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    Clinical Trial Results:
    Randomized phase II study to explore the influence of BRAF and PIK3K status on the efficacy of FOLFIRI plus Bevacizumab or Cetuximab, as first line therapy of patients with KRAS wild-type metastatic colorectal carcinoma and < 3 circulating tumor cells.

    Summary
    EudraCT number
    		 2012-000840-90
    Trial protocol
    		 ES  
    Global end of trial date
    04 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Aug 2020
    First version publication date
    01 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TTD-12-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01640444
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo de Tratamiento de los Tumores Digestivos (TTD)
    Sponsor organisation address
    C/ Téllez Nº 30 posterior 1º oficina 4.2 28007 – Madrid , Madrid, Spain, 28007
    Public contact
    Grupo de Tratamiento de los Tumores Digestivos (TTD), Grupo de Tratamiento de los Tumores Digestivos (TTD), +34 913788 275, ttd@ttdgroup.org
    Scientific contact
    Grupo de Tratamiento de los Tumores Digestivos (TTD), Grupo de Tratamiento de los Tumores Digestivos (TTD), +34 913788 275, ttd@ttdgroup.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    to explore the impact of the status of BRAF and PI3K expression on efficacy, assessed as progression free survival (PFS), of FOLFIRI+Bevacizumab and FOLFIRI+Cetuximab, in quimo-naïve patients with KRAS wild-type metastatic colorectal carcinoma with < 3 circulating tumor cells.
    Protection of trial subjects
    all patients have been treated according to GCP criteria. Patients were entitled to withdraw from the study at any time and for any reason without prejudice of their future medical care on the part of the doctor or the center.
    Background therapy
    		 There has been no restriction on the use of drugs to treat underlying non-malignant diseases diagnosed before or during the study
    Evidence for comparator
    		 At the moment of the design and the study development there were no evidence of superiority of the most used chemotherapy schedule, FOLFOX vs FOLFIRI. And so, there was no evidence about which monoclonal AB is more useful for the combination.
    Actual start date of recruitment
    10 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 240
    Worldwide total number of subjects
    240
    EEA total number of subjects
    240
    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)
    170
    From 65 to 84 years
    70
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 First consent 10-10-2012 Last consent 03-11-2016 First randomized patient 10-10-2012 Last randomized patient 04-11-2016 First dose administered 11-10-2012 Last dose administered 22-10-2018 Last end-of-study date 04-11-2018 COUNTRY: Spain. Number of hospitals: 44

    Pre-assignment
    Screening details
    		 Patients were stratified by center according to the number of metastatic organs affected (1 vs > 1) and the state of BRAF and PI3K: BRAF and PI3K native vs BRAF and/or PI3K mutated. Patients were randomized to receive FOLFIRI+bevacizumab) vs FOLFIRI+cetuximab). Stratification and randomization were centralized and results were faxed.

    Pre-assignment period milestones
    Number of subjects started
    		 240
    Number of subjects completed

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PI3K/BRAF mutated
    Arm description
    		 Patients with < 3 CTCs, Ras naive, PI3K and/or BRAF mutated
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizunab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg Iv/ 2 weeks

    Investigational medicinal product name
    cetuximab
    Investigational medicinal product code
    Other name
    Erbitux
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion, Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    initial dose of 400 mg/m2 i.v. in 120 minutes on day 1, followed by weekly infusions of 250 mg/m2 i.v. in a 60-minute period.

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Fluorouracilo
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    400 mgr/m2

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 2,400 mg/m2 IV in continuous infusion of 46 hours

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Calcic folinate
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion, Concentrate and solvent for solution for injection/infusion, Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    400 mg/m2 of racemic formulation, in case of levogyre formulation 200 mg/m2 was used.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    CPT11
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    180 mg/m2

    Arm title
    		 PI3K/BRAF naive
    Arm description
    		 Patients with < 3 CTCs, Ras, PI3K and BRAF naive.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizunab
    Investigational medicinal product code
    Other name
    Aavstin
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    5 mg/kg Iv/ 2 weeks

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Fluorouracilo
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    400 mgr/m2

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 2,400 mg/m2 IV in continuous infusion of 46 hours

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Calcic folinate
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion, Concentrate and solvent for solution for injection/infusion, Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    400 mg/m2

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    CPT11
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    180 mg/m2

    Investigational medicinal product name
    cetuximab
    Investigational medicinal product code
    Other name
    Erbitux
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion, Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    initial dose of 400 mg/m2 i.v. in 120 minutes on day 1, followed by weekly infusions of 250 mg/m2 i.v. in a 60-minute period.

