count decreased
         subjects affected / exposed
    52 / 332 (15.66%)
    53 / 329 (16.11%)
         occurrences all number
    231
    172
    White blood cell count decreased
         subjects affected / exposed
    19 / 332 (5.72%)
    34 / 329 (10.33%)
         occurrences all number
    65
    113
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    27 / 332 (8.13%)
    21 / 329 (6.38%)
         occurrences all number
    32
    33
    Dysgeusia
         subjects affected / exposed
    32 / 332 (9.64%)
    21 / 329 (6.38%)
         occurrences all number
    39
    22
    Headache
         subjects affected / exposed
    82 / 332 (24.70%)
    71 / 329 (21.58%)
         occurrences all number
    155
    125
    Peripheral sensory neuropathy
         subjects affected / exposed
    39 / 332 (11.75%)
    34 / 329 (10.33%)
         occurrences all number
    57
    48
    Polyneuropathy
         subjects affected / exposed
    23 / 332 (6.93%)
    0 / 329 (0.00%)
         occurrences all number
    34
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    121 / 332 (36.45%)
    132 / 329 (40.12%)
         occurrences all number
    463
    441
    Leukopenia
         subjects affected / exposed
    29 / 332 (8.73%)
    45 / 329 (13.68%)
         occurrences all number
    88
    152
    Neutropenia
         subjects affected / exposed
    59 / 332 (17.77%)
    102 / 329 (31.00%)
         occurrences all number
    209
    355
    Thrombocytopenia
         subjects affected / exposed
    61 / 332 (18.37%)
    93 / 329 (28.27%)
         occurrences all number
    215
    286
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    17 / 332 (5.12%)
    0 / 329 (0.00%)
         occurrences all number
    26
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    45 / 332 (13.55%)
    56 / 329 (17.02%)
         occurrences all number
    65
    100
    Abdominal pain upper
         subjects affected / exposed
    33 / 332 (9.94%)
    22 / 329 (6.69%)
         occurrences all number
    48
    32
    Constipation
         subjects affected / exposed
    111 / 332 (33.43%)
    109 / 329 (33.13%)
         occurrences all number
    169
    161
    Diarrhoea
         subjects affected / exposed
    82 / 332 (24.70%)
    68 / 329 (20.67%)
         occurrences all number
    176
    124
    Nausea
         subjects affected / exposed
    168 / 332 (50.60%)
    176 / 329 (53.50%)
         occurrences all number
    352
    354
    Stomatitis
         subjects affected / exposed
    56 / 332 (16.87%)
    42 / 329 (12.77%)
         occurrences all number
    96
    78
    Vomiting
         subjects affected / exposed
    88 / 332 (26.51%)
    78 / 329 (23.71%)
         occurrences all number
    148
    115
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    59 / 332 (17.77%)
    82 / 329 (24.92%)
         occurrences all number
    64
    104
    Dry skin
         subjects affected / exposed
    22 / 332 (6.63%)
    0 / 329 (0.00%)
         occurrences all number
    30
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    65 / 332 (19.58%)
    0 / 329 (0.00%)
         occurrences all number
    127
    0
    Rash
         subjects affected / exposed
    32 / 332 (9.64%)
    21 / 329 (6.38%)
         occurrences all number
    46
    30
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    75 / 332 (22.59%)
    70 / 329 (21.28%)
         occurrences all number
    286
    209
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    42 / 332 (12.65%)
    37 / 329 (11.25%)
         occurrences all number
    55
    49
    Back pain
         subjects affected / exposed
    23 / 332 (6.93%)
    43 / 329 (13.07%)
         occurrences all number
    29
    64
    Myalgia
         subjects affected / exposed
    27 / 332 (8.13%)
    17 / 329 (5.17%)
         occurrences all number
    31
    33
    Pain in extremity
         subjects affected / exposed
    19 / 332 (5.72%)
    28 / 329 (8.51%)
         occurrences all number
    27
    33
    Infections and infestations
    Cystitis
         subjects affected / exposed
    17 / 332 (5.12%)
    18 / 329 (5.47%)
         occurrences all number
    24
    27
    Nasopharyngitis
         subjects affected / exposed
    35 / 332 (10.54%)
    30 / 329 (9.12%)
         occurrences all number
    48
    43
    Rhinitis
         subjects affected / exposed
    18 / 332 (5.42%)
    0 / 329 (0.00%)
         occurrences all number
    20
    0
    Urinary tract infection
         subjects affected / exposed
    47 / 332 (14.16%)
    51 / 329 (15.50%)
         occurrences all number
    71
    72
    Blood creatinine increased
         subjects affected / exposed
    29 / 332 (8.73%)
    0 / 329 (0.00%)
         occurrences all number
    77
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    38 / 332 (11.45%)
    25 / 329 (7.60%)
         occurrences all number
    51
    37

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2013
    - Amendment 1 (Protocol V1.1F of 19-MAR-2013 Non-inferiority study design was changed into a superiority study design. The rationale has been adapted to the new design. The resulting new sample size estimation (enrolment of 654 instead of 870 patients (327 instead of 435 per arm)) arose out of considerations which minimum clinically relevant effect has to be evidenced in the experimental arm to justify the rationale in consideration of a similar safety profiles in both arms. Inclusion/exclusion criteria have been amended. Specific quantitative and qualitative criteria for termination of the trial have been added
    05 Apr 2013
    - Amendment 2 (Protocol V1.2F of 05-APR-2013): upper limit for blood pressure blood pressure was lowered to systolic <= 140 mmHg and diastolic <= 90 mmHg.
    23 Feb 2015
    - Amendment 4 (Protocol V02F of 20-FEB-2015): In the reformatted Section 6, biomarker data are not longer presented as these are not considered relevant to investigators when making therapeutic decisions. The biomarker data presented in Section 5 remains in this Investigator’s Brochure. There have been no changes in the identified risks associated with the use of bevacizumab with the exception that embryofetal development disturbance is now considered an identified risk.
    22 Mar 2016
    - Amendment 6 (Protocol V03F of 22-MAR-2016): Protocol V03F contains substantial changes regarding the address of the coordinating investigator (LKP), changes for the post treatment follow-up.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/32305099
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