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    Clinical Trial Results:
    An open-label, randomised, phase III Study cOmparing trifLuridine/tipiracil (S 95005) in combination with bevacizumab to capecitabine in combination with bevacizumab in firST-line treatment of patients with metastatIC colorectal cancer who are not candidatE for intensive therapy (SOLSTICE study)

    Summary
    EudraCT number
    		 2017-004059-22
    Trial protocol
    		 GB   IE   SE   AT   ES   DK   LT   NL   LV   SK   CZ   HU   DE   PL   PT   BG   IT   RO  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 May 2022
    First version publication date
    26 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL3-95005-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03869892
    WHO universal trial number (UTN)
    		 U1111-1206-3198
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 1.55.72.43.66, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 1.55.72.43.66, clinicaltrials@servier.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    09 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jun 2021
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of S 95005 in combination with bevacizumab over capecitabine in combination with bevacizumab in terms of progression-free survival (PFS) based on Investigator assessment in first-line treatment of patients with unresectable metastatic colorectal cancer who are not candidate for intensive therapy.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Mar 2019
    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
    Netherlands: 21
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Romania: 23
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 83
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    United Kingdom: 53
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Bulgaria: 23
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    Denmark: 36
    Country: Number of subjects enrolled
    Estonia: 14
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 74
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 57
    Country: Number of subjects enrolled
    Latvia: 11
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Russian Federation: 126
    Country: Number of subjects enrolled
    Ukraine: 132
    Country: Number of subjects enrolled
    Argentina: 15
    Country: Number of subjects enrolled
    Brazil: 42
    Country: Number of subjects enrolled
    Australia: 15
    Worldwide total number of subjects
    856
    EEA total number of subjects
    473
    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)
    204
    From 65 to 84 years
    608
    85 years and over
    44

    Subject disposition

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    Recruitment
    Recruitment details
    		 Investigators were oncologists.

    Pre-assignment
    Screening details
    		 Male or female participant aged ≥ 18 years old with metastatic colorectal cancer (mCRC), RAS status determined on tumour biopsy, neither candidate for standard full dose combination chemotherapy with irinotecan or oxaliplatin nor for curative resection of metastatic lesions. No previous systemic anticancer therapy for unresectable mCRC.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 S95005 + bevacizumab
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    S95005
    Investigational medicinal product code
    Other name
    trifluridine/tipiracil
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    S95005 was administered orally twice a day (35 mg/m²/dose), within 1 hour after completion of morning and evening meals, Days 1 to 5 and Days 8 to 12, followed by a 14-day rest; with bevacizumab (5 mg/kg, intravenously) administered every 2 weeks (Day 1 and Day 15).

    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
    Bevacizumab was administered intravenously at 5 mg/kg at Day 1 and Day 15 of each cycle in combination with S95005.

    Arm title
    		 Capecitabine + bevacizumab
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered orally twice daily (1250 mg/m²) on Days 1 to 14 of each cycle, with bevacizumab (7.5 mg/kg, IV) administered on Day 1 of each cycle. This treatment cycle was repeated every 3 weeks. The starting dose of capecitabine could be reduced to 1000mg/m² according to local clinical practice.

    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
    Bevacizumab was administered intravenously at 7.5 mg/kg on Day 1 of each cycle in combination with capecitabine.

    Number of subjects in period 1
    		S95005 + bevacizumab Capecitabine + bevacizumab
    Started
    426
    430
    Completed
    0
    0
    Not completed
    426
    430
         Radiological progressive disease
    168
    165
         Other, Medical reason
    8
    8
         Clinical progressive disease
    39
    38
         Radiological and clinical progressive disease
    34
    23
         Continuing study on-treatment
    74
    59
         Adverse event
    71
    101
         Patient becoming resectable
    2
    3
         Randomised but not enrolled or not treated
    3
    -
         Randomised but not enrolled
    -
    3
         Lost to follow-up
    -
    1
         Non-medical reason
    27
    26
         Protocol deviation
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S95005 + bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Capecitabine + bevacizumab
    Reporting group description
    		 -

