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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
    24 Mar 2021

    Results information
    Results version number
    		 v2
    This version publication date
    19 Mar 2022
    First version publication date
    12 Jun 2020
    Other versions
    		 v1 , v3
    Version creation reason

    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
    Final
    Date of interim/final analysis
    24 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Mar 2021
    Was the trial ended prematurely?
    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: 25
    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: 54
    Country: Number of subjects enrolled
    Germany: 94
    Country: Number of subjects enrolled
    Greece: 36
    Country: Number of subjects enrolled
    Italy: 95
    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: 25
    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: 62
    Worldwide total number of subjects
    620
    EEA total number of subjects
    417
    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)
    370
    From 65 to 84 years
    248
    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
    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.

    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

    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
    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.

    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

    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
    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.

    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

    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
    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.

    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

    Arm title
    		 Early Progressing BRAFmut Cohort
    Arm description
    		 BRAFmut participants experiencing early disease progression during induction treatment
    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
    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.

    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

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3 Cohort 4 Early Progressing BRAFmut Cohort
    Started
    60
    445
    5
    99
    11
    Completed
    58
    436
    5
    98
    11
    Not completed
    2
    9
    0
    1
    0
         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
    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.

    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

    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
    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.

    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

    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
    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

    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

    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
    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

    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

    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
    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.

    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

    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
    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

    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

    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
    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.

    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

    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
    -
    -
    -
    -
    Period 3
    Period 3 title
    Early Disease Progression
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Early Progressing BRAFmut Cohort
    Arm description
    		 BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumour is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumour is MSI-H.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Fluoropyrimidine (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
    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.

    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
    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

    Number of subjects in period 3
    		Early Progressing BRAFmut Cohort
    Started
    11
    Completed
    1
    Not completed
    10
         Adverse event, serious fatal
    9
         Lost to follow-up
    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 title
    Early Progressing BRAFmut Cohort
    Reporting group description
    		 BRAFmut participants experiencing early disease progression during induction treatment

    Reporting group values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Early Progressing BRAFmut Cohort Total
    Number of subjects
    		 60 445 5 99 11 620
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 39 254 5 66 6 370
        From 65-84 years
    		 21 189 0 33 5 248
        85 years and over
    		 0 2 0 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 60.0 ± 17.8 -
    Sex: Female, Male
    Units:
        Female
    		 34 174 3 41 6 258
        Male
    		 26 271 2 58 5 362

    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
    Early Progressing BRAFmut Cohort
    Reporting group description
    		 BRAFmut participants experiencing early disease progression during induction treatment
    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.
    Reporting group title
    Early Progressing BRAFmut Cohort
    Reporting group description
    		 BRAFmut participants experiencing early disease progression during induction treatment will have the option of proceeding immediately to receive second-line treatment with 5-FU/LV, cetuximab and vemurafenib if their primary tumour is MSS, or with a fluoropyrimidine (5-FU/LV or capecitabine), bevacizumab, and atezolizumab if their primary tumour is MSI-H.

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    PFS is defined as the time from randomization to the first occurrence of disease progression according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
    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
    OS is defined as the time from randomization into the MTP to time of death from any cause.
    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 Early Progressing BRAFmut Cohort 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
    11
    20
    297
    148
    0 [1]
    0 [2]
    65
    34
    Units: months
        median (confidence interval 95%)
    24.02 (16.07 to 34.00)
    10.51 (4.83 to 19.78)
    21.73 (7.92 to 37.19)
    22.54 (20.04 to 26.87)
    22.24 (18.50 to 25.13)
    ( to )
    ( to )
    22.60 (14.23 to 27.40)
    25.17 (15.90 to 32.59)
    Notes
    [1] - Both the Median and the 95% CI were not evaluable due to the low number of participants/events.
    [2] - Both the Median and the 95% CI were not evaluable due to the low number of participants/events.
    Statistical analysis title
    		 Cohort 1 (MP) vs Cohort 1 Control (MP)
    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
    		 = 0.276
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.32
    Statistical analysis title
    		 Cohort 4 (MP) vs. Cohort 4 (MP) 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
    		 = 0.415
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 2.14
    Statistical analysis title
    		 Cohort 2 (MP) vs Cohort 2 Control (MP)
    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
    		 = 0.076
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.02