    Number of subjects in period 1
    		PI3K/BRAF mutated PI3K/BRAF naive
    Started
    44
    196
    Completed
    44
    196

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 240 240
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 170 170
        From 65-84 years
    		 70 70
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 76 76
        Male
    		 164 164
    Subject analysis sets

    Subject analysis set title
    Folfiri+Beva in BRAF or PI3K mutated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients diagnosed of Ras naïve CRC and < 3 wit mutated BRAF and/or PI3K. First line FOLFIRI + bevacizumab vs FOLFIRI + cetuximab in first line

    Subject analysis set title
    Folfiri+Cetuxi in BRAF or PI3K mutated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients assigned to Folfiri+Cetuxi in the subgroup of Ras wild tipe, muatted BRAF and/or PI3K

    Subject analysis set title
    Folfiri+Beva in BRAF and PI3K naive
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients assigned to Folfiri+Bevacizumab in the subgroup of Ras, BRAF and/or PI3K wild tipe

    Subject analysis set title
    Folfiri+Cetuxi in BRAF and PI3K naive
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients assigned to Folfiri+Cetuxi in the subgroup of Ras , BRAF and/or PI3K wild tipe

    Subject analysis set title
    Folfiri Bevacizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    patients assigned to Folfiri Bevacizumab regardless of mutations in PI3K and/or BRAF

    Subject analysis set title
    Folfiri cetuximab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    patients assigned to Folfiri cetuximab regardless of mutations in PI3K and/or BRAF

    Subject analysis set title
    PI3K/BRAF naive
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    CRC, Ras and PI3K/BRAF naive patients

    Subject analysis set title
    PI3K and/or BRAF mutated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Ras naïve CRC with mutation in PI3K and/or BRAF

    Subject analysis sets values
    		 Folfiri+Beva in BRAF or PI3K mutated Folfiri+Cetuxi in BRAF or PI3K mutated Folfiri+Beva in BRAF and PI3K naive Folfiri+Cetuxi in BRAF and PI3K naive Folfiri Bevacizumab Folfiri cetuximab PI3K/BRAF naive PI3K and/or BRAF mutated
    Number of subjects
    24
    20
    102
    94
    126
    114
    196
    44
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    18
    11
    74
    67
    92
    78
    141
    29
        From 65-84 years
    6
    9
    28
    27
    34
    36
    55
    15
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    PI3K/BRAF mutated
    Reporting group description
    		 Patients with < 3 CTCs, Ras naive, PI3K and/or BRAF mutated

    Reporting group title
    PI3K/BRAF naive
    Reporting group description
    		 Patients with < 3 CTCs, Ras, PI3K and BRAF naive.

    Subject analysis set title
    Folfiri+Beva in BRAF or PI3K mutated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients diagnosed of Ras naïve CRC and < 3 wit mutated BRAF and/or PI3K. First line FOLFIRI + bevacizumab vs FOLFIRI + cetuximab in first line

    Subject analysis set title
    Folfiri+Cetuxi in BRAF or PI3K mutated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients assigned to Folfiri+Cetuxi in the subgroup of Ras wild tipe, muatted BRAF and/or PI3K

    Subject analysis set title
    Folfiri+Beva in BRAF and PI3K naive
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients assigned to Folfiri+Bevacizumab in the subgroup of Ras, BRAF and/or PI3K wild tipe

    Subject analysis set title
    Folfiri+Cetuxi in BRAF and PI3K naive
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients assigned to Folfiri+Cetuxi in the subgroup of Ras , BRAF and/or PI3K wild tipe

    Subject analysis set title
    Folfiri Bevacizumab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    patients assigned to Folfiri Bevacizumab regardless of mutations in PI3K and/or BRAF

    Subject analysis set title
    Folfiri cetuximab
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    patients assigned to Folfiri cetuximab regardless of mutations in PI3K and/or BRAF

    Subject analysis set title
    PI3K/BRAF naive
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    CRC, Ras and PI3K/BRAF naive patients

    Subject analysis set title
    PI3K and/or BRAF mutated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Ras naïve CRC with mutation in PI3K and/or BRAF

    Primary: PFS PI3K naive vs mutated

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    End point title
    		 PFS PI3K naive vs mutated
    End point description
    End point type
    Primary
    End point timeframe
    10-10-2012 to 04-11-2018
    End point values
    		 PI3K/BRAF mutated PI3K/BRAF naive
    Number of subjects analysed
    44
    196
    Units: months
        number (confidence interval 95%)
    8.8 (8.2 to 12.4)
    12.7 (11.3 to 14.9)
    Statistical analysis title
    		 PI3K/BRAF mutated vs Naive
    Statistical analysis description
    Primary objective
    Comparison groups
    PI3K/BRAF mutated v PI3K/BRAF naive
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval

