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    Clinical Trial Results:
    A prospective randomised Phase III trial to evaluate optimal treatment duration of first-line bevacizumab in combination with carboplatin and paclitaxel in patients with primary epithelial ovarian, fallopian tube or peritoneal cancer.

    Summary
    EudraCT number
    		 2011-001015-32
    Trial protocol
    		 DE   FR   FI   NO   DK   SE  
    Global end of trial date
    26 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jul 2022
    First version publication date
    21 Jul 2022
    Other versions
    Summary report(s)
    		 OVAR17_E3-Synopse_V01F_2021-11-

    Trial information

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    Trial identification
    Sponsor protocol code
    AGO-OVAR17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01462890
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 GINECO OV118: ENGOT Ov-15 Trial
    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 6118804 670, gelser@ago-ovar.de
    Scientific contact
    Study Office, AGO Research GmbH, 0049 6118804 670, gelser@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
    07 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare progression-free survival (PFS) (by RECIST v1.1, clinical or symptomatic) of patients randomized to front-line paclitaxel/carboplatin with bevacizumab for 15 months or 30 months.
    Protection of trial subjects
    The study consisted of a screening/baseline period, a treatment period and a posttreatment or follow-up period.
    Background therapy
    		 --
    Evidence for comparator
    		 --
    Actual start date of recruitment
    01 Jul 2011
    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
    Norway: 12
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    Finland: 14
    Country: Number of subjects enrolled
    France: 126
    Country: Number of subjects enrolled
    Germany: 764
    Worldwide total number of subjects
    927
    EEA total number of subjects
    927
    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)
    575
    From 65 to 84 years
    350
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard arm
    Arm description
    		 Bevacizumab, Paclitaxel, 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
    15 mg/kg on day 1 every 3 weeks (together with chemotherapy treatment) up to and including cycle 21 or 22

    Arm title
    		 Experimental arm
    Arm description
    		 Bevacizumab, Paclitaxel, 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
    15 mg/kg on day 1 every 3 weeks (together with chemotherapy treatment) up to and including cycle 43 or 44

    Number of subjects in period 1
    		Standard arm Experimental arm
    Started
    464
    463
    Completed
    448
    442
    Not completed
    16
    21
         Consent withdrawn by subject
    7
    5
         Disease progression
    1
    -
         Adverse event, non-fatal
    4
    4
         Death
    2
    4
         Another urgent surgery
    1
    -
         Refused treatment
    -
    2
         Intercurrent illness
    1
    4
         Further therapy outside study (sponsor decision)
    -
    1
         Incomplete wound healing (sponsor decision)
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 927 927
    Age categorical
    female patients 18 years and older
    Units: Subjects
        Adults (18-64 years)
    		 575 575
        From 65-84 years
    		 350 350
        85 years and over
    		 2 2
    Gender categorical
    Units: Subjects
        Female
    		 927 927
        Male
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Standard arm
    Reporting group description
    		 Bevacizumab, Paclitaxel, Carboplatin

    Reporting group title
    Experimental arm
    Reporting group description
    		 Bevacizumab, Paclitaxel, Carboplatin

    Primary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    End point type
    Primary
    End point timeframe
    Progression-free survival (PFS) is defined as the time from the date of randomization to investigator assessed disease progression.
    End point values
    		 Standard arm Experimental arm
    Number of subjects analysed
    464
    463
    Units: months
        number (not applicable)
    24.2
    26.0
    Statistical analysis title
    		 Primary statistical analysis
    Comparison groups
    Standard arm v Experimental arm
    Number of subjects included in analysis
    927
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.15

    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
    Reporting groups
    Reporting group title
    Standard arm
    Reporting group description
    		 -

    Reporting group title
    Experimental arm
    Reporting group description
    		 -