    Secondary: Percentage of Participants with Adverse Events

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    End point title
    		 Percentage of Participants with Adverse Events [3]
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline until end of study (up to 5 years)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Results for all arms have been provided. Due to registry limitations and study complexity, the setup of the Early Progressing BRAFmut arm (which is not part of either the Induction or Maintenance phase) is generating this validation error.
    End point values
    		 Cohort 1 Cohort 1: 5-FU/LV,cetuximab,vemurafenib Early Progressing BRAFmut Cohort 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
    60
    40
    11
    445
    18
    5
    297
    98
    148
    3
    2
    64
    34
    Units: percentage of participants
        number (not applicable)
    100
    100
    90.9
    95.7
    94.4
    100
    95.6
    98.0
    88.1
    100
    100
    98.4
    88.2
    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. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. OR= CR + PR.
    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 Early Progressing BRAFmut Cohort 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
    11
    20
    297
    148
    3
    2
    65
    34
    Units: participants
    20
    2
    5
    49
    22
    1
    0
    7
    8
    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
    Statistical analysis title
    		 Cohort 4 (MP) vs. Cohort 4 (MP) 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
    		 = 0.093
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Disease Control Rate

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    End point title
    		 Disease Control Rate
    End point description
    DCR is defined as the percentage of participants with CR, PR, or stable disease (SD) at 16 weeks. Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions.
    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 Early Progressing BRAFmut Cohort 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
    11
    20
    297
    148
    3
    2
    65
    34
    Units: participants
    36
    9
    15
    227
    111
    1
    0
    44
    26
    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
    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
    		 = 0.362
    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. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
    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 [4]
    0 [5]
    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
    [4] - Target number of patients not enrolled and the target number of PFS events could not be reached
    [5] - 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. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
    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 [6]
    0 [7]
    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
    [6] - Target number of patients not enrolled and the target number of PFS events could not be reached
    [7] - Target number of patients not enrolled and the target number of PFS events could not be reached
    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
    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

    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 [8]
    0 [9]
    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
    [8] - Target number of patients not enrolled and the target number of PFS events could not be reached
    [9] - Target number of patients not enrolled and the target number of PFS events could not be reached
    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
    23.1
    Reporting groups
    Reporting group title
    Cohort 1 (MP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 (IP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 (MP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 Control (MP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 2 (IP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 1 Control (MP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 3 (IP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 3 (MP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 3 Control (MP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 4 (IP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 4 (MP)
    Reporting group description
    		 -

    Reporting group title
    Cohort 4 Control (MP)
    Reporting group description
    		 -

