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    Clinical Trial Results:
    A Multi-Centre Randomised Clinical Trial of Biomarker-Driven Maintenance Treatment for First-Line Metastatic Colorectal Cancer (MODUL)

    Summary
    EudraCT number
    		 2014-001017-61
    Trial protocol
    		 IT   GB   DE   PT   DK   SK   NL   FR   SE   BE   GR   ES   SI   CY  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    12 Jun 2020
    First version publication date
    12 Jun 2020
    Other versions
    		 v2 , v3

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MO29112
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02291289
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    31 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the progression free survival (PFS) within each cohort.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Apr 2015
    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
    Argentina: 4
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 5
    Country: Number of subjects enrolled
    Brazil: 41
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Egypt: 5
    Country: Number of subjects enrolled
    France: 50
    Country: Number of subjects enrolled
    Germany: 91
    Country: Number of subjects enrolled
    Greece: 36
    Country: Number of subjects enrolled
    Italy: 94
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 24
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 45
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Turkey: 27
    Country: Number of subjects enrolled
    United Kingdom: 61
    Worldwide total number of subjects
    609
    EEA total number of subjects
    469
    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)
    364
    From 65 to 84 years
    243
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 To be eligible for the study, patients provided a primary tumour sample for biomarker assessment. This sample from the original diagnosis was used for the biomarker assessment which determined treatment assignment during the Maintenance Treatment Phase.

    Period 1
    Period 1 title
    Induction Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
    Arm type
    		 Induction Treatment

    Investigational medicinal product name
    5-fluorouracil (5-FU), leucovorin calcium (LV), and Oxaliplatin (FOLFOX)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered per the Investigator's discretion in accordance with locally approved prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression or death from any cause, whichever occurs first.

    Arm title
    		 Cohort 2
    Arm description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
    Arm type
    		 Induction Treatment

    Investigational medicinal product name
    5-fluorouracil (5-FU), leucovorin calcium (LV), and Oxaliplatin (FOLFOX)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered per the Investigator's discretion in accordance with locally approved prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression or death from any cause, whichever occurs first.

    Arm title
    		 Cohort 3
    Arm description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
    Arm type
    		 Induction Treatment

    Investigational medicinal product name
    5-fluorouracil (5-FU), leucovorin calcium (LV), and Oxaliplatin (FOLFOX)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered per the Investigator's discretion in accordance with locally approved prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression or death from any cause, whichever occurs first.

    Arm title
    		 Cohort 4
    Arm description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
    Arm type
    		 Induction Treatment

    Investigational medicinal product name
    5-fluorouracil (5-FU), leucovorin calcium (LV), and Oxaliplatin (FOLFOX)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered per the Investigator's discretion in accordance with locally approved prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression or death from any cause, whichever occurs first.

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Started
    60
    445
    5
    99
    Completed
    58
    436
    5
    98
    Not completed
    2
    9
    0
    1
         Not Dosed
    2
    9
    -
    1
    Period 2
    Period 2 title
    Maintenance Treatment Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Cohort 1: 5-FU/LV,cetuximab,vemurafenib
    Arm description
    		 Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m^2 via IV infusion on Day 1 of every 2-week cycle

    Investigational medicinal product name
    Vemurafenib
    Investigational medicinal product code
    Other name
    RO5185426
    Pharmaceutical forms
    Solution for infusion, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    960 mg vermurafenib BID by mouth

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first.

    Arm title
    		 Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab
    Arm description
    		 Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-FU/LV or capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per Investigator's discretion: 1600-2400 mg/m^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first.

    Arm title
    		 Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab
    Arm description
    		 Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-FU/LV or capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per Investigator's discretion: 1600-2400 mg/m^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg

    Arm title
    		 Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab
    Arm description
    		 Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-FU/LV or capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per Investigator's discretion: 1600-2400 mg/m^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first.

    Arm title
    		 Cohort 3: capecitabine,trastuzumab,pertuzumab
    Arm description
    		 Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin; RO0452317
    Pharmaceutical forms
    Solution for infusion, Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses by IV infusion on Day 1 of every 3-week treatment cycle

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    RO4368451
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses by IV infusion on Day 1 of each 3-week treatment cycle

    Arm title
    		 Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab
    Arm description
    		 Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-FU/LV or capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per Investigator's discretion: 1600-2400 mg/m^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first.

    Arm title
    		 Cohort 4: Cobimetinib,atezolizumab
    Arm description
    		 Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cobimetinib
    Investigational medicinal product code
    Other name
    RO5514041
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg orally once daily for 3 weeks followed by a 1-week treatment break

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    RO5541267
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle, or a fixed dose of 840 mg

    Arm title
    		 Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Arm description
    		 Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-FU/LV or capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per Investigator's discretion: 1600-2400 mg/m^2 administered via 46-hour IV infusion on Day 1 of every 2-week cycle and LV 400 mg/m^2 administered via a 2-hour infusion on Day 1 every 2 weeks or 1000 mg/m^2 twice-daily capecitabine (BID) by mouth given days 1-14 every 2 weeks. The chosen fluoropyrimidine should be administered in accordance with local prescribing information.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/kg bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle per local prescribing information

    Investigational medicinal product name
    5-FU/LV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle until disease progression per the Investigator's assessment using modified Response Evaluation Criteria in Solid Tumors or death from any cause, whichever occurs first.

    Number of subjects in period 2
    		Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Started
    40
    20
    297
    148
    3
    2
    65
    34
    Completed
    16
    4
    45
    19
    1
    0
    34
    18
    Not completed
    24
    16
    252
    129
    2
    2
    31
    16
         Adverse event, serious fatal
    23
    13
    185
    100
    1
    1
    26
    11
         Consent withdrawn by subject
    -
    -
    13
    11
    -
    -
    2
    3
         Physician decision
    -
    -
    2
    -
    -
    -
    -
    1
         unknown
    -
    1
    29
    8
    -
    1
    -
    -
         Adverse event, non-fatal
    -
    -
    1
    -
    -
    -
    -
    -
         No Treatment Received
    -
    2
    4
    5
    -
    -
    1
    -
         Multiple Reasons
    -
    -
    4
    1
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    12
    3
    1
    -
    2
    1
         Protocol deviation
    1
    -
    2
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.

    Reporting group title
    Cohort 2
    Reporting group description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.

    Reporting group title
    Cohort 3
    Reporting group description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.

    Reporting group title
    Cohort 4
    Reporting group description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.

    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total
    Number of subjects
    		 60 445 5 99 609
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 39 254 5 66 364
        From 65-84 years
    		 21 189 0 33 243
        85 years and over
    		 0 2 0 0 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.2 ± 11.0 60.6 ± 12.3 49.6 ± 7.4 59.5 ± 10.2 -
    Sex: Female, Male
    Units:
        Female
    		 34 174 3 41 252
        Male
    		 26 271 2 58 357

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.