    Serious adverse events
    		 Standard arm Experimental arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    199 / 448 (44.42%)
    204 / 442 (46.15%)
         number of deaths (all causes)
    257
    277
         number of deaths resulting from adverse events
    8
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to kidney
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic cerebellar degenaration
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    2 / 448 (0.45%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 448 (0.67%)
    3 / 442 (0.68%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    11 / 448 (2.46%)
    16 / 442 (3.62%)
         occurrences causally related to treatment / all
    12 / 12
    17 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 448 (0.00%)
    4 / 442 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    7 / 448 (1.56%)
    9 / 442 (2.04%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    2 / 448 (0.45%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 448 (0.00%)
    4 / 442 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bladder catheter removal
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder catheter replacement
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 448 (0.00%)
    3 / 442 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 448 (0.67%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Device dislocation
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device leakage
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 448 (0.67%)
    5 / 442 (1.13%)
         occurrences causally related to treatment / all
    0 / 4
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    20 / 448 (4.46%)
    20 / 442 (4.52%)
         occurrences causally related to treatment / all
    3 / 26
    7 / 32
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Hernia obstructive
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    2 / 448 (0.45%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 448 (2.46%)
    16 / 442 (3.62%)
         occurrences causally related to treatment / all
    0 / 12
    4 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    2 / 448 (0.45%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    2 / 448 (0.45%)
    3 / 442 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    3 / 448 (0.67%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    3 / 448 (0.67%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 448 (1.34%)
    11 / 442 (2.49%)
         occurrences causally related to treatment / all
    2 / 6
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 448 (0.89%)
    6 / 442 (1.36%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 448 (1.34%)
    7 / 442 (1.58%)
         occurrences causally related to treatment / all
    3 / 6
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystoscopy
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder injury
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal injury
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 448 (0.22%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (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 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urostomy complication
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 448 (0.45%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 448 (0.00%)
    3 / 442 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 448 (0.22%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    5 / 448 (1.12%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial venous sinus thrombosis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 448 (0.00%)
    3 / 442 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    2 / 448 (0.45%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 448 (0.45%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 448 (1.34%)
    5 / 442 (1.13%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    9 / 448 (2.01%)
    4 / 442 (0.90%)
         occurrences causally related to treatment / all
    2 / 9
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    4 / 448 (0.89%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 448 (0.45%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Lens dislocation
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    2 / 448 (0.45%)
    3 / 442 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    17 / 448 (3.79%)
    16 / 442 (3.62%)
         occurrences causally related to treatment / all
    3 / 21
    3 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 448 (0.22%)
    6 / 442 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    4 / 448 (0.89%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    10 / 448 (2.23%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel movement irregularity
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    6 / 448 (1.34%)
    8 / 442 (1.81%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (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
    9 / 448 (2.01%)
    6 / 442 (1.36%)
         occurrences causally related to treatment / all
    3 / 9
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecal incontinence
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal fistula
         subjects affected / exposed
    2 / 448 (0.45%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    9 / 448 (2.01%)
    11 / 442 (2.49%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 11
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    2 / 448 (0.45%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 448 (0.22%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric artery embolism
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 448 (0.22%)
    5 / 442 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral cavity fistula