    Reporting group title
    Early Progressing BRAFmut Cohort
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort 1 (MP) Cohort 1 (IP) Cohort 2 (MP) Cohort 2 Control (MP) Cohort 2 (IP) Cohort 1 Control (MP) Cohort 3 (IP) Cohort 3 (MP) Cohort 3 Control (MP) Cohort 4 (IP) Cohort 4 (MP) Cohort 4 Control (MP) Early Progressing BRAFmut Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 40 (37.50%)
    13 / 58 (22.41%)
    76 / 293 (25.94%)
    20 / 143 (13.99%)
    59 / 436 (13.53%)
    5 / 18 (27.78%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    11 / 98 (11.22%)
    26 / 64 (40.63%)
    3 / 34 (8.82%)
    3 / 11 (27.27%)
         number of deaths (all causes)
    0
    0
    5
    1
    6
    0
    0
    0
    0
    4
    4
    0
    1
         number of deaths resulting from adverse events
    0
    0
    2
    1
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Second primary malignancy
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Tumour perforation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 293 (1.02%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Surgical and medical procedures
    Ureteral stent removal
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    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
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    1 / 1
    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
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    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
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Implant site dehiscence
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Implant site thrombosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    6 / 293 (2.05%)
    0 / 143 (0.00%)
    5 / 436 (1.15%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 6
    0 / 0
    3 / 6
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    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
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (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
    2 / 2
    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
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    2 / 2
    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
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    3 / 64 (4.69%)
    0 / 34 (0.00%)
    0 / 11 (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
    3 / 3
    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
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic ulcer
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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 / 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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences 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
    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
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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 / 1
    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
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences 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
    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
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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 / 1
    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
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
    0 / 0
    4 / 4
    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
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    6 / 436 (1.38%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    9 / 9
    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
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 1
    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
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 293 (1.02%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 5
    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
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    5 / 293 (1.71%)
    2 / 143 (1.40%)
    3 / 436 (0.69%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 5
    1 / 2
    2 / 3
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    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
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    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
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    1 / 1
    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
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 4
    0 / 0
    4 / 4
    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
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hepatorenal failure
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (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 / 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 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (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 / 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 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Abdominal infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    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
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Gingivitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    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
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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 / 1
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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 / 1
    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