    Reporting group title
    Cohort 2
    Reporting group description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.

    Reporting group title
    Cohort 3
    Reporting group description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.

    Reporting group title
    Cohort 4
    Reporting group description
    		 All participants will receive either eight 2-week cycles of 5-fluorouracil (5-FU)/ leucovorin calcium (LV) and oxaliplatin (FOLFOX) in combination with bevacizumab, or six 2-week cycles of FOLFOX in combination with bevacizumab, followed by two 2-week cycles of 5-FU/LV with bevacizumab.
    Reporting group title
    Cohort 1: 5-FU/LV,cetuximab,vemurafenib
    Reporting group description
    		 Participants with v-raf murine sarcoma viral oncogene homolog B1 mutation positive (BRAFmut)/human epidermal growth factor receptor 2 negative (HER2-)/microsatellite stable (MSS)/rat sarcoma wild type (RASwt) will receive 1600-2400 milligrams per square meter (mg/m^2) 5-FU via 46-hour intravenous (IV) infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle with 500 mg/m^2 cetuximab via infusion on Day 1 of every 2-week cycle and 960 milligrams (mg) vemurafenib twice daily (BID) by mouth.

    Reporting group title
    Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab
    Reporting group description
    		 Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.

    Reporting group title
    Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab
    Reporting group description
    		 Participants with BRAFwt will receive fluoropyrimidine (1600-2400 mg/m^2 5-FU via 46-hour IV infusion in combination with 400 mg/m^2 LV via 2-hour infusion on Day 1 of every 2-week cycle or 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break) with 5 milligrams per kilogram (mg/kg) bevacizumab via 15-30 minute IV infusion on Day 1 of every 2-week cycle and 800 mg atezolizumab via 60-minute IV infusion on Day 1 of every 2-week cycle.

    Reporting group title
    Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab
    Reporting group description
    		 Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.

    Reporting group title
    Cohort 3: capecitabine,trastuzumab,pertuzumab
    Reporting group description
    		 Participants with human epidermal growth factor receptor 2 positive (HER2+) will receive 1000 mg/m^2 twice-daily capecitabine BID by mouth on Days 1-14 every 2 weeks followed by a 1-week break with trastuzumab by IV infusion on Day 1 of every 3-week treatment cycle at an initial loading dose of 8 mg/kg followed by 6 mg/kg for subsequent doses, and pertuzumab by IV infusion on Day 1 of each 3-week treatment cycle at an initial fixed loading dose of 840 mg followed by 420 mg for subsequent doses.

    Reporting group title
    Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab
    Reporting group description
    		 Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.

    Reporting group title
    Cohort 4: Cobimetinib,atezolizumab
    Reporting group description
    		 Participants with HER2-/high microsatellite instability (MSI-H); HER2-/MSS/v-raf murine sarcoma viral oncogene homolog B1 wild type (BRAFwt); HER2-/MSS/BRAFmut/rat sarcoma mutation positive (RASmut) will receive 60 mg cobimetinib orally for 3 weeks followed by a 1-week treatment break and atezolizumab at a fixed dose of 840 mg via 60-minute IV infusion on Day 1 of every 2-week cycle.

    Reporting group title
    Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Reporting group description
    		 Per Investigator discretion, participants will receive fluoropyrimidine (5-FU/LV or capecitabine) at a dose and schedule per the Investigator's discretion in accordance with locally approved prescribing information and 5 mg/kg bevacizumab via 1-30 minute IV on Day 1 of every 2-week cycle.

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Progression-Free Survival (PFS) was evaluated according to response evaluation criteria in solid tumors version 1.1 (RECIST 1.1)
    End point type
    Primary
    End point timeframe
    From randomization until disease progression or death from any cause, up to 5 years
    End point values
    		 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects analysed
    40
    20
    297
    148
    3
    2
    65
    34
    Units: months
        median (confidence interval 95%)
    9.99 (7.72 to 12.55)
    11.60 (3.58 to 15.67)
    7.13 (6.14 to 8.41)
    7.36 (5.82 to 8.94)
    4.44 (3.55 to 14.69)
    4.04 (4.04 to 5.39)
    3.75 (3.42 to 3.91)
    7.79 (3.98 to 9.46)
    Statistical analysis title
    		 Cohort 1 vs. Control
    Comparison groups
    Cohort 1: 5-FU/LV,cetuximab,vemurafenib v Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.872
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.82
    Statistical analysis title
    		 Cohort 2 vs. Control
    Comparison groups
    Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab v Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.666
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.18
    Statistical analysis title
    		 Cohort 4 vs. Control
    Comparison groups
    Cohort 4: Cobimetinib,atezolizumab v Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.128
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.29

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization until death from any cause, up to 5 years
    End point values
    		 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects analysed
    0 [1]
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [1] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [2] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [3] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [4] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [5] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [6] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [7] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [8] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    No statistical analyses for this end point

    Secondary: Overall Response

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    End point title
    		 Overall Response
    End point description
    Calculated as the number of participants with a best overall response of CR or PR according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression, up to 5 years
    End point values
    		 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects analysed
    40
    20
    297
    148
    3
    2
    0 [9]
    0 [10]
    Units: participants
    20
    5
    49
    22
    1
    0
    Notes
    [9] - Target number of patients not enrolled and the target number of PFS events could not be reached
    [10] - Target number of patients not enrolled and the target number of PFS events could not be reached
    Statistical analysis title
    		 Cohort 1 vs. Control
    Comparison groups
    Cohort 1: 5-FU/LV,cetuximab,vemurafenib v Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.064
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Cohort 2 vs. Control
    Comparison groups
    Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab v Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.658
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Disease Control Rate

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    End point title
    		 Disease Control Rate
    End point description
    Calculated as the proportion of participants with a best overall response of CR, PR or Stable Disease according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression, up to 5 years
    End point values
    		 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects analysed
    40
    20
    297
    148
    3
    2
    0 [11]
    0 [12]
    Units: participants
    36
    15
    227
    111
    1
    0
    Notes
    [11] - Target number of patients not enrolled and the target number of PFS events could not be reached
    [12] - Target number of patients not enrolled and the target number of PFS events could not be reached
    Statistical analysis title
    		 Cohort 1 vs. Control
    Comparison groups
    Cohort 1: 5-FU/LV,cetuximab,vemurafenib v Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.125
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Cohort 2 vs. Control
    Comparison groups
    Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab v Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.739
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Time to Treatment Response