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sigmoiditis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    15 / 448 (3.35%)
    7 / 442 (1.58%)
         occurrences causally related to treatment / all
    2 / 15
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 448 (0.22%)
    8 / 442 (1.81%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder disorder
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    7 / 448 (1.56%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 448 (0.22%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    3 / 448 (0.67%)
    6 / 442 (1.36%)
         occurrences causally related to treatment / all
    3 / 3
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelocaliectasis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 448 (0.45%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 448 (0.00%)
    3 / 442 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 448 (0.45%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    2 / 448 (0.45%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatic disorder
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (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
    Abdominal abscess
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall infection
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess of salivary gland
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 448 (0.00%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    3 / 448 (0.67%)
    3 / 442 (0.68%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    5 / 448 (1.12%)
    4 / 442 (0.90%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    2 / 448 (0.45%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    5 / 448 (1.12%)
    6 / 442 (1.36%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 448 (0.45%)
    5 / 442 (1.13%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 448 (0.00%)
    4 / 442 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 448 (0.22%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 448 (0.45%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 448 (0.22%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 448 (1.56%)
    6 / 442 (1.36%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 448 (0.45%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal abscess
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suture rupture
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Wound haemorrhage
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (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 / 448 (0.45%)
    5 / 442 (1.13%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypercalcaemia
         subjects affected / exposed
    1 / 448 (0.22%)
    0 / 442 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 448 (0.00%)
    1 / 442 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 448 (0.67%)
    2 / 442 (0.45%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard arm Experimental arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    445 / 448 (99.33%)
    439 / 442 (99.32%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    33 / 448 (7.37%)
    35 / 442 (7.92%)
         occurrences all number
    61
    62
    Hypertension
         subjects affected / exposed
    168 / 448 (37.50%)
    232 / 442 (52.49%)
         occurrences all number
    546
    783
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    40 / 448 (8.93%)
    53 / 442 (11.99%)
         occurrences all number
    91
    101
    Fatigue
         subjects affected / exposed
    204 / 448 (45.54%)
    208 / 442 (47.06%)
         occurrences all number
    421
    447
    General physical health deterioration
         subjects affected / exposed
    23 / 448 (5.13%)
    24 / 442 (5.43%)
         occurrences all number
    34
    36
    Mucosal inflammation
         subjects affected / exposed
    67 / 448 (14.96%)
    65 / 442 (14.71%)
         occurrences all number
    114
    111
    Oedema
         subjects affected / exposed
    20 / 448 (4.46%)
    35 / 442 (7.92%)
         occurrences all number
    28
    53
    Oedema peripheral
         subjects affected / exposed
    26 / 448 (5.80%)
    35 / 442 (7.92%)
         occurrences all number
    30
    47
    Pain
         subjects affected / exposed
    45 / 448 (10.04%)
    28 / 442 (6.33%)
         occurrences all number
    71
    59
    Pyrexia
         subjects affected / exposed
    47 / 448 (10.49%)
    53 / 442 (11.99%)
         occurrences all number
    69
    66
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    15 / 448 (3.35%)
    32 / 442 (7.24%)
         occurrences all number
    22
    55
    Hypersensitivity
         subjects affected / exposed
    29 / 448 (6.47%)
    25 / 442 (5.66%)
         occurrences all number
    33
    31
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 448 (5.13%)
    40 / 442 (9.05%)
         occurrences all number
    28
    47
    Dysphonia
         subjects affected / exposed
    19 / 448 (4.24%)
    35 / 442 (7.92%)
         occurrences all number
    25
    41
    Dyspnoea
         subjects affected / exposed
    82 / 448 (18.30%)
    88 / 442 (19.91%)
         occurrences all number
    119
    133
    Epistaxis
         subjects affected / exposed
    86 / 448 (19.20%)
    101 / 442 (22.85%)
         occurrences all number
    106
    150
    Psychiatric disorders
    Depression
         subjects affected / exposed
    23 / 448 (5.13%)
    23 / 442 (5.20%)
         occurrences all number
    27
    31
    Insomnia
         subjects affected / exposed
    47 / 448 (10.49%)
    41 / 442 (9.28%)
         occurrences all number
    71
    60
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 448 (4.02%)
    27 / 442 (6.11%)
         occurrences all number
    32