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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 / 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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 293 (1.02%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    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 / 1
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    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
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 2
         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
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    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
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    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
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (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
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 (MP) Cohort 1 (IP) Cohort 2 (MP) Cohort 2 Control (MP) Cohort 2 (IP) Cohort 1 Control (MP) Cohort 3 (IP) Cohort 3 (MP) Cohort 3 Control (MP) Cohort 4 (IP) Cohort 4 (MP) Cohort 4 Control (MP) Early Progressing BRAFmut Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 40 (100.00%)
    58 / 58 (100.00%)
    270 / 293 (92.15%)
    120 / 143 (83.92%)
    417 / 436 (95.64%)
    17 / 18 (94.44%)
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    2 / 2 (100.00%)
    96 / 98 (97.96%)
    61 / 64 (95.31%)
    29 / 34 (85.29%)
    11 / 11 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Cancer pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    1
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 40 (2.50%)
    9 / 58 (15.52%)
    49 / 293 (16.72%)
    15 / 143 (10.49%)
    90 / 436 (20.64%)
    1 / 18 (5.56%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    19 / 98 (19.39%)
    3 / 64 (4.69%)
    5 / 34 (14.71%)
    1 / 11 (9.09%)
         occurrences all number
    1
    11
    70
    19
    119
    1
    1
    0
    0
    27
    4
    7
    1
    Hypotension
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 58 (3.45%)
    3 / 293 (1.02%)
    1 / 143 (0.70%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    3 / 64 (4.69%)
    0 / 34 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    4
    2
    3
    1
    4
    0
    0
    0
    0
    0
    3
    0
    2
    Phlebitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    5 / 436 (1.15%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    0
    0
    5
    0
    0
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 40 (12.50%)
    11 / 58 (18.97%)
    40 / 293 (13.65%)
    12 / 143 (8.39%)
    73 / 436 (16.74%)
    1 / 18 (5.56%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    15 / 98 (15.31%)
    13 / 64 (20.31%)
    3 / 34 (8.82%)
    1 / 11 (9.09%)
         occurrences all number
    9
    12
    58
    20
    109
    2
    1
    0
    0
    28
    18
    3
    1
    Face oedema
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    5 / 64 (7.81%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    3
    0
    2
    0
    0
    0
    0
    0
    5
    0
    0
    Fatigue
         subjects affected / exposed
    9 / 40 (22.50%)
    17 / 58 (29.31%)
    52 / 293 (17.75%)
    23 / 143 (16.08%)
    134 / 436 (30.73%)
    2 / 18 (11.11%)
    3 / 5 (60.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    34 / 98 (34.69%)
    12 / 64 (18.75%)
    7 / 34 (20.59%)
    3 / 11 (27.27%)
         occurrences all number
    11
    28
    77
    27
    205
    2
    4
    1
    0
    49
    20
    8
    3
    Influenza like illness
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    9 / 293 (3.07%)
    3 / 143 (2.10%)
    9 / 436 (2.06%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    1 / 64 (1.56%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    2
    2
    10
    3
    9
    0
    0
    0
    0
    2
    1
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    7 / 40 (17.50%)
    5 / 58 (8.62%)
    20 / 293 (6.83%)
    7 / 143 (4.90%)
    31 / 436 (7.11%)
    2 / 18 (11.11%)
    2 / 5 (40.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    15 / 98 (15.31%)
    4 / 64 (6.25%)
    1 / 34 (2.94%)
    2 / 11 (18.18%)
         occurrences all number
    8
    6
    26
    9
    34
    4
    2
    1
    0
    19
    5
    1
    3
    Oedema peripheral
         subjects affected / exposed
    3 / 40 (7.50%)
    3 / 58 (5.17%)
    8 / 293 (2.73%)
    2 / 143 (1.40%)
    6 / 436 (1.38%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    6 / 64 (9.38%)
    1 / 34 (2.94%)
    2 / 11 (18.18%)
         occurrences all number
    6
    3
    8
    2
    6
    0
    0
    0
    0
    1
    8
    1
    3
    Pain
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    1 / 143 (0.70%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    4
    1
    4
    0
    0
    1
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    8 / 40 (20.00%)
    8 / 58 (13.79%)
    32 / 293 (10.92%)
    13 / 143 (9.09%)
    43 / 436 (9.86%)
    1 / 18 (5.56%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    11 / 98 (11.22%)
    20 / 64 (31.25%)
    3 / 34 (8.82%)
    0 / 11 (0.00%)
         occurrences all number
    8
    9
    52
    14
    53
    1
    1
    0
    0
    13
    27
    3
    0
    Catheter site pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    2
    0
    0
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    1
    Malaise
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    5 / 293 (1.71%)
    1 / 143 (0.70%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    5
    1
    1
    0
    0
    1
    0
    1
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    1 / 143 (0.70%)
    10 / 436 (2.29%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    2