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    End point title
    		 Time to Treatment Response
    End point description
    Calculated as the time from randomization to the first Occurrence of a documented Objective Response (CR or PR) determined according to RECIST 1.1
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression or death from any cause, up to 5 years
    End point values
    		 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects analysed
    40
    20
    297
    148
    3
    2
    0 [13]
    0 [14]
    Units: months
        median (full range (min-max))
    3.943 (1.18 to 29.70)
    5.552 (1.38 to 8.02)
    5.224 (1.22 to 26.74)
    4.616 (1.25 to 19.91)
    5.490 (5.490 to 5.490)
    0 (0 to 0)
    ( to )
    ( to )
    Notes
    [13] - Target number of patients not enrolled and the target number of PFS events could not be reached
    [14] - Target number of patients not enrolled and the target number of PFS events could not be reached
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Defined as the time from the first assessment of CR or PR until disease progression or death from any cause, whichever occurs first
    End point type
    Secondary
    End point timeframe
    From first objective response until disease progression or death from any cause, up to 5 years
    End point values
    		 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects analysed
    40
    20
    297
    148
    3
    2
    0 [15]
    0 [16]
    Units: months
        median (confidence interval 95%)
    11.50 (7.66 to 21.49)
    8.74 (5.36 to 19.02)
    9.30 (5.55 to 11.30)
    7.59 (6.93 to 13.90)
    9.205 (9.205 to 9.205)
    0 (0 to 0)
    ( to )
    ( to )
    Notes
    [15] - Target number of patients not enrolled and the target number of PFS events could not be reached
    [16] - Target number of patients not enrolled and the target number of PFS events could not be reached
    Statistical analysis title
    		 Cohort 1 vs. Control
    Comparison groups
    Cohort 1: 5-FU/LV,cetuximab,vemurafenib v Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.421
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Cohort 2 vs. Control
    Comparison groups
    Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab v Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.495
    Method
    		 Logrank
    Confidence interval

    Secondary: Change from Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS)

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    End point title
    		 Change from Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline until end of study (up to 5 years)
    End point values
    		 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects analysed
    40
    20
    297
    148
    3
    2
    0 [17]
    0 [18]
    Units: percentage of participants
    number (not applicable)
        Improved
    10.0
    5.0
    10.4
    5.4
    0
    0
        Improved or stayed the same
    75.0
    85.0
    76.7
    82.5
    100
    100
    Notes
    [17] - Target number of patients not enrolled and the target number of PFS events could not be reached
    [18] - Target number of patients not enrolled and the target number of PFS events could not be reached
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events

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    End point title
    		 Percentage of Participants with Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline until end of study (up to 5 years)
    End point values
    		 Cohort 1 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Cohort 2 Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3 Cohort 2: 5-FU/LV or capecitabine,bevacizumab,atezolizumab Cohort 4 Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine,trastuzumab,pertuzumab Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib,atezolizumab Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    0 [26]
    0 [27]
    0 [28]
    0 [29]
    0 [30]
    Units: percentage of participants
        number (not applicable)
    Notes
    [19] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [20] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [21] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [22] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [23] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [24] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [25] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [26] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [27] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [28] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [29] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    [30] - Final Results will be provided at the time of final results disclosure (estimated July 2021).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline until end of study (up to 5 years)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Cohort 1 (Induction Treatment)
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Cohort 1: 5-FU/LV,cetuximab, vemurafenib
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 (Induction Treatment)
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Cohort 2: 5-FU/LV or capecitabine, bevacizumab, atezolizumab
    Reporting group description
    		 -

    Reporting group title
    Cohort 3 (Induction Treatment)
    Reporting group description
    		 -

    Reporting group title
    Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Cohort 3: capecitabine, trastuzumab, pertuzumab
    Reporting group description
    		 -

    Reporting group title
    Cohort 4 (Induction Treatment)
    Reporting group description
    		 -

    Reporting group title
    Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab
    Reporting group description
    		 -