    Post-hoc: PFS Folfiri + Bevacizumab vs Folfiri + Cetuximab

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    End point title
    		 PFS Folfiri + Bevacizumab vs Folfiri + Cetuximab
    End point description
    End point type
    Post-hoc
    End point timeframe
    10-10-2012 to 04-11-2018
    End point values
    		 Folfiri Bevacizumab Folfiri cetuximab
    Number of subjects analysed
    126
    114 [1]
    Units: month
        median (confidence interval 95%)
    12.5 (10.0 to 14.1)
    11.5 (9.3 to 15.4)
    Notes
    [1] - A patient randomized to Folfiri cetuxi didn't begin the treatment, not included in safety analýsis
    Statistical analysis title
    		 Log-rank Test
    Comparison groups
    Folfiri Bevacizumab v Folfiri cetuximab
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval

    Post-hoc: PFS Beva vs Cetuxi in mutated BRAF/PI3K

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    End point title
    		 PFS Beva vs Cetuxi in mutated BRAF/PI3K
    End point description
    End point type
    Post-hoc
    End point timeframe
    10-10-2012 to 04-11-2018
    End point values
    		 Folfiri+Beva in BRAF or PI3K mutated Folfiri+Cetuxi in BRAF or PI3K mutated
    Number of subjects analysed
    24
    20
    Units: months
        median (confidence interval 95%)
    9.3 (3.7 to 15.0)
    8.5 (5.3 to 12.4)
    Statistical analysis title
    		 Log-rank Test
    Comparison groups
    Folfiri+Beva in BRAF or PI3K mutated v Folfiri+Cetuxi in BRAF or PI3K mutated
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 > 0.05
    Method
    		 Logrank
    Confidence interval

    Post-hoc: PFS Bevacizumab vs Cetuximab in wild BRAF/PI3K

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    End point title
    		 PFS Bevacizumab vs Cetuximab in wild BRAF/PI3K
    End point description
    End point type
    Post-hoc
    End point timeframe
    10-10-2012 to 04-11-2018
    End point values
    		 Folfiri+Beva in BRAF and PI3K naive Folfiri+Cetuxi in BRAF and PI3K naive
    Number of subjects analysed
    102
    94
    Units: month
        number (confidence interval 95%)
    12.9 (10.3 to 14.9)
    12.5 (10.5 to 16.1)
    Statistical analysis title
    		 Naive patients cetuxi vs bevacizumab
    Comparison groups
    Folfiri+Beva in BRAF and PI3K naive v Folfiri+Cetuxi in BRAF and PI3K naive
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First consent 10-10-2012 Last end-of-study date 04-11-2018
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Folfiri+Bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Folfiri+Cetuximab
    Reporting group description
    		 -

    Reporting group title
    Folfiri + Bevacizumab, mutated
    Reporting group description
    		 -

    Reporting group title
    Folfiri + Bevacizumab naive
    Reporting group description
    		 -

    Reporting group title
    Folfiri + Cetuxi, mutated
    Reporting group description
    		 -

    Reporting group title
    Folfiri + Cetuxi, naive
    Reporting group description
    		 -

    Reporting group title
    PI3K and BRAF naive
    Reporting group description
    		 -

    Reporting group title
    PI3K or BRAF mutated
    Reporting group description
    		 -