    1
    10
    0
    0
    0
    0
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    5 / 40 (12.50%)
    3 / 58 (5.17%)
    30 / 293 (10.24%)
    9 / 143 (6.29%)
    31 / 436 (7.11%)
    3 / 18 (16.67%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    6 / 98 (6.12%)
    7 / 64 (10.94%)
    3 / 34 (8.82%)
    0 / 11 (0.00%)
         occurrences all number
    6
    3
    39
    11
    33
    3
    1
    0
    0
    6
    7
    3
    0
    Dysphonia
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 58 (6.90%)
    15 / 293 (5.12%)
    3 / 143 (2.10%)
    25 / 436 (5.73%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    4 / 98 (4.08%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    4
    18
    3
    35
    1
    0
    0
    0
    4
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 58 (5.17%)
    12 / 293 (4.10%)
    3 / 143 (2.10%)
    17 / 436 (3.90%)
    2 / 18 (11.11%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    5 / 98 (5.10%)
    2 / 64 (3.13%)
    1 / 34 (2.94%)
    2 / 11 (18.18%)
         occurrences all number
    2
    3
    12
    3
    18
    2
    0
    1
    0
    5
    2
    1
    3
    Epistaxis
         subjects affected / exposed
    4 / 40 (10.00%)
    7 / 58 (12.07%)
    23 / 293 (7.85%)
    16 / 143 (11.19%)
    68 / 436 (15.60%)
    1 / 18 (5.56%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    2 / 2 (100.00%)
    18 / 98 (18.37%)
    6 / 64 (9.38%)
    3 / 34 (8.82%)
    3 / 11 (27.27%)
         occurrences all number
    4
    9
    29
    20
    74
    1
    1
    0
    2
    19
    6
    4
    3
    Hiccups
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    12 / 436 (2.75%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    4 / 98 (4.08%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    17
    1
    0
    0
    0
    4
    0
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    2
    0
    1
    1
    0
    0
    0
    0
    0
    1
    1
    Nasal ulcer
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 58 (5.17%)
    3 / 293 (1.02%)
    1 / 143 (0.70%)
    9 / 436 (2.06%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    2
    3
    3
    1
    9
    1
    0
    0
    0
    1
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    6 / 293 (2.05%)
    3 / 143 (2.10%)
    12 / 436 (2.75%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    9
    4
    14
    0
    0
    1
    0
    1
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 58 (6.90%)
    4 / 293 (1.37%)
    1 / 143 (0.70%)
    10 / 436 (2.29%)
    1 / 18 (5.56%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    5 / 98 (5.10%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    4
    4
    1
    10
    1
    1
    0
    0
    5
    1
    0
    0
    Insomnia
         subjects affected / exposed
    2 / 40 (5.00%)
    7 / 58 (12.07%)
    10 / 293 (3.41%)
    3 / 143 (2.10%)
    19 / 436 (4.36%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    3 / 64 (4.69%)
    0 / 34 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    7
    10
    3
    20
    1
    0
    0
    0
    3
    3
    0
    2
    Depression
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    3 / 293 (1.02%)
    5 / 143 (3.50%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    3
    5
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 58 (5.17%)
    8 / 293 (2.73%)
    6 / 143 (4.20%)
    19 / 436 (4.36%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    12 / 64 (18.75%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    4
    14
    9
    25
    0
    0
    0
    0
    2
    13
    0
    0
    Amylase increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    4 / 64 (6.25%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    0
    0
    0
    1
    4
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 58 (6.90%)
    10 / 293 (3.41%)
    6 / 143 (4.20%)
    16 / 436 (3.67%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    15 / 64 (23.44%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    6
    13
    7
    19
    1
    0
    0
    0
    2
    15
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    5 / 293 (1.71%)
    4 / 143 (2.80%)
    7 / 436 (1.61%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    6 / 64 (9.38%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    2
    5
    5
    7
    0
    0
    0
    0
    2
    6
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    8 / 293 (2.73%)
    5 / 143 (3.50%)
    5 / 436 (1.15%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    1
    10
    6
    5
    1
    0
    0
    0
    0
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    31 / 64 (48.44%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    39
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    1 / 143 (0.70%)
    7 / 436 (1.61%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    6
    0
    4
    4
    8
    0
    0
    0
    0
    1
    1
    0
    1
    Ejection fraction decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    5 / 64 (7.81%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    1
    6
    0
    0
    Lipase increased
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    5 / 64 (7.81%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    3
    0
    3
    0
    0
    0
    0
    0
    0
    2
    7
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 40 (2.50%)
    10 / 58 (17.24%)
    7 / 293 (2.39%)
    3 / 143 (2.10%)
    46 / 436 (10.55%)
    0 / 18 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    9 / 98 (9.18%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    12
    11
    4
    68
    0
    2
    0
    0
    15
    2
    0
    1
    Platelet count decreased