    Reporting group values
    		 S95005 + bevacizumab Capecitabine + bevacizumab Total
    Number of subjects
    		 426 430 856
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 97 107 204
        From 65-84 years
    		 309 299 608
        85 years and over
    		 20 24 44
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.6 ( 10.0 ) 71.2 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 186 204 390
        Male
    		 240 226 466

    End points

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    End points reporting groups
    Reporting group title
    S95005 + bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Capecitabine + bevacizumab
    Reporting group description
    		 -

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Tumour assessments were performed by the investigator based on RECIST 1.1 at baseline then every 8 weeks until radiologic progression.
    End point type
    Primary
    End point timeframe
    PFS was defined as the time from the date of randomisation until the date of radiologic disease progression or death due to any cause.
    End point values
    		 S95005 + bevacizumab Capecitabine + bevacizumab
    Number of subjects analysed
    426
    430
    Units: Number of PFS events
    309
    320
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The primary analysis was conducted after reaching 628 PFS events.
    Comparison groups
    S95005 + bevacizumab v Capecitabine + bevacizumab
    Number of subjects included in analysis
    856
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.02

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred or worsened or became serious between the first or bevacizumab intake and the last IMP intake + 35 days (both included).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    S95005 + bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Capecitabine + bevacizumab
    Reporting group description
    		 -