    Serious adverse events
    		 Folfiri+Bevacizumab Folfiri+Cetuximab Folfiri + Bevacizumab, mutated Folfiri + Bevacizumab naive Folfiri + Cetuxi, mutated Folfiri + Cetuxi, naive PI3K and BRAF naive PI3K or BRAF mutated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 126 (28.57%)
    43 / 113 (38.05%)
    10 / 24 (41.67%)
    27 / 102 (26.47%)
    4 / 20 (20.00%)
    39 / 93 (41.94%)
    66 / 195 (33.85%)
    14 / 44 (31.82%)
         number of deaths (all causes)
    77
    66
    2
    58
    14
    52
    110
    33
         number of deaths resulting from adverse events
    3
    0
    2
    4
    1
    0
    5
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    1 / 20 (5.00%)
    0 / 93 (0.00%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Venous thrombosis extremities
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    1 / 20 (5.00%)
    0 / 93 (0.00%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 126 (1.59%)
    5 / 113 (4.42%)
    1 / 24 (4.17%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    5 / 93 (5.38%)
    6 / 195 (3.08%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
    0 / 1
    0 / 1
    0 / 0
    2 / 5
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    1 / 24 (4.17%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Urinary retention
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 126 (1.59%)
    2 / 113 (1.77%)
    0 / 24 (0.00%)
    2 / 102 (1.96%)
    0 / 20 (0.00%)
    2 / 93 (2.15%)
    4 / 195 (2.05%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
    2 / 2
    0 / 0
    0 / 2
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Dehydration
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complication of a gastrointestinal stoma
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive heart failure
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar syndrome
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 126 (0.79%)
    5 / 113 (4.42%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    5 / 93 (5.38%)
    6 / 195 (3.08%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
    0 / 0
    1 / 1
    0 / 0
    5 / 5
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    2 / 195 (1.03%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
    1 / 1
    0 / 0
    3 / 3
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    5 / 126 (3.97%)
    3 / 113 (2.65%)
    1 / 24 (4.17%)
    4 / 102 (3.92%)
    0 / 20 (0.00%)
    3 / 93 (3.23%)
    7 / 195 (3.59%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 3
    1 / 1
    3 / 4
    0 / 0
    1 / 3
    4 / 7
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 126 (0.79%)
    3 / 113 (2.65%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    3 / 93 (3.23%)
    4 / 195 (2.05%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 0
    1 / 1
    0 / 0
    0 / 3
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 113 (1.77%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    2 / 93 (2.15%)
    3 / 195 (1.54%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    1 / 1
    0 / 0
    1 / 2
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    2 / 102 (1.96%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    2 / 195 (1.03%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 126 (0.00%)
    3 / 113 (2.65%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    1 / 20 (5.00%)
    2 / 93 (2.15%)
    2 / 195 (1.03%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic disorder
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    2 / 126 (1.59%)
    1 / 113 (0.88%)
    2 / 24 (8.33%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    2 / 44 (4.55%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 2
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal fistula infection
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Diarrhoea
         subjects affected / exposed
    7 / 126 (5.56%)
    3 / 113 (2.65%)
    3 / 24 (12.50%)
    4 / 102 (3.92%)
    0 / 20 (0.00%)
    3 / 93 (3.23%)
    7 / 195 (3.59%)
    3 / 44 (6.82%)
         occurrences causally related to treatment / all
    8 / 9
    3 / 3
    3 / 4
    5 / 5
    0 / 0
    3 / 3
    8 / 8