    54
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 448 (6.70%)
    26 / 442 (5.88%)
         occurrences all number
    43
    40
    Dysgeusia
         subjects affected / exposed
    23 / 448 (5.13%)
    34 / 442 (7.69%)
         occurrences all number
    29
    40
    Headache
         subjects affected / exposed
    70 / 448 (15.63%)
    95 / 442 (21.49%)
         occurrences all number
    124
    160
    Neuropathy peripheral
         subjects affected / exposed
    49 / 448 (10.94%)
    47 / 442 (10.63%)
         occurrences all number
    90
    90
    Paraesthesia
         subjects affected / exposed
    40 / 448 (8.93%)
    47 / 442 (10.63%)
         occurrences all number
    48
    71
    Peripheral sensory neuropathy
         subjects affected / exposed
    144 / 448 (32.14%)
    129 / 442 (29.19%)
         occurrences all number
    263
    284
    Polyneuropathy
         subjects affected / exposed
    81 / 448 (18.08%)
    98 / 442 (22.17%)
         occurrences all number
    141
    182
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    83 / 448 (18.53%)
    87 / 442 (19.68%)
         occurrences all number
    202
    196
    Leukopenia
         subjects affected / exposed
    37 / 448 (8.26%)
    49 / 442 (11.09%)
         occurrences all number
    111
    138
    Neutropenia
         subjects affected / exposed
    63 / 448 (14.06%)
    80 / 442 (18.10%)
         occurrences all number
    165
    219
    Thrombocytopenia
         subjects affected / exposed
    36 / 448 (8.04%)
    39 / 442 (8.82%)
         occurrences all number
    79
    90
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    21 / 448 (4.69%)
    27 / 442 (6.11%)
         occurrences all number
    25
    36
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    92 / 448 (20.54%)
    96 / 442 (21.72%)
         occurrences all number
    132
    152
    Abdominal pain upper
         subjects affected / exposed
    47 / 448 (10.49%)
    60 / 442 (13.57%)
         occurrences all number
    80
    82
    Constipation
         subjects affected / exposed
    170 / 448 (37.95%)
    169 / 442 (38.24%)
         occurrences all number
    282
    322
    Diarrhoea
         subjects affected / exposed
    141 / 448 (31.47%)
    117 / 442 (26.47%)
         occurrences all number
    291
    256
    Nausea
         subjects affected / exposed
    202 / 448 (45.09%)
    180 / 442 (40.72%)
         occurrences all number
    386
    348
    Stomatitis
         subjects affected / exposed
    62 / 448 (13.84%)
    72 / 442 (16.29%)
         occurrences all number
    93
    106
    Vomiting
         subjects affected / exposed
    111 / 448 (24.78%)
    88 / 442 (19.91%)
         occurrences all number
    171
    135
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    288 / 448 (64.29%)
    294 / 442 (66.52%)
         occurrences all number
    354
    364
    Rash
         subjects affected / exposed
    20 / 448 (4.46%)
    31 / 442 (7.01%)
         occurrences all number
    20
    39
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    42 / 448 (9.38%)
    73 / 442 (16.52%)
         occurrences all number
    95
    262
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    127 / 448 (28.35%)
    138 / 442 (31.22%)
         occurrences all number
    225
    295
    Back pain
         subjects affected / exposed
    35 / 448 (7.81%)
    53 / 442 (11.99%)
         occurrences all number
    38
    69
    Bone pain
         subjects affected / exposed
    47 / 448 (10.49%)
    46 / 442 (10.41%)
         occurrences all number
    75
    68
    Musculoskeletal pain
         subjects affected / exposed
    22 / 448 (4.91%)
    36 / 442 (8.14%)
         occurrences all number
    39
    54
    Myalgia
         subjects affected / exposed
    84 / 448 (18.75%)
    91 / 442 (20.59%)
         occurrences all number
    149
    171
    Pain in extremity
         subjects affected / exposed
    59 / 448 (13.17%)
    59 / 442 (13.35%)
         occurrences all number
    97
    85
    Infections and infestations
    Cystitis
         subjects affected / exposed
    54 / 448 (12.05%)
    49 / 442 (11.09%)
         occurrences all number
    88
    92
    Nasopharyngitis
         subjects affected / exposed
    47 / 448 (10.49%)
    63 / 442 (14.25%)
         occurrences all number
    59
    82
    Urinary tract infection
         subjects affected / exposed
    66 / 448 (14.73%)
    85 / 442 (19.23%)
         occurrences all number
    102
    133
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    30 / 448 (6.70%)
    39 / 442 (8.82%)
         occurrences all number
    58
    65

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2011
    New Protocol V03 F (21/11/2011): Specification of exclusion criteria no. 22, Additions regarding the second opinion pathology for patients from France, Update of Patient Information and Informed Consent Form
    27 Mar 2013
    New Protokoll V05 F (14/03/2013): Update of the statistical considerations including increase of the number of patients to 900, Update of Patient Information and Informed Consent Form
    19 Jul 2013
    Update of Patient Information and Informed Consent Form due to "Roter-Hand-Brief" of 15.05.2013
    06 Jan 2015
    Additional Patient Information and Informed Consent Form due to changes in the German Summary of Product Characteristics Avastin 09/2014
    28 Dec 2016
    New Protocol V06 F (15/11/2016): Wording for the efficacy follow-up period has been corrected or rather adjusted
    24 Sep 2020
    Amendment No. 1 (31/08/2020) to Protocol V06 F: Removes PFS events as a condition of the timing of the data cutoff for primary analysis

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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