    Serious adverse events
    		 S95005 + bevacizumab Capecitabine + bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    176 / 423 (41.61%)
    197 / 427 (46.14%)
         number of deaths (all causes)
    172
    177
         number of deaths resulting from adverse events
    5
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bronchial neoplasm
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroma
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    19 / 423 (4.49%)
    32 / 427 (7.49%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 32
         deaths causally related to treatment / all
    0 / 14
    0 / 23
    Metastases to bladder
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to ovary
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spinal cord
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to uterus
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Recurrent cancer
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Tumour necrosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour perforation
         subjects affected / exposed
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    7 / 423 (1.65%)
    15 / 427 (3.51%)
         occurrences causally related to treatment / all
    4 / 7
    11 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    4 / 423 (0.95%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 423 (0.71%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 423 (0.24%)
    4 / 427 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 423 (0.47%)
    4 / 427 (0.94%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    7 / 423 (1.65%)
    6 / 427 (1.41%)
         occurrences causally related to treatment / all
    0 / 7
    3 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Generalised oedema
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (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
    6 / 423 (1.42%)
    4 / 427 (0.94%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 423 (0.24%)
    4 / 427 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Loss of personal independence in daily activities
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian vein thrombosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic haemorrhage
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 423 (0.24%)
    3 / 427 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopnoea
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (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
    10 / 423 (2.36%)
    30 / 427 (7.03%)
         occurrences causally related to treatment / all
    8 / 10
    19 / 31
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyphrenia
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         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
    2 / 423 (0.47%)
    5 / 427 (1.17%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hallucinations, mixed
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (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
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood urea increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 423 (0.00%)
    3 / 427 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoembryonic antigen increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia test positive
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma output increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory marker increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella test positive
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (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
    2 / 423 (0.47%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein C increased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine output decreased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count increased
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic stenosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to anastomose
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 423 (0.71%)
    6 / 427 (1.41%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomal hernia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 423 (0.47%)
    5 / 427 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 423 (0.95%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 423 (0.71%)
    3 / 427 (0.70%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    4 / 423 (0.95%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Extrasystoles
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (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
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apraxia
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral atrophy
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (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
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral small vessel ischaemic disease
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ventricle dilatation
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drop attacks
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysgeusia
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (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 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemianaesthesia
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemic seizure
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    3 / 423 (0.71%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Memory impairment
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    4 / 423 (0.95%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 423 (0.47%)
    5 / 427 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    0 / 423 (0.00%)
    3 / 427 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vertebral artery stenosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White matter lesion
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 423 (6.62%)
    7 / 427 (1.64%)
         occurrences causally related to treatment / all
    19 / 30
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    10 / 423 (2.36%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    10 / 11
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 423 (0.71%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myelosuppression
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenia
         subjects affected / exposed
    12 / 423 (2.84%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    15 / 15
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Splenic vein thrombosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 423 (0.95%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    5 / 423 (1.18%)
    5 / 427 (1.17%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 423 (0.24%)
    3 / 427 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    11 / 423 (2.60%)
    10 / 427 (2.34%)
         occurrences causally related to treatment / all
    8 / 11
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dieulafoy's vascular malformation
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (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 / 423 (0.00%)
    3 / 427 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         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
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastric perforation
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 423 (0.71%)
    5 / 427 (1.17%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ileus paralytic
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    9 / 423 (2.13%)
    6 / 427 (1.41%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Intestinal perforation
         subjects affected / exposed
    3 / 423 (0.71%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    2 / 423 (0.47%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant gastrointestinal obstruction
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 423 (0.71%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising colitis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis haemorrhagic
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal obstruction
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal stenosis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (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 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (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
    4 / 423 (0.95%)
    5 / 427 (1.17%)
         occurrences causally related to treatment / all
    0 / 5
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus of small bowel
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 423 (1.18%)
    4 / 427 (0.94%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (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 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder fistula
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant biliary obstruction
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (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
    Acute kidney injury
         subjects affected / exposed
    3 / 423 (0.71%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder perforation
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage urinary tract
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         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
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcapsular renal haematoma