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bleeding urinary bladder
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    2 / 195 (1.03%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 113 (0.88%)
    1 / 24 (4.17%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    In-hospital infection
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall infection
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-procedure sepsis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Serratia bacteraemia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis pseudomonas
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    1 / 20 (5.00%)
    0 / 93 (0.00%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    1 / 24 (4.17%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 113 (0.00%)
    1 / 24 (4.17%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 113 (0.88%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    1 / 20 (5.00%)
    0 / 93 (0.00%)
    0 / 195 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Folfiri+Bevacizumab Folfiri+Cetuximab Folfiri + Bevacizumab, mutated Folfiri + Bevacizumab naive Folfiri + Cetuxi, mutated Folfiri + Cetuxi, naive PI3K and BRAF naive PI3K or BRAF mutated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 126 (100.00%)
    113 / 113 (100.00%)
    24 / 24 (100.00%)
    99 / 102 (97.06%)
    20 / 20 (100.00%)
    93 / 93 (100.00%)
    195 / 195 (100.00%)
    44 / 44 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 126 (20.63%)
    5 / 113 (4.42%)
    4 / 24 (16.67%)
    22 / 102 (21.57%)
    0 / 20 (0.00%)
    5 / 93 (5.38%)
    27 / 195 (13.85%)
    4 / 44 (9.09%)
         occurrences all number
    79
    6
    7
    72
    0
    6
    78
    7
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    15 / 126 (11.90%)
    9 / 113 (7.96%)
    4 / 24 (16.67%)
    11 / 102 (10.78%)
    2 / 20 (10.00%)
    7 / 93 (7.53%)
    18 / 195 (9.23%)
    6 / 44 (13.64%)
         occurrences all number
    32
    12
    8
    23
    5
    7
    30
    13
    Dizziness
         subjects affected / exposed
    8 / 126 (6.35%)
    5 / 113 (4.42%)
    1 / 24 (4.17%)
    7 / 102 (6.86%)
    2 / 20 (10.00%)
    3 / 93 (3.23%)
    10 / 195 (5.13%)
    3 / 44 (6.82%)
         occurrences all number
    9
    6
    1
    8
    2
    4
    12
    3
    Syncope
         subjects affected / exposed
    5 / 126 (3.97%)
    1 / 113 (0.88%)
    2 / 24 (8.33%)
    3 / 102 (2.94%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    4 / 195 (2.05%)
    2 / 44 (4.55%)
         occurrences all number
    8
    1
    2
    6
    0
    1
    7
    2
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    59 / 126 (46.83%)
    45 / 113 (39.82%)
    15 / 24 (62.50%)
    44 / 102 (43.14%)
    7 / 20 (35.00%)
    38 / 93 (40.86%)
    82 / 195 (42.05%)
    22 / 44 (50.00%)
         occurrences all number
    132
    97
    32
    100
    14
    83
    183
    46
    Pyrexia
         subjects affected / exposed
    28 / 126 (22.22%)
    22 / 113 (19.47%)
    6 / 24 (25.00%)
    22 / 102 (21.57%)
    2 / 20 (10.00%)
    20 / 93 (21.51%)
    42 / 195 (21.54%)
    8 / 44 (18.18%)
         occurrences all number
    40
    31
    10
    30
    2
    29
    59
    12
    Xerosis
         subjects affected / exposed
    0 / 126 (0.00%)
    10 / 113 (8.85%)
    0 / 24 (0.00%)
    0 / 102 (0.00%)
    4 / 20 (20.00%)
    6 / 93 (6.45%)
    6 / 195 (3.08%)
    4 / 44 (9.09%)
         occurrences all number
    0
    12
    0
    0
    4
    8
    8
    4
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    60 / 126 (47.62%)
    47 / 113 (41.59%)
    11 / 24 (45.83%)
    49 / 102 (48.04%)
    7 / 20 (35.00%)
    40 / 93 (43.01%)
    89 / 195 (45.64%)
    18 / 44 (40.91%)
         occurrences all number
    183
    101
    39
    144
    10
    91
    235
    49
    Anaemia
         subjects affected / exposed
    18 / 126 (14.29%)
    22 / 113 (19.47%)
    2 / 24 (8.33%)
    16 / 102 (15.69%)
    0 / 20 (0.00%)
    22 / 93 (23.66%)
    38 / 195 (19.49%)
    2 / 44 (4.55%)
         occurrences all number
    31
    37
    2
    29
    0
    37
    66
    2
    Leukopenia