    Reporting group title
    Cohort 4: Cobimetinib, atezolizumab
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort 1 (Induction Treatment) Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 1: 5-FU/LV,cetuximab, vemurafenib Cohort 2 (Induction Treatment) Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine, bevacizumab, atezolizumab Cohort 3 (Induction Treatment) Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine, trastuzumab, pertuzumab Cohort 4 (Induction Treatment) Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib, atezolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 58 (15.52%)
    8 / 18 (44.44%)
    13 / 40 (32.50%)
    16 / 436 (3.67%)
    30 / 143 (20.98%)
    90 / 293 (30.72%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    6 / 98 (6.12%)
    3 / 34 (8.82%)
    25 / 64 (39.06%)
         number of deaths (all causes)
    36
    13
    23
    292
    100
    185
    2
    1
    1
    38
    11
    26
         number of deaths resulting from adverse events
    2
    5
    5
    3
    20
    46
    0
    0
    0
    2
    3
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Second primary malignancy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour perforation
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial thrombosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Ureteral stent removal
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Gait disturbance
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site dehiscence
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site thrombosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion site extravasation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    2 / 143 (1.40%)
    9 / 293 (3.07%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    3 / 9
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    2 / 8
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    Blood lactate dehydrogenase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood triglycerides increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    2 / 143 (1.40%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic ulcer
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stoma site haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheal haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Coronary artery disease
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Restrictive cardiomyopathy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Haemorrhage intracranial
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Syncope
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Febrile neutropenia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    4 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    2 / 143 (1.40%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    5 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    4 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Chorioretinopathy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    2 / 436 (0.46%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Abdominal pain upper
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 6
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    2 / 143 (1.40%)
    7 / 293 (2.39%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 2
    5 / 7
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    4 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    2 / 143 (1.40%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Intestinal perforation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal stenosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    1 / 1
    4 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    1 / 1
    3 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal failure
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Rash maculo-papular
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    4 / 436 (0.92%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 4
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 4
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Nephrolithiasis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Muscular weakness
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Gastroenteritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis clostridial
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gingivitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyelonephritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urosepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    2 / 143 (1.40%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Diabetic ketoacidosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 (Induction Treatment) Cohort 1 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 1: 5-FU/LV,cetuximab, vemurafenib Cohort 2 (Induction Treatment) Cohort 2 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 2: 5-FU/LV or capecitabine, bevacizumab, atezolizumab Cohort 3 (Induction Treatment) Cohort 3 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 3: capecitabine, trastuzumab, pertuzumab Cohort 4 (Induction Treatment) Cohort 4 Control: 5-FU/LV or capecitabin, bevacizumab Cohort 4: Cobimetinib, atezolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 58 (100.00%)
    17 / 18 (94.44%)
    39 / 40 (97.50%)
    415 / 436 (95.18%)
    118 / 143 (82.52%)
    270 / 293 (92.15%)
    5 / 5 (100.00%)
    2 / 2 (100.00%)
    3 / 3 (100.00%)
    96 / 98 (97.96%)
    27 / 34 (79.41%)
    61 / 64 (95.31%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Seborrhoeic keratosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 58 (15.52%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    90 / 436 (20.64%)
    16 / 143 (11.19%)
    49 / 293 (16.72%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    19 / 98 (19.39%)
    5 / 34 (14.71%)
    3 / 64 (4.69%)
         occurrences all number
    11
    1
    1
    116
    21
    70
    1
    0
    0
    27
    7
    4
    Hypotension
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 18 (0.00%)
    4 / 40 (10.00%)
    4 / 436 (0.92%)
    1 / 143 (0.70%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    3 / 3 (100.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    2
    0
    4
    4
    1
    3
    0
    0
    3
    0
    0
    3
    General disorders and administration site conditions
    Asthenia
    alternative assessment type: Systematic
         subjects affected / exposed
    11 / 58 (18.97%)
    1 / 18 (5.56%)
    5 / 40 (12.50%)
    73 / 436 (16.74%)
    12 / 143 (8.39%)
    39 / 293 (13.31%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    15 / 98 (15.31%)
    3 / 34 (8.82%)
    11 / 64 (17.19%)
         occurrences all number
    12
    2
    9
    109
    20
    57
    1
    0
    0
    26
    3
    11
    Face oedema
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    2 / 436 (0.46%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    0
    0
    0
    2
    0
    3
    0
    0
    0
    0
    0
    5
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    17 / 58 (29.31%)
    2 / 18 (11.11%)
    9 / 40 (22.50%)
    132 / 436 (30.28%)
    23 / 143 (16.08%)
    54 / 293 (18.43%)
    3 / 5 (60.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    34 / 98 (34.69%)
    6 / 34 (17.65%)
    12 / 64 (18.75%)
         occurrences all number
    27
    2
    12
    202
    28
    78
    4
    0
    1
    49
    7
    16
    Influenza like illness
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    9 / 436 (2.06%)
    3 / 143 (2.10%)
    8 / 293 (2.73%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    3
    9
    3
    9
    0
    0
    0
    2
    1
    0
    Mucosal inflammation
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 18 (11.11%)
    7 / 40 (17.50%)
    31 / 436 (7.11%)
    7 / 143 (4.90%)
    19 / 293 (6.48%)
    2 / 5 (40.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    15 / 98 (15.31%)
    1 / 34 (2.94%)
    3 / 64 (4.69%)
         occurrences all number
    6
    4
    8
    34
    9
    25
    2
    0
    1
    19
    1
    3
    Oedema peripheral
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    6 / 436 (1.38%)
    2 / 143 (1.40%)
    6 / 293 (2.05%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    7 / 64 (10.94%)
         occurrences all number
    3
    0
    6
    6
    2
    6
    0
    0
    0
    0
    1
    9
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    3 / 436 (0.69%)
    2 / 143 (1.40%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    3
    3
    2
    4
    0
    0
    1
    0
    0
    0
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 58 (12.07%)
    1 / 18 (5.56%)
    9 / 40 (22.50%)