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric dilatation
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         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 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (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
    3 / 423 (0.71%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asymptomatic COVID-19
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial prostatitis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colostomy infection
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    5 / 423 (1.18%)
    4 / 427 (0.94%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    5 / 423 (1.18%)
    8 / 427 (1.87%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         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
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site abscess
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (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 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    2 / 423 (0.47%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal abscess
         subjects affected / exposed
    0 / 423 (0.00%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    5 / 423 (1.18%)
    4 / 427 (0.94%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Pneumonia
         subjects affected / exposed
    9 / 423 (2.13%)
    5 / 427 (1.17%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia chlamydial
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    2 / 423 (0.47%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Small intestine gangrene
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Staphylococcal infection
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal endocarditis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (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 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract candidiasis
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 423 (0.24%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 423 (0.24%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 423 (0.47%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 423 (0.47%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    9 / 423 (2.13%)
    14 / 427 (3.28%)
         occurrences causally related to treatment / all
    4 / 9
    9 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 423 (0.47%)
    3 / 427 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 423 (0.47%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 423 (0.24%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 423 (0.00%)
    1 / 427 (0.23%)
         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
    		 S95005 + bevacizumab Capecitabine + bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    412 / 423 (97.40%)
    402 / 427 (94.15%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    52 / 423 (12.29%)
    73 / 427 (17.10%)
         occurrences all number
    69
    96
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    27 / 423 (6.38%)
    23 / 427 (5.39%)
         occurrences all number
    33
    23
    Asthenia
         subjects affected / exposed
    95 / 423 (22.46%)
    73 / 427 (17.10%)
         occurrences all number
    149
    104
    Fatigue
         subjects affected / exposed
    100 / 423 (23.64%)
    105 / 427 (24.59%)
         occurrences all number
    148
    151
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    23 / 423 (5.44%)
    24 / 427 (5.62%)
         occurrences all number
    28
    27
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    25 / 423 (5.91%)
    24 / 427 (5.62%)
         occurrences all number
    44
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    23 / 423 (5.44%)
    29 / 427 (6.79%)
         occurrences all number
    34
    33
    Blood bilirubin increased
         subjects affected / exposed
    22 / 423 (5.20%)
    47 / 427 (11.01%)
         occurrences all number
    35
    87
    Neutrophil count decreased
         subjects affected / exposed
    91 / 423 (21.51%)
    9 / 427 (2.11%)
         occurrences all number
    359
    11
    Platelet count decreased
         subjects affected / exposed
    38 / 423 (8.98%)
    12 / 427 (2.81%)
         occurrences all number
    88
    20
    Weight decreased
         subjects affected / exposed
    47 / 423 (11.11%)
    40 / 427 (9.37%)
         occurrences all number
    50
    42
    White blood cell count decreased
         subjects affected / exposed
    23 / 423 (5.44%)
    2 / 427 (0.47%)
         occurrences all number
    73
    3
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    2 / 423 (0.47%)
    35 / 427 (8.20%)
         occurrences all number
    2
    40
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    22 / 423 (5.20%)
    13 / 427 (3.04%)
         occurrences all number
    39
    28
    Headache
         subjects affected / exposed
    23 / 423 (5.44%)
    21 / 427 (4.92%)
         occurrences all number
    41
    21
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    171 / 423 (40.43%)
    54 / 427 (12.65%)
         occurrences all number
    321
    71
    Leukopenia
         subjects affected / exposed
    69 / 423 (16.31%)
    13 / 427 (3.04%)
         occurrences all number
    226
    21
    Thrombocytopenia
         subjects affected / exposed
    79 / 423 (18.68%)
    25 / 427 (5.85%)
         occurrences all number
    193
    36
    Neutropenia
         subjects affected / exposed
    274 / 423 (64.78%)
    36 / 427 (8.43%)
         occurrences all number
    1299
    69
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    51 / 423 (12.06%)
    44 / 427 (10.30%)
         occurrences all number
    70
    53
    Abdominal pain
         subjects affected / exposed
    47 / 423 (11.11%)
    60 / 427 (14.05%)
         occurrences all number
    59
    83
    Abdominal pain upper
         subjects affected / exposed
    28 / 423 (6.62%)
    21 / 427 (4.92%)
         occurrences all number
    43
    26
    Diarrhoea
         subjects affected / exposed
    149 / 423 (35.22%)
    137 / 427 (32.08%)
         occurrences all number
    345
    265
    Dyspepsia
         subjects affected / exposed
    22 / 423 (5.20%)
    11 / 427 (2.58%)
         occurrences all number
    32
    12
    Stomatitis
         subjects affected / exposed
    54 / 423 (12.77%)
    50 / 427 (11.71%)
         occurrences all number
    83
    64
    Vomiting
         subjects affected / exposed
    65 / 423 (15.37%)
    42 / 427 (9.84%)
         occurrences all number
    117
    52
    Nausea
         subjects affected / exposed
    146 / 423 (34.52%)
    101 / 427 (23.65%)
         occurrences all number
    346
    173
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    5 / 423 (1.18%)
    32 / 427 (7.49%)
         occurrences all number
    9
    42
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    18 / 423 (4.26%)
    23 / 427 (5.39%)
         occurrences all number
    19
    27
    Alopecia
         subjects affected / exposed
    38 / 423 (8.98%)
    5 / 427 (1.17%)
         occurrences all number
    41
    5
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 423 (1.18%)
    225 / 427 (52.69%)
         occurrences all number
    5
    317
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    27 / 423 (6.38%)
    27 / 427 (6.32%)
         occurrences all number
    46
    34
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    24 / 423 (5.67%)
    29 / 427 (6.79%)
         occurrences all number
    27
    29
    Arthralgia
         subjects affected / exposed
    23 / 423 (5.44%)
    15 / 427 (3.51%)
         occurrences all number
    26
    17
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    31 / 423 (7.33%)
    29 / 427 (6.79%)
         occurrences all number
    41
    38
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    94 / 423 (22.22%)
    76 / 427 (17.80%)
         occurrences all number
    142
    97
    Hypomagnesaemia
         subjects affected / exposed
    10 / 423 (2.36%)
    23 / 427 (5.39%)
         occurrences all number
    14
    39

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2018
    Modification of statistical assumptions based on the results of the primary analysis of the TASCO1 phase 2 study, resulting in a decrease in the study sample size. Update of capecitabine Product Information dated 22 March 2018.
    02 Apr 2020
    Modifications of the inclusion criteria: - To consider systemic use of radiosensitizers chemotherapy agents as a previous systemic anticancer therapy for unresectable mCRC - To clarify adequate coagulation function Modifications of the exclusion criteria: -To clarify detection of hepatitis B and C - To clarify other malignancies as exclusion criterion. - radiotherapy (short course for symptoms palliation only) was no more considered as exclusion criteria if completed less than 4 weeks before randomisation Precisions on the study investigational schedule, IMP administration and dose management Clarifications on prohibited treatments Cancellation of the optional genomics biomarkers assessment
    25 Jan 2021
    Additional guidance on treatment of study patients in specific situations caused by COVID-19 infection Clarification of reporting rules for fatal adverse events occurring between patient consent signature and the first IMP intake.

    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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