         subjects affected / exposed
    9 / 126 (7.14%)
    7 / 113 (6.19%)
    1 / 24 (4.17%)
    8 / 102 (7.84%)
    1 / 20 (5.00%)
    6 / 93 (6.45%)
    14 / 195 (7.18%)
    2 / 44 (4.55%)
         occurrences all number
    21
    10
    1
    20
    2
    8
    28
    3
    Immune system disorders
    Urinary tract infection
         subjects affected / exposed
    8 / 126 (6.35%)
    11 / 113 (9.73%)
    0 / 24 (0.00%)
    8 / 102 (7.84%)
    3 / 20 (15.00%)
    8 / 93 (8.60%)
    16 / 195 (8.21%)
    3 / 44 (6.82%)
         occurrences all number
    11
    12
    0
    11
    4
    8
    19
    4
    Social circumstances
    Alopecia
         subjects affected / exposed
    38 / 126 (30.16%)
    18 / 113 (15.93%)
    10 / 24 (41.67%)
    28 / 102 (27.45%)
    3 / 20 (15.00%)
    15 / 93 (16.13%)
    43 / 195 (22.05%)
    13 / 44 (29.55%)
         occurrences all number
    50
    22
    12
    38
    5
    17
    55
    17
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    49 / 126 (38.89%)
    39 / 113 (34.51%)
    9 / 24 (37.50%)
    40 / 102 (39.22%)
    4 / 20 (20.00%)
    30 / 93 (32.26%)
    70 / 195 (35.90%)
    13 / 44 (29.55%)
         occurrences all number
    148
    63
    31
    117
    4
    59
    176
    34
    Vomiting
         subjects affected / exposed
    36 / 126 (28.57%)
    33 / 113 (29.20%)
    9 / 24 (37.50%)
    26 / 102 (25.49%)
    2 / 20 (10.00%)
    23 / 93 (24.73%)
    49 / 195 (25.13%)
    11 / 44 (25.00%)
         occurrences all number
    69
    53
    20
    48
    2
    49
    97
    22
    Constipation
         subjects affected / exposed
    29 / 126 (23.02%)
    34 / 113 (30.09%)
    7 / 24 (29.17%)
    21 / 102 (20.59%)
    4 / 20 (20.00%)
    27 / 93 (29.03%)
    48 / 195 (24.62%)
    11 / 44 (25.00%)
         occurrences all number
    48
    42
    15
    32
    8
    34
    66
    23
    Abdominal pain
         subjects affected / exposed
    26 / 126 (20.63%)
    23 / 113 (20.35%)
    9 / 24 (37.50%)
    16 / 102 (15.69%)
    1 / 20 (5.00%)
    20 / 93 (21.51%)
    36 / 195 (18.46%)
    10 / 44 (22.73%)
         occurrences all number
    46
    43
    16
    29
    2
    38
    67
    18
    Diarrhoea
         subjects affected / exposed
    90 / 126 (71.43%)
    75 / 113 (66.37%)
    18 / 24 (75.00%)
    69 / 102 (67.65%)
    12 / 20 (60.00%)
    63 / 93 (67.74%)
    132 / 195 (67.69%)
    30 / 44 (68.18%)
         occurrences all number
    294
    224
    81
    204
    23
    197
    401
    104
    Stomatitis
         subjects affected / exposed
    9 / 126 (7.14%)
    10 / 113 (8.85%)
    4 / 24 (16.67%)
    5 / 102 (4.90%)
    4 / 20 (20.00%)
    7 / 93 (7.53%)
    12 / 195 (6.15%)
    8 / 44 (18.18%)
         occurrences all number
    20
    14
    9
    11
    4
    10
    21
    13
    Rectal Bleeding
         subjects affected / exposed
    13 / 126 (10.32%)
    12 / 113 (10.62%)
    4 / 24 (16.67%)
    9 / 102 (8.82%)
    2 / 20 (10.00%)
    10 / 93 (10.75%)
    19 / 195 (9.74%)
    6 / 44 (13.64%)
         occurrences all number
    14
    22
    4
    10
    3
    19
    29
    7
    Odynophagia
         subjects affected / exposed
    9 / 126 (7.14%)
    3 / 113 (2.65%)
    3 / 24 (12.50%)
    6 / 102 (5.88%)
    2 / 20 (10.00%)
    1 / 93 (1.08%)
    7 / 195 (3.59%)
    5 / 44 (11.36%)
         occurrences all number
    11
    3
    5
    6
    2
    1
    7
    7
    Dry mouth
         subjects affected / exposed
    8 / 126 (6.35%)
    9 / 113 (7.96%)
    2 / 24 (8.33%)
    6 / 102 (5.88%)
    2 / 20 (10.00%)
    7 / 93 (7.53%)
    13 / 195 (6.67%)
    4 / 44 (9.09%)
         occurrences all number
    10
    12
    2
    8
    3
    9
    17
    5
    Dyspepsia
         subjects affected / exposed
    9 / 126 (7.14%)
    8 / 113 (7.08%)
    1 / 24 (4.17%)
    8 / 102 (7.84%)
    2 / 20 (10.00%)
    6 / 93 (6.45%)
    14 / 195 (7.18%)
    3 / 44 (6.82%)
         occurrences all number
    13
    8
    3
    10
    2
    6
    16
    5
    Pain in upper abdomen
         subjects affected / exposed
    9 / 126 (7.14%)
    6 / 113 (5.31%)
    2 / 24 (8.33%)
    7 / 102 (6.86%)
    1 / 20 (5.00%)
    5 / 93 (5.38%)
    12 / 195 (6.15%)