    43 / 436 (9.86%)
    13 / 143 (9.09%)
    31 / 293 (10.58%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    11 / 98 (11.22%)
    3 / 34 (8.82%)
    17 / 64 (26.56%)
         occurrences all number
    8
    1
    9
    52
    15
    50
    1
    0
    0
    13
    3
    23
    Immune system disorders
    Hypersensitivity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    10 / 436 (2.29%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    3
    10
    0
    1
    0
    0
    0
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    0
    0
    0
    0
    0
    0
    Cough
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 18 (16.67%)
    5 / 40 (12.50%)
    30 / 436 (6.88%)
    10 / 143 (6.99%)
    30 / 293 (10.24%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    6 / 98 (6.12%)
    3 / 34 (8.82%)
    6 / 64 (9.38%)
         occurrences all number
    3
    3
    6
    32
    12
    38
    1
    0
    0
    6
    3
    6
    Dysphonia
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    25 / 436 (5.73%)
    3 / 143 (2.10%)
    15 / 293 (5.12%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    4 / 98 (4.08%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    4
    1
    1
    35
    3
    17
    0
    0
    0
    4
    0
    1
    Dyspnoea
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 18 (11.11%)
    2 / 40 (5.00%)
    17 / 436 (3.90%)
    2 / 143 (1.40%)
    12 / 293 (4.10%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    5 / 98 (5.10%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    3
    2
    2
    18
    2
    12
    0
    0
    0
    5
    0
    2
    Epistaxis
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 58 (12.07%)
    1 / 18 (5.56%)
    5 / 40 (12.50%)
    68 / 436 (15.60%)
    15 / 143 (10.49%)
    22 / 293 (7.51%)
    1 / 5 (20.00%)
    2 / 2 (100.00%)
    0 / 3 (0.00%)
    18 / 98 (18.37%)
    3 / 34 (8.82%)
    6 / 64 (9.38%)
         occurrences all number
    8
    1
    5
    74
    19
    27
    1
    0
    0
    19
    4
    6
    Hiccups
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    12 / 436 (2.75%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    4 / 98 (4.08%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    17
    1
    0
    0
    0
    0
    0
    0
    0
    Nasal dryness
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    2
    0
    0
    0
    0
    1
    0
    Nasal ulcer
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Pulmonary embolism
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    9 / 436 (2.06%)
    1 / 143 (0.70%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    3
    1
    2
    9
    1
    3
    0
    0
    0
    1
    1
    0
    Psychiatric disorders
    Anxiety
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    9 / 436 (2.06%)
    1 / 143 (0.70%)
    5 / 293 (1.71%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    5 / 98 (5.10%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    4
    1
    1
    9
    1
    5
    1
    0
    0
    5
    0
    1
    Insomnia
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 58 (12.07%)
    1 / 18 (5.56%)
    2 / 40 (5.00%)
    19 / 436 (4.36%)
    3 / 143 (2.10%)
    10 / 293 (3.41%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    0 / 34 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    7
    1
    2
    20
    3
    10
    0
    0
    0
    3
    0
    3
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    19 / 436 (4.36%)
    6 / 143 (4.20%)
    8 / 293 (2.73%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    0 / 34 (0.00%)
    12 / 64 (18.75%)
         occurrences all number
    3
    0
    3
    25
    9
    14
    0
    0
    0
    2
    0
    13
    Amylase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    0
    0
    0
    1
    0
    4
    Aspartate aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 18 (5.56%)
    2 / 40 (5.00%)
    15 / 436 (3.44%)
    6 / 143 (4.20%)
    11 / 293 (3.75%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    0 / 34 (0.00%)
    15 / 64 (23.44%)
         occurrences all number
    5
    1
    2
    18
    7
    14
    0
    0
    0
    2
    0
    15
    Blood alkaline phosphatase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    7 / 436 (1.61%)
    4 / 143 (2.80%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    6 / 64 (9.38%)
         occurrences all number
    2
    0
    0
    7
    5
    5
    0
    0
    0
    2
    0
    6
    Blood bilirubin increased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    2 / 40 (5.00%)
    5 / 436 (1.15%)
    4 / 143 (2.80%)
    8 / 293 (2.73%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    3
    5
    5
    10
    0
    0
    0
    0
    0
    4
    Blood creatine phosphokinase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    32 / 64 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    39
    Blood creatinine increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    6 / 436 (1.38%)
    2 / 143 (1.40%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    5
    7
    5
    4
    0
    0
    0
    1
    0
    1
    Ejection fraction decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    6
    Lipase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    0 / 34 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    0
    0
    3
    0
    0
    2
    0
    0
    0
    2
    0
    7
    Neutrophil count decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 58 (17.24%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    46 / 436 (10.55%)
    2 / 143 (1.40%)
    6 / 293 (2.05%)
    2 / 5 (40.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    9 / 98 (9.18%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    12
    0
    0
    68
    3
    10
    2
    0
    0
    15
    0
    0
    Platelet count decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    23 / 436 (5.28%)
    3 / 143 (2.10%)
    6 / 293 (2.05%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    11 / 98 (11.22%)
    1 / 34 (2.94%)
    5 / 64 (7.81%)
         occurrences all number
    3
    0
    1
    35
    4
    19
    0
    0
    0
    13
    1
    6
    Weight decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 18 (11.11%)
    4 / 40 (10.00%)
    32 / 436 (7.34%)
    2 / 143 (1.40%)
    11 / 293 (3.75%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    4 / 98 (4.08%)
    0 / 34 (0.00%)
    5 / 64 (7.81%)
         occurrences all number
    3
    2
    4
    33
    3
    12
    0
    0
    0
    4
    0
    5
    Weight increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    7 / 436 (1.61%)
    1 / 143 (0.70%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    2 / 34 (5.88%)
    3 / 64 (4.69%)
         occurrences all number
    0
    0
    1
    7
    1
    3
    0
    0
    0
    3
    2
    7
    Injury, poisoning and procedural complications
    Infusion related reaction
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    7 / 436 (1.61%)
    0 / 143 (0.00%)
    9 / 293 (3.07%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    6 / 98 (6.12%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    2
    0
    3
    12
    0
    11
    0
    0
    0
    11
    0
    2
    Nervous system disorders
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 18 (5.56%)
    4 / 40 (10.00%)
    15 / 436 (3.44%)
    1 / 143 (0.70%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    4 / 98 (4.08%)
    1 / 34 (2.94%)
    4 / 64 (6.25%)
         occurrences all number
    5
    2
    4
    17
    1
    6
    0
    0
    0
    4
    1
    4
    Dysgeusia
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 58 (10.34%)
    0 / 18 (0.00%)
    4 / 40 (10.00%)
    30 / 436 (6.88%)
    3 / 143 (2.10%)
    8 / 293 (2.73%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    6 / 98 (6.12%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    6
    0
    4
    39
    3
    8
    1
    0
    0
    7
    0
    0
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    38 / 436 (8.72%)
    6 / 143 (4.20%)
    23 / 293 (7.85%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    14 / 98 (14.29%)
    3 / 34 (8.82%)
    6 / 64 (9.38%)
         occurrences all number
    4
    0
    2
    70
    16
    75
    1
    0
    0
    24
    5
    8
    Neuropathy peripheral
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 58 (10.34%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    67 / 436 (15.37%)
    10 / 143 (6.99%)
    18 / 293 (6.14%)
    2 / 5 (40.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    18 / 98 (18.37%)
    5 / 34 (14.71%)
    1 / 64 (1.56%)
         occurrences all number