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 58 (3.45%)
    6 / 293 (2.05%)
    3 / 143 (2.10%)
    23 / 436 (5.28%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    11 / 98 (11.22%)
    6 / 64 (9.38%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    1
    3
    19
    4
    35
    0
    0
    0
    0
    13
    7
    1
    0
    Weight decreased
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 58 (5.17%)
    11 / 293 (3.75%)
    2 / 143 (1.40%)
    33 / 436 (7.57%)
    2 / 18 (11.11%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    4 / 98 (4.08%)
    6 / 64 (9.38%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    3
    12
    3
    34
    2
    0
    0
    0
    4
    6
    0
    0
    Weight increased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    1 / 143 (0.70%)
    7 / 436 (1.61%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    3 / 64 (4.69%)
    2 / 34 (5.88%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    3
    1
    7
    0
    0
    0
    0
    3
    7
    2
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    9 / 436 (2.06%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    1
    14
    0
    0
    1
    0
    1
    4
    0
    0
    Body temperature increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    3 / 293 (1.02%)
    1 / 143 (0.70%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    3
    1
    3
    0
    0
    0
    0
    0
    0
    0
    1
    Cardiac murmur
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    10 / 293 (3.41%)
    0 / 143 (0.00%)
    6 / 436 (1.38%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    6 / 98 (6.12%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    2
    12
    0
    11
    0
    0
    0
    0
    11
    2
    0
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Sunburn
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    3
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 58 (5.17%)
    6 / 293 (2.05%)
    1 / 143 (0.70%)
    15 / 436 (3.44%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    4 / 98 (4.08%)
    4 / 64 (6.25%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    4
    5
    7
    1
    17
    2
    0
    0
    0
    4
    4
    1
    0
    Dysgeusia
         subjects affected / exposed
    4 / 40 (10.00%)
    6 / 58 (10.34%)
    8 / 293 (2.73%)
    3 / 143 (2.10%)
    30 / 436 (6.88%)
    0 / 18 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    6 / 98 (6.12%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    4
    6
    8
    3
    39
    0
    1
    0
    0
    7
    0
    0
    1
    Headache
         subjects affected / exposed
    2 / 40 (5.00%)
    4 / 58 (6.90%)
    24 / 293 (8.19%)
    5 / 143 (3.50%)
    39 / 436 (8.94%)
    0 / 18 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    14 / 98 (14.29%)
    6 / 64 (9.38%)
    3 / 34 (8.82%)
    0 / 11 (0.00%)
         occurrences all number
    2
    4
    83
    15
    71
    0
    1
    0
    0
    24
    8
    5
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 40 (2.50%)
    7 / 58 (12.07%)
    18 / 293 (6.14%)
    9 / 143 (6.29%)
    68 / 436 (15.60%)
    0 / 18 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    18 / 98 (18.37%)
    1 / 64 (1.56%)
    5 / 34 (14.71%)
    0 / 11 (0.00%)
         occurrences all number
    1
    8
    21
    9
    96
    0
    2
    0
    0
    25
    2
    5
    0
    Neurotoxicity
         subjects affected / exposed
    3 / 40 (7.50%)
    4 / 58 (6.90%)
    2 / 293 (0.68%)
    2 / 143 (1.40%)
    14 / 436 (3.21%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    8 / 98 (8.16%)
    3 / 64 (4.69%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    3
    7
    3
    3
    20
    0
    0
    0
    0
    16
    3
    1
    0
    Paraesthesia
         subjects affected / exposed
    4 / 40 (10.00%)
    12 / 58 (20.69%)
    18 / 293 (6.14%)
    10 / 143 (6.99%)
    63 / 436 (14.45%)
    0 / 18 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    14 / 98 (14.29%)
    1 / 64 (1.56%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    4
    17
    21
    11
    75
    0
    2
    0
    0
    17
    1
    1
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    3 / 293 (1.02%)
    0 / 143 (0.00%)
    5 / 436 (1.15%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    5 / 98 (5.10%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    2
    3
    0
    5
    0
    0
    0
    0
    5
    1
    0
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 40 (10.00%)
    14 / 58 (24.14%)
    32 / 293 (10.92%)
    15 / 143 (10.49%)
    153 / 436 (35.09%)
    1 / 18 (5.56%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    28 / 98 (28.57%)
    3 / 64 (4.69%)
    4 / 34 (11.76%)
    0 / 11 (0.00%)
         occurrences all number
    5
    19
    38
    16
    233
    1
    3
    0
    0
    42
    6
    4
    0
    Polyneuropathy
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    6 / 293 (2.05%)
    1 / 143 (0.70%)
    16 / 436 (3.67%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    6
    2
    18
    1
    0
    0
    0
    1
    0
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Sensory loss
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    5
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Taste disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    3 / 58 (5.17%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    9 / 436 (2.06%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    3
    1
    1
    9
    0
    0
    0
    0
    1
    0
    0
    1
    Ageusia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    3
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 40 (17.50%)
    9 / 58 (15.52%)
    21 / 293 (7.17%)