    3 / 44 (6.82%)
         occurrences all number
    12
    10
    3
    9
    2
    8
    17
    5
    Rectal tenesmus
         subjects affected / exposed
    2 / 126 (1.59%)
    1 / 113 (0.88%)
    2 / 24 (8.33%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    2 / 44 (4.55%)
         occurrences all number
    2
    1
    2
    0
    0
    1
    1
    2
    Aphthous ulcer
         subjects affected / exposed
    8 / 126 (6.35%)
    3 / 113 (2.65%)
    2 / 24 (8.33%)
    6 / 102 (5.88%)
    0 / 20 (0.00%)
    3 / 93 (3.23%)
    9 / 195 (4.62%)
    2 / 44 (4.55%)
         occurrences all number
    8
    3
    2
    6
    0
    3
    9
    2
    Asthenia
         subjects affected / exposed
    80 / 126 (63.49%)
    62 / 113 (54.87%)
    20 / 24 (83.33%)
    60 / 102 (58.82%)
    12 / 20 (60.00%)
    50 / 93 (53.76%)
    110 / 195 (56.41%)
    32 / 44 (72.73%)
         occurrences all number
    249
    150
    79
    170
    22
    128
    298
    101
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    33 / 126 (26.19%)
    11 / 113 (9.73%)
    6 / 24 (25.00%)
    27 / 102 (26.47%)
    1 / 20 (5.00%)
    10 / 93 (10.75%)
    37 / 195 (18.97%)
    7 / 44 (15.91%)
         occurrences all number
    68
    15
    13
    55
    1
    14
    69
    14
    Rhinorrhoea
         subjects affected / exposed
    10 / 126 (7.94%)
    6 / 113 (5.31%)
    2 / 24 (8.33%)
    8 / 102 (7.84%)
    1 / 20 (5.00%)
    5 / 93 (5.38%)
    13 / 195 (6.67%)
    3 / 44 (6.82%)
         occurrences all number
    23
    9
    3
    20
    1
    8
    28
    4
    Dyspnoea
         subjects affected / exposed
    8 / 126 (6.35%)
    5 / 113 (4.42%)
    2 / 24 (8.33%)
    6 / 102 (5.88%)
    1 / 20 (5.00%)
    4 / 93 (4.30%)
    10 / 195 (5.13%)
    3 / 44 (6.82%)
         occurrences all number
    12
    6
    6
    6
    1
    5
    11
    7
    Cold
         subjects affected / exposed
    12 / 126 (9.52%)
    7 / 113 (6.19%)
    3 / 24 (12.50%)
    9 / 102 (8.82%)
    0 / 20 (0.00%)
    7 / 93 (7.53%)
    16 / 195 (8.21%)
    3 / 44 (6.82%)
         occurrences all number
    17
    9
    4
    11
    0
    9
    20
    4
    Dysphonia
         subjects affected / exposed
    7 / 126 (5.56%)
    2 / 113 (1.77%)
    2 / 24 (8.33%)
    5 / 102 (4.90%)
    0 / 20 (0.00%)
    2 / 93 (2.15%)
    7 / 195 (3.59%)
    2 / 44 (4.55%)
         occurrences all number
    7
    2
    2
    5
    0
    2
    7
    2
    Cough
         subjects affected / exposed
    6 / 126 (4.76%)
    1 / 113 (0.88%)
    2 / 24 (8.33%)
    4 / 102 (3.92%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    5 / 195 (2.56%)
    2 / 44 (4.55%)
         occurrences all number
    7
    1
    3
    4
    0
    1
    5
    3
    Skin and subcutaneous tissue disorders
    Eruption
         subjects affected / exposed
    5 / 126 (3.97%)
    67 / 113 (59.29%)
    0 / 24 (0.00%)
    5 / 102 (4.90%)
    11 / 20 (55.00%)
    56 / 93 (60.22%)
    61 / 195 (31.28%)
    11 / 44 (25.00%)
         occurrences all number
    7
    176
    0
    7
    30
    146
    153
    30
    Palmoplantar erythrodysesthesia syndrome
         subjects affected / exposed
    8 / 126 (6.35%)
    16 / 113 (14.16%)
    1 / 24 (4.17%)
    7 / 102 (6.86%)
    5 / 20 (25.00%)
    11 / 93 (11.83%)
    18 / 195 (9.23%)
    6 / 44 (13.64%)
         occurrences all number
    11
    24
    1
    10
    11
    13
    23
    12
    Skin fissures
         subjects affected / exposed
    4 / 126 (3.17%)
    25 / 113 (22.12%)
    1 / 24 (4.17%)
    3 / 102 (2.94%)
    4 / 20 (20.00%)
    21 / 93 (22.58%)
    24 / 195 (12.31%)
    5 / 44 (11.36%)
         occurrences all number
    4
    46
    1
    3
    8
    38
    41
    9
    Dry skin
         subjects affected / exposed
    6 / 126 (4.76%)
    21 / 113 (18.58%)
    1 / 24 (4.17%)
    5 / 102 (4.90%)
    4 / 20 (20.00%)
    17 / 93 (18.28%)
    22 / 195 (11.28%)
    5 / 44 (11.36%)
         occurrences all number
    6
    30
    1
    5
    9
    21
    26
    10
    Acne
         subjects affected / exposed
    2 / 126 (1.59%)
    21 / 113 (18.58%)
    0 / 24 (0.00%)
    4 / 102 (3.92%)
    5 / 20 (25.00%)
    16 / 93 (17.20%)