    7
    0
    2
    95
    10
    21
    2
    0
    0
    25
    5
    2
    Neurotoxicity
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    14 / 436 (3.21%)
    2 / 143 (1.40%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    8 / 98 (8.16%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    7
    0
    3
    20
    3
    3
    0
    0
    0
    15
    1
    0
    Paraesthesia
    alternative assessment type: Systematic
         subjects affected / exposed
    12 / 58 (20.69%)
    0 / 18 (0.00%)
    4 / 40 (10.00%)
    63 / 436 (14.45%)
    10 / 143 (6.99%)
    18 / 293 (6.14%)
    2 / 5 (40.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    14 / 98 (14.29%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    17
    0
    4
    75
    11
    21
    2
    0
    0
    17
    1
    0
    Peripheral motor neuropathy
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    5 / 436 (1.15%)
    0 / 143 (0.00%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    5 / 98 (5.10%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    2
    0
    3
    5
    0
    3
    0
    0
    0
    5
    0
    1
    Peripheral sensory neuropathy
    alternative assessment type: Systematic
         subjects affected / exposed
    14 / 58 (24.14%)
    1 / 18 (5.56%)
    4 / 40 (10.00%)
    153 / 436 (35.09%)
    15 / 143 (10.49%)
    32 / 293 (10.92%)
    2 / 5 (40.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    28 / 98 (28.57%)
    4 / 34 (11.76%)
    3 / 64 (4.69%)
         occurrences all number
    19
    1
    5
    233
    16
    38
    3
    0
    0
    42
    4
    6
    Polyneuropathy
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    16 / 436 (3.67%)
    1 / 143 (0.70%)
    6 / 293 (2.05%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    1
    0
    18
    2
    6
    0
    0
    0
    1
    0
    0
    Restless legs syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Sensory loss
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Somnolence
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    5
    0
    0
    0
    0
    0
    0
    Taste disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    9 / 436 (2.06%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    3
    0
    0
    9
    1
    1
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 58 (13.79%)
    2 / 18 (11.11%)
    7 / 40 (17.50%)
    35 / 436 (8.03%)
    8 / 143 (5.59%)
    19 / 293 (6.48%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    10 / 98 (10.20%)
    1 / 34 (2.94%)
    6 / 64 (9.38%)
         occurrences all number
    9
    3
    10
    41
    13
    25
    0
    0
    0
    11
    1
    8
    Leukopenia
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    24 / 436 (5.50%)
    3 / 143 (2.10%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    0
    32
    3
    8
    0
    0
    0
    3
    1
    0
    Neutropenia
    alternative assessment type: Systematic
         subjects affected / exposed
    13 / 58 (22.41%)
    2 / 18 (11.11%)
    5 / 40 (12.50%)
    96 / 436 (22.02%)
    9 / 143 (6.29%)
    11 / 293 (3.75%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    25 / 98 (25.51%)
    3 / 34 (8.82%)
    1 / 64 (1.56%)
         occurrences all number
    15
    2
    5
    149
    18
    11
    0
    0
    0
    40
    4
    1
    Thrombocytopenia
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    27 / 436 (6.19%)
    4 / 143 (2.80%)
    10 / 293 (3.41%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    6 / 98 (6.12%)
    1 / 34 (2.94%)
    4 / 64 (6.25%)
         occurrences all number
    5
    0
    0
    35
    10
    11
    0
    0
    0
    8
    5
    4
    Eye disorders
    Cataract
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    0
    3
    1
    0
    1
    0
    0
    0
    1
    0
    2
    Conjunctival haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Lacrimation increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    6 / 436 (1.38%)
    5 / 143 (3.50%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    6
    5
    5
    0
    0
    0
    2
    0
    0
    Periorbital oedema
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 58 (15.52%)
    1 / 18 (5.56%)
    7 / 40 (17.50%)
    51 / 436 (11.70%)
    13 / 143 (9.09%)
    39 / 293 (13.31%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    11 / 98 (11.22%)
    5 / 34 (14.71%)
    12 / 64 (18.75%)
         occurrences all number
    10
    1
    9
    63
    16
    44
    0
    0
    0
    13
    5
    15
    Abdominal pain upper
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 58 (12.07%)
    3 / 18 (16.67%)
    2 / 40 (5.00%)
    19 / 436 (4.36%)
    12 / 143 (8.39%)
    17 / 293 (5.80%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    0 / 34 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    8
    3
    2
    22
    16
    21
    0
    0
    0
    3
    0
    5
    Angular cheilitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    2 / 436 (0.46%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    1
    1
    2
    0
    0
    0
    0
    0
    1
    0
    0
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 58 (15.52%)
    0 / 18 (0.00%)
    5 / 40 (12.50%)
    81 / 436 (18.58%)
    18 / 143 (12.59%)
    36 / 293 (12.29%)
    1 / 5 (20.00%)
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    20 / 98 (20.41%)
    2 / 34 (5.88%)
    6 / 64 (9.38%)
         occurrences all number
    10
    0
    6
    104
    27
    47
    1
    1
    0
    23
    2
    7
    Dental cyst
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    26 / 58 (44.83%)
    4 / 18 (22.22%)
    16 / 40 (40.00%)
    158 / 436 (36.24%)
    19 / 143 (13.29%)
    74 / 293 (25.26%)
    2 / 5 (40.00%)
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    33 / 98 (33.67%)
    8 / 34 (23.53%)
    40 / 64 (62.50%)
         occurrences all number
    34
    5
    39
    264
    34
    114
    2
    0
    4
    68
    11
    84
    Dyspepsia
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    14 / 436 (3.21%)
    3 / 143 (2.10%)
    9 / 293 (3.07%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    8 / 98 (8.16%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    4
    1
    1
    17
    3
    11
    0
    0
    0
    8
    0
    1
    Dysphagia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    11 / 436 (2.52%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    2 / 34 (5.88%)
    1 / 64 (1.56%)
         occurrences all number
    3
    0
    4
    18
    1
    1
    0
    0
    0
    1
    2
    1
    Gingival bleeding
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    3 / 436 (0.69%)
    0 / 143 (0.00%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    3
    3
    0
    5
    0
    1
    0
    0
    0
    0
    Haemorrhoids
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    10 / 436 (2.29%)
    1 / 143 (0.70%)
    6 / 293 (2.05%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    4
    1
    1
    11
    2
    6
    0
    0
    0
    0
    0
    2
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    30 / 58 (51.72%)
    0 / 18 (0.00%)
    16 / 40 (40.00%)
    177 / 436 (40.60%)
    28 / 143 (19.58%)
    60 / 293 (20.48%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    43 / 98 (43.88%)
    5 / 34 (14.71%)
    14 / 64 (21.88%)
         occurrences all number
    60
    0
    23
    295
    42
    126
    1
    0
    0
    90
    21
    18
    Palatal ulcer
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Rectal haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    2 / 40 (5.00%)
    8 / 436 (1.83%)
    3 / 143 (2.10%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    2
    8
    5
    5
    0
    0
    0
    0
    0
    0
    Stomatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    14 / 58 (24.14%)
    3 / 18 (16.67%)
    5 / 40 (12.50%)
    82 / 436 (18.81%)
    11 / 143 (7.69%)
    35 / 293 (11.95%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    16 / 98 (16.33%)
    3 / 34 (8.82%)
    1 / 64 (1.56%)
         occurrences all number
    19
    3
    6
    111
    19
    48
    0
    0
    0
    21
    3
    1
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    14 / 58 (24.14%)
    1 / 18 (5.56%)
    7 / 40 (17.50%)
    82 / 436 (18.81%)
    9 / 143 (6.29%)
    38 / 293 (12.97%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    19 / 98 (19.39%)
    2 / 34 (5.88%)
    11 / 64 (17.19%)
         occurrences all number
    18
    1
    11
    112
    12
    59
    0
    0
    0
    31
    8
    15
    Skin and subcutaneous tissue disorders
    Alopecia
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 58 (10.34%)
    2 / 18 (11.11%)