    8 / 143 (5.59%)
    35 / 436 (8.03%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    10 / 98 (10.20%)
    8 / 64 (12.50%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    10
    11
    27
    13
    42
    2
    0
    0
    0
    11
    10
    1
    1
    Leukopenia
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 58 (6.90%)
    4 / 293 (1.37%)
    3 / 143 (2.10%)
    24 / 436 (5.50%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    1
    4
    8
    3
    32
    0
    0
    0
    0
    3
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    2 / 40 (5.00%)
    15 / 58 (25.86%)
    12 / 293 (4.10%)
    8 / 143 (5.59%)
    97 / 436 (22.25%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    25 / 98 (25.51%)
    7 / 64 (10.94%)
    3 / 34 (8.82%)
    0 / 11 (0.00%)
         occurrences all number
    2
    19
    12
    17
    151
    1
    0
    0
    0
    40
    9
    4
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 40 (0.00%)
    4 / 58 (6.90%)
    10 / 293 (3.41%)
    4 / 143 (2.80%)
    27 / 436 (6.19%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    6 / 98 (6.12%)
    4 / 64 (6.25%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    0
    5
    12
    10
    35
    0
    0
    0
    0
    8
    4
    5
    0
    Ear and labyrinth disorders
    Auditory meatus external erosion
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    3 / 64 (4.69%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    5
    0
    3
    0
    1
    0
    0
    0
    0
    1
    3
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    5 / 143 (3.50%)
    6 / 436 (1.38%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    5
    5
    6
    1
    0
    0
    0
    2
    0
    0
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 58 (3.45%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    1 / 293 (0.34%)
    2 / 143 (1.40%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    2
    1
    0
    0
    0
    0
    1
    0
    1
    1
    Visual impairment
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    2
    0
    3
    0
    0
    1
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 40 (20.00%)
    9 / 58 (15.52%)
    39 / 293 (13.31%)
    12 / 143 (8.39%)
    53 / 436 (12.16%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    11 / 98 (11.22%)
    12 / 64 (18.75%)
    5 / 34 (14.71%)
    4 / 11 (36.36%)
         occurrences all number
    10
    10
    44
    15
    66
    1
    0
    0
    0
    13
    15
    5
    5
    Abdominal pain upper
         subjects affected / exposed
    2 / 40 (5.00%)
    7 / 58 (12.07%)
    18 / 293 (6.14%)
    11 / 143 (7.69%)
    20 / 436 (4.59%)
    3 / 18 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    5 / 64 (7.81%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    2
    8
    22
    15
    23
    3
    0
    0
    0
    3
    6
    1
    0
    Angular cheilitis
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    2
    1
    0
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    5 / 40 (12.50%)
    9 / 58 (15.52%)
    38 / 293 (12.97%)
    17 / 143 (11.89%)
    82 / 436 (18.81%)
    0 / 18 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    20 / 98 (20.41%)
    7 / 64 (10.94%)
    2 / 34 (5.88%)
    1 / 11 (9.09%)
         occurrences all number
    6
    10
    48
    26
    106
    0
    1
    0
    1
    23
    9
    2
    1
    Dental cyst
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    16 / 40 (40.00%)
    26 / 58 (44.83%)
    78 / 293 (26.62%)
    21 / 143 (14.69%)
    158 / 436 (36.24%)
    4 / 18 (22.22%)
    2 / 5 (40.00%)
    2 / 3 (66.67%)
    0 / 2 (0.00%)
    33 / 98 (33.67%)
    40 / 64 (62.50%)
    8 / 34 (23.53%)
    5 / 11 (45.45%)
         occurrences all number
    43
    35
    120
    36
    266
    5
    2
    5
    0
    68
    87
    11
    5
    Dyspepsia
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 58 (5.17%)
    10 / 293 (3.41%)
    4 / 143 (2.80%)
    14 / 436 (3.21%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    8 / 98 (8.16%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    4
    12
    4
    17
    1
    0
    0
    0
    8
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 58 (3.45%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    11 / 436 (2.52%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    1 / 64 (1.56%)
    2 / 34 (5.88%)
    0 / 11 (0.00%)
         occurrences all number
    4
    3
    1
    1
    18
    0
    0
    0
    0
    1
    1
    2
    0
    Gingival bleeding
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    5 / 293 (1.71%)
    0 / 143 (0.00%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    5
    0
    3
    0
    0
    0
    1
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 40 (2.50%)
    4 / 58 (6.90%)
    5 / 293 (1.71%)
    1 / 143 (0.70%)
    11 / 436 (2.52%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    4
    5
    2
    12
    1
    0
    0
    0
    0
    2
    0
    0
    Nausea
         subjects affected / exposed
    16 / 40 (40.00%)
    30 / 58 (51.72%)
    64 / 293 (21.84%)
    27 / 143 (18.88%)
    177 / 436 (40.60%)
    0 / 18 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    43 / 98 (43.88%)
    17 / 64 (26.56%)
    6 / 34 (17.65%)
    3 / 11 (27.27%)
         occurrences all number
    23
    60
    134
    41
    297
    0
    1
    0
    0
    90
    22
    22
    4
    Palatal ulcer
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    6 / 293 (2.05%)
    4 / 143 (2.80%)
    8 / 436 (1.83%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    6
    6
    8
    1
    0
    0
    0
    0
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    5 / 40 (12.50%)
    14 / 58 (24.14%)