    20 / 195 (10.26%)
    5 / 44 (11.36%)
         occurrences all number
    4
    43
    0
    4
    11
    32
    36
    11
    Dermatitis
         subjects affected / exposed
    3 / 126 (2.38%)
    20 / 113 (17.70%)
    0 / 24 (0.00%)
    3 / 102 (2.94%)
    3 / 20 (15.00%)
    17 / 93 (18.28%)
    20 / 195 (10.26%)
    3 / 44 (6.82%)
         occurrences all number
    4
    23
    0
    4
    3
    20
    24
    3
    Nail disorder
         subjects affected / exposed
    3 / 126 (2.38%)
    3 / 113 (2.65%)
    2 / 24 (8.33%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    3 / 93 (3.23%)
    4 / 195 (2.05%)
    2 / 44 (4.55%)
         occurrences all number
    3
    7
    2
    1
    0
    7
    8
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 126 (7.94%)
    7 / 113 (6.19%)
    5 / 24 (20.83%)
    5 / 102 (4.90%)
    1 / 20 (5.00%)
    6 / 93 (6.45%)
    11 / 195 (5.64%)
    6 / 44 (13.64%)
         occurrences all number
    13
    7
    7
    6
    1
    6
    12
    8
    Bone pain
         subjects affected / exposed
    3 / 126 (2.38%)
    1 / 113 (0.88%)
    2 / 24 (8.33%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    2 / 195 (1.03%)
    2 / 44 (4.55%)
         occurrences all number
    3
    1
    2
    1
    0
    1
    2
    2
    Infections and infestations
    Paronychia
         subjects affected / exposed
    1 / 126 (0.79%)
    30 / 113 (26.55%)
    0 / 24 (0.00%)
    1 / 102 (0.98%)
    6 / 20 (30.00%)
    24 / 93 (25.81%)
    25 / 195 (12.82%)
    6 / 44 (13.64%)
         occurrences all number
    2
    48
    0
    2
    9
    39
    41
    9
    Respiratory tract infection
         subjects affected / exposed
    7 / 126 (5.56%)
    1 / 113 (0.88%)
    2 / 24 (8.33%)
    5 / 102 (4.90%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    6 / 195 (3.08%)
    2 / 44 (4.55%)
         occurrences all number
    7
    1
    2
    5
    0
    1
    6
    2
    Gingivitis
         subjects affected / exposed
    3 / 126 (2.38%)
    2 / 113 (1.77%)
    2 / 24 (8.33%)
    1 / 102 (0.98%)
    0 / 20 (0.00%)
    2 / 93 (2.15%)
    3 / 195 (1.54%)
    2 / 44 (4.55%)
         occurrences all number
    5
    2
    4
    1
    0
    2
    3
    4
    Pharyngitis
         subjects affected / exposed
    2 / 126 (1.59%)
    1 / 113 (0.88%)
    2 / 24 (8.33%)
    0 / 102 (0.00%)
    0 / 20 (0.00%)
    1 / 93 (1.08%)
    1 / 195 (0.51%)
    2 / 44 (4.55%)
         occurrences all number
    3
    1
    3
    0
    0
    1
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    6 / 126 (4.76%)
    4 / 113 (3.54%)
    2 / 24 (8.33%)
    4 / 102 (3.92%)
    0 / 20 (0.00%)
    4 / 93 (4.30%)
    8 / 195 (4.10%)
    2 / 44 (4.55%)
         occurrences all number
    7
    5
    3
    4
    0
    4
    8
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 126 (23.02%)
    21 / 113 (18.58%)
    5 / 24 (20.83%)
    24 / 102 (23.53%)
    3 / 20 (15.00%)
    18 / 93 (19.35%)
    42 / 195 (21.54%)
    8 / 44 (18.18%)
         occurrences all number
    54
    28
    13
    41
    3
    28
    69
    16
    Hyperglycaemia
         subjects affected / exposed
    4 / 126 (3.17%)
    0 / 113 (0.00%)
    2 / 24 (8.33%)
    2 / 102 (1.96%)
    0 / 20 (0.00%)
    0 / 93 (0.00%)
    2 / 195 (1.03%)
    2 / 44 (4.55%)
         occurrences all number
    14
    0
    4
    10
    0
    0
    10
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2013
    Relevant modification to the Protocol (version 4 is generated), expansion of 5 centers, PI´s updates.
    18 Mar 2014
    Relevant modification to the Protocol (version 5 is generated with addition of sub-study and IC for subs study), expansion of 1 center, change of PiS-IC of the project and that of the sub study.
    26 Jul 2016
    Modifications of annexes 8 and 10 (sub study) to the protocol, HIP-CI change of project screening, general and specific PiS-IC change of sub study assay, change of 2 test lab managers, addition of new central laboratory to the trial.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32278676
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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