    1 / 40 (2.50%)
    40 / 436 (9.17%)
    2 / 143 (1.40%)
    8 / 293 (2.73%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    6 / 98 (6.12%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    6
    2
    1
    40
    2
    8
    1
    0
    0
    6
    1
    0
    Dermatitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    1 / 143 (0.70%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    1
    1
    0
    1
    1
    3
    0
    0
    0
    0
    0
    1
    Dermatitis acneiform
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    11 / 40 (27.50%)
    4 / 436 (0.92%)
    0 / 143 (0.00%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    2 / 34 (5.88%)
    18 / 64 (28.13%)
         occurrences all number
    0
    0
    13
    5
    0
    4
    0
    0
    0
    1
    2
    20
    Dermatitis contact
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dry skin
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 18 (16.67%)
    11 / 40 (27.50%)
    24 / 436 (5.50%)
    3 / 143 (2.10%)
    19 / 293 (6.48%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    3 / 98 (3.06%)
    1 / 34 (2.94%)
    6 / 64 (9.38%)
         occurrences all number
    2
    3
    12
    24
    6
    22
    0
    0
    1
    3
    1
    6
    Eczema
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    2 / 436 (0.46%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    2
    0
    0
    0
    0
    0
    0
    Erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    8 / 40 (20.00%)
    6 / 436 (1.38%)
    2 / 143 (1.40%)
    12 / 293 (4.10%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    4
    10
    6
    2
    13
    0
    0
    0
    0
    0
    1
    Nail ridging
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    3 / 143 (2.10%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    0
    0
    1
    0
    0
    0
    Onychoclasis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 18 (22.22%)
    5 / 40 (12.50%)
    23 / 436 (5.28%)
    25 / 143 (17.48%)
    44 / 293 (15.02%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    3 / 3 (100.00%)
    3 / 98 (3.06%)
    3 / 34 (8.82%)
    0 / 64 (0.00%)
         occurrences all number
    4
    5
    5
    30
    40
    64
    1
    0
    5
    3
    3
    0
    Photosensitivity reaction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    9 / 40 (22.50%)
    3 / 436 (0.69%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    10
    3
    0
    0
    0
    0
    0
    0
    0
    0
    Pruritus
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 18 (11.11%)
    4 / 40 (10.00%)
    8 / 436 (1.83%)
    6 / 143 (4.20%)
    19 / 293 (6.48%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    1 / 34 (2.94%)
    7 / 64 (10.94%)
         occurrences all number
    0
    2
    4
    9
    6
    24
    0
    0
    0
    3
    1
    7
    Rash
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 18 (0.00%)
    13 / 40 (32.50%)
    15 / 436 (3.44%)
    0 / 143 (0.00%)
    23 / 293 (7.85%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    0 / 34 (0.00%)
    28 / 64 (43.75%)
         occurrences all number
    2
    0
    17
    16
    0
    28
    0
    0
    0
    3
    0
    32
    Rash erythematous
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    2 / 436 (0.46%)
    0 / 143 (0.00%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    4
    2
    0
    3
    0
    0
    0
    0
    0
    0
    Rash macular
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Skin disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Skin fissures
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    6 / 40 (15.00%)
    3 / 436 (0.69%)
    0 / 143 (0.00%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    10
    3
    0
    2
    0
    0
    0
    0
    1
    1
    Skin toxicity
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    3 / 40 (7.50%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    3 / 293 (1.02%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    4
    0
    0
    4
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Dysuria
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    9 / 436 (2.06%)
    1 / 143 (0.70%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    1
    1
    0
    9
    1
    2
    0
    0
    0
    4
    0
    2
    Proteinuria
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    17 / 436 (3.90%)
    4 / 143 (2.80%)
    17 / 293 (5.80%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    2 / 34 (5.88%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    19
    5
    25
    0
    0
    0
    1
    4
    1
    Endocrine disorders
    Hyperthyroidism
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    15 / 293 (5.12%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    1
    0
    0
    1
    0
    16
    0
    0
    0
    0
    0
    2
    Hypothyroidism
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    2 / 436 (0.46%)
    1 / 143 (0.70%)
    24 / 293 (8.19%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    1
    0
    0
    2
    1
    32
    0
    0
    0
    0
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 18 (16.67%)
    17 / 40 (42.50%)
    10 / 436 (2.29%)
    6 / 143 (4.20%)
    44 / 293 (15.02%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    3 / 34 (8.82%)
    7 / 64 (10.94%)
         occurrences all number
    6
    4
    29
    11
    7
    53
    1
    0
    0
    1
    4
    7
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 58 (10.34%)
    2 / 18 (11.11%)
    5 / 40 (12.50%)
    13 / 436 (2.98%)
    9 / 143 (6.29%)
    22 / 293 (7.51%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    3 / 34 (8.82%)
    5 / 64 (7.81%)
         occurrences all number
    6
    2
    5
    14
    9
    32
    0
    0
    0
    3
    3
    5
    Bone pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    3 / 436 (0.69%)
    0 / 143 (0.00%)
    7 / 293 (2.39%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    7
    0
    0
    0
    0
    0
    0
    Muscle spasms
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    9 / 436 (2.06%)
    0 / 143 (0.00%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    1
    0
    2
    9
    0
    5
    0
    0
    1
    0
    0
    1
    Muscle tightness
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal chest pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    4 / 436 (0.92%)
    2 / 143 (1.40%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    2
    5
    2
    6
    0
    0
    0
    0
    0
    0
    Musculoskeletal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    4 / 436 (0.92%)
    4 / 143 (2.80%)
    14 / 293 (4.78%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    4 / 98 (4.08%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    1
    4
    4
    15
    0
    0
    0
    4
    1
    0
    Myalgia
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 18 (5.56%)
    6 / 40 (15.00%)
    8 / 436 (1.83%)
    3 / 143 (2.10%)
    15 / 293 (5.12%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    5 / 98 (5.10%)
    2 / 34 (5.88%)
    5 / 64 (7.81%)
         occurrences all number
    4
    1
    8
    12
    3
    17
    0
    0
    0
    9
    3
    5
    Pain in extremity
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    7 / 40 (17.50%)
    15 / 436 (3.44%)
    8 / 143 (5.59%)
    13 / 293 (4.44%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    2 / 34 (5.88%)
    5 / 64 (7.81%)
         occurrences all number
    1
    0
    10
    19
    9
    18
    0
    0
    0
    3
    2
    6
    Infections and infestations
    Bronchitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    3 / 436 (0.69%)
    3 / 143 (2.10%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    2
    0
    3
    3
    5
    0
    0
    0
    0
    0
    0
    Conjunctivitis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 18 (5.56%)
    3 / 40 (7.50%)
    4 / 436 (0.92%)
    2 / 143 (1.40%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    3
    4
    2
    6
    0
    0
    0
    0
    1
    1
    Eye infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Folliculitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    6 / 40 (15.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    8
    0
    1
    3
    0
    0
    0
    0
    0
    0
    Gastroenteritis viral
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    15 / 436 (3.44%)
    10 / 143 (6.99%)
    15 / 293 (5.12%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    3 / 98 (3.06%)
    1 / 34 (2.94%)
    3 / 64 (4.69%)
         occurrences all number
    1
    1
    1
    17
    12
    20
    0
    0
    1
    3
    1
    4
    Onychomycosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 18 (11.11%)
    0 / 40 (0.00%)
    2 / 436 (0.46%)
    2 / 143 (1.40%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    2
    0
    2
    2
    4
    0
    0
    0
    0
    0
    0
    Oral herpes
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    4 / 436 (0.92%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    1 / 34 (2.94%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    1
    4
    0
    0
    0
    0
    0
    0
    1
    0
    Paronychia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    5 / 40 (12.50%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    1 / 293 (0.34%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    1
    0
    13
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Rash pustular
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    0
    0
    0
    0
    0
    3
    Rhinitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    0 / 40 (0.00%)
    15 / 436 (3.44%)
    3 / 143 (2.10%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    3 / 34 (8.82%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    0
    15
    3
    5
    0
    0
    0
    2
    3
    1
    Tracheitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    1 / 143 (0.70%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 18 (11.11%)
    3 / 40 (7.50%)
    12 / 436 (2.75%)
    2 / 143 (1.40%)
    12 / 293 (4.10%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    4 / 98 (4.08%)
    3 / 34 (8.82%)
    5 / 64 (7.81%)
         occurrences all number
    0
    2
    4
    13
    2
    20
    0
    0
    0
    5
    3
    2
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 18 (5.56%)
    1 / 40 (2.50%)
    21 / 436 (4.82%)
    4 / 143 (2.80%)
    11 / 293 (3.75%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    3 / 98 (3.06%)
    1 / 34 (2.94%)
    7 / 64 (10.94%)
         occurrences all number
    1
    1
    1
    25
    4
    13
    0
    0
    0
    3
    1
    10
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 58 (13.79%)
    0 / 18 (0.00%)
    8 / 40 (20.00%)
    64 / 436 (14.68%)
    15 / 143 (10.49%)
    22 / 293 (7.51%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    14 / 98 (14.29%)
    1 / 34 (2.94%)
    10 / 64 (15.63%)
         occurrences all number
    9
    0
    10
    84
    16
    24
    1
    0
    0
    17
    1
    11
    Food craving
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    0 / 436 (0.00%)
    0 / 143 (0.00%)
    0 / 293 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Hyperglycaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    1 / 40 (2.50%)
    22 / 436 (5.05%)
    2 / 143 (1.40%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    5 / 98 (5.10%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    0
    1
    29
    5
    6
    0
    0
    0
    7
    0
    1
    Hypoalbuminaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    0 / 40 (0.00%)
    9 / 436 (2.06%)
    2 / 143 (1.40%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 98 (0.00%)
    0 / 34 (0.00%)
    1 / 64 (1.56%)
         occurrences all number
    0
    1
    0
    9
    4
    2
    0
    0
    0
    0
    0
    1
    Hypocalcaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 18 (5.56%)
    2 / 40 (5.00%)
    12 / 436 (2.75%)
    6 / 143 (4.20%)
    5 / 293 (1.71%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    2 / 64 (3.13%)
         occurrences all number
    0
    1
    3
    16
    10
    10
    0
    0
    0
    1
    0
    2
    Hypokalaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 58 (12.07%)
    1 / 18 (5.56%)
    3 / 40 (7.50%)
    34 / 436 (7.80%)
    9 / 143 (6.29%)
    6 / 293 (2.05%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    2 / 98 (2.04%)
    1 / 34 (2.94%)
    4 / 64 (6.25%)
         occurrences all number
    8
    1
    6
    43
    10
    7
    0
    0
    1
    2
    1
    4
    Hypomagnesaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 18 (0.00%)
    6 / 40 (15.00%)
    1 / 436 (0.23%)
    0 / 143 (0.00%)
    4 / 293 (1.37%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 98 (1.02%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    2
    0
    6
    1
    0
    4
    0
    0
    0
    1
    0
    0
    Hypophosphataemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 18 (0.00%)
    2 / 40 (5.00%)
    4 / 436 (0.92%)
    3 / 143 (2.10%)
    2 / 293 (0.68%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    2 / 98 (2.04%)
    0 / 34 (0.00%)
    0 / 64 (0.00%)
         occurrences all number
    0
    0
    2
    4
    3
    2
    0
    0
    0
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2015
    Changes include the replacement of terms “MPDL3280A” and “MPDL3280A (anti-PD-L1 antibody)” with “atezolizumab” (international, non-proprietary name); revision of study eligibility criteria to allow patients with cerebellar metastases, exclude patients with progression of CNS disease between last CNS-directed therapy and study baseline prior to baseline, exclude patients requiring steroid therapy for CNS disease; revision of Cohort 2 eligibility criteria to exclude patients continuing RANKL inhibitor therapy; clarifications and updates on drug products; updates to address any safety concerns or knowledge gaps; and other minor details.
    11 Apr 2016
    Changes include increasing the Cohort 2 target sample size from 330 to 405 patients to increase statistical power for Cohort 2 analyses and accommodate rapid accrual into Cohort 2. As a result of this change, the estimated duration of the study for Cohort 2 was increased from 17 to 22 months and the estimated overall study accrual was increased from 610 to 700 patients.
    24 Nov 2016
    Changes include Cohort 2 closure due to completion of accrual; incorporation of two new cohorts (Cohort 3: capecitabine/trastuzumab/pertuzumab vs fluoropyrimidine/bevacizumab in HER2+ patients; Cohort 4: cobimetinib/atezolizumab vs fluoropyrimidine/bevacizumab in HER2-/MSI-H; HER2-/MSS/BRAFwt or HER2-/MSS/BRAFmut/RASmut patients); adaptation of cohort assignment decision tree and study length estimates to accommodate new cohorts and Cohort 2 closure; removal of co-primary endpoint “early efficacy during the Maintenance Treatment Phase” based on advisory committees’ advice (PFS remains as single primary efficacy endpoint); optional stool sample collection added to address a new exploratory microbiome biomarker evaluation objective; preliminary assessments of efficacy in each cohort removed based on advisory committees’ advice; maximum allowable 5-FU dosing in Cohort 1 increased to 2,400 mg/m2 based on completion of safety run-in review by the iDMC; local ablation for liver metastases now allowed during the induction treatment phase; second-line treatment for BRAFmut early progressors modified to 5-FU/vemurafenib/cetuximab for BRAFmut/MSS patients and FP/bevacizumab/atezolizumab for BRAFmut/MSI-H patients; updates to cohort-specific exclusion criteria, safety monitoring, and treatment management based on current safety data. Country specific protocols versions introduced for Spain and France due to jurisdictional requirements for safety monitoring and for Egypt and the UK where Cohorts 3 and 4 were not opened (study enrolment closed in Egypt and UK).
    08 Aug 2018
    In accordance with independent Data Monitoring Committee recommendations following review of safety data, accrual into Cohort 4 was closed.
    19 Dec 2019
    Enrolment into study was closed. Cohort 4 (now closed due to iDMC recommendations) had broad biomarker eligibility criteria and was introduced to replace Cohort 2 (previously closed due to completion of accrual). No new or modified cohorts with broad eligibility criteria suitable for addition to protocol MO29112 were identified. Without a broad eligibility cohort to replace Cohort 4, the majority of patients eligible for study entry would not be eligible for any maintenance cohort assignment upon completion of study induction treatment. For this reason, the Sponsor decided to permanently discontinue enrolment.
    18 Feb 2020
    Changes include updates to safety information and treatment management for patients receiving atezolizumab; update to responsible Medical Monitor. Not Available - Will be provided at the time of final results disclosure.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Feb 2018
    Following the iDMC review of cohort 4 data a temporary recruitment halt to the whole study and a temporary halt to randomisation into cohort 4 was undertaken.
    -

    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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