    35 / 293 (11.95%)
    11 / 143 (7.69%)
    82 / 436 (18.81%)
    3 / 18 (16.67%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    16 / 98 (16.33%)
    1 / 64 (1.56%)
    3 / 34 (8.82%)
    1 / 11 (9.09%)
         occurrences all number
    6
    19
    50
    19
    111
    3
    0
    0
    0
    21
    1
    3
    2
    Vomiting
         subjects affected / exposed
    8 / 40 (20.00%)
    14 / 58 (24.14%)
    39 / 293 (13.31%)
    8 / 143 (5.59%)
    82 / 436 (18.81%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    19 / 98 (19.39%)
    13 / 64 (20.31%)
    3 / 34 (8.82%)
    4 / 11 (36.36%)
         occurrences all number
    12
    18
    61
    11
    113
    1
    0
    0
    0
    32
    19
    9
    5
    Toothache
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    8 / 293 (2.73%)
    2 / 143 (1.40%)
    8 / 436 (1.83%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    8
    2
    8
    0
    0
    1
    0
    1
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    12 / 436 (2.75%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    3 / 64 (4.69%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    4
    0
    13
    0
    0
    0
    0
    1
    3
    0
    1
    Eructation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    6 / 293 (2.05%)
    1 / 143 (0.70%)
    11 / 436 (2.52%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    8
    1
    11
    0
    0
    0
    0
    0
    0
    0
    2
    Odynophagia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    0
    0
    1
    0
    0
    1
    Cheilitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Anal haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    5 / 436 (1.15%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    5
    0
    5
    0
    0
    0
    0
    0
    1
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    2 / 293 (0.68%)
    1 / 143 (0.70%)
    11 / 436 (2.52%)
    0 / 18 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    1
    15
    0
    1
    0
    0
    0
    0
    1
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 40 (2.50%)
    6 / 58 (10.34%)
    8 / 293 (2.73%)
    2 / 143 (1.40%)
    40 / 436 (9.17%)
    2 / 18 (11.11%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    6 / 98 (6.12%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    1
    6
    8
    2
    40
    2
    1
    0
    0
    6
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    3 / 293 (1.02%)
    1 / 143 (0.70%)
    1 / 436 (0.23%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    3
    1
    1
    1
    0
    0
    0
    0
    2
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    11 / 40 (27.50%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    18 / 64 (28.13%)
    2 / 34 (5.88%)
    1 / 11 (9.09%)
         occurrences all number
    13
    0
    4
    0
    5
    0
    0
    0
    0
    1
    20
    2
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    12 / 40 (30.00%)
    2 / 58 (3.45%)
    18 / 293 (6.14%)
    3 / 143 (2.10%)
    24 / 436 (5.50%)
    3 / 18 (16.67%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    6 / 64 (9.38%)
    1 / 34 (2.94%)
    3 / 11 (27.27%)
         occurrences all number
    16
    2
    21
    6
    24
    3
    0
    1
    0
    3
    6
    1
    3
    Eczema
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    2
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    8 / 40 (20.00%)
    0 / 58 (0.00%)
    11 / 293 (3.75%)
    2 / 143 (1.40%)
    7 / 436 (1.61%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    11
    0
    12
    2
    7
    4
    0
    0
    0
    0
    1
    0
    4
    Nail ridging
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    3 / 143 (2.10%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    3
    0
    1
    0
    1
    0
    0
    0
    0
    1
    Onychoclasis
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 40 (12.50%)
    3 / 58 (5.17%)
    44 / 293 (15.02%)
    25 / 143 (17.48%)
    23 / 436 (5.28%)
    4 / 18 (22.22%)
    1 / 5 (20.00%)
    3 / 3 (100.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    1 / 64 (1.56%)
    3 / 34 (8.82%)
    2 / 11 (18.18%)
         occurrences all number
    5
    4
    66
    40
    30
    5
    1
    6
    0
    3
    1
    3
    2
    Photosensitivity reaction
         subjects affected / exposed
    9 / 40 (22.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    10
    0
    0
    0
    3
    0
    0
    0
    0
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    5 / 40 (12.50%)
    0 / 58 (0.00%)
    20 / 293 (6.83%)
    6 / 143 (4.20%)
    8 / 436 (1.83%)
    2 / 18 (11.11%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    7 / 64 (10.94%)
    1 / 34 (2.94%)
    3 / 11 (27.27%)
         occurrences all number
    5
    0
    25
    6
    9
    2
    0
    0
    0
    3
    14
    1
    3
    Rash
         subjects affected / exposed
    13 / 40 (32.50%)
    2 / 58 (3.45%)
    24 / 293 (8.19%)
    1 / 143 (0.70%)
    15 / 436 (3.44%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    28 / 64 (43.75%)
    0 / 34 (0.00%)
    4 / 11 (36.36%)
         occurrences all number
    17
    2
    30
    1
    16
    0
    0
    0
    0
    3
    33
    0
    4
    Rash erythematous
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    0
    2
    0
    4
    0
    0
    0
    0
    0
    0
    0
    0
    Rash macular
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Skin disorder
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Skin fissures
         subjects affected / exposed
    7 / 40 (17.50%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    11
    0
    2
    0
    3
    0
    0
    0
    0
    0
    1
    1
    1
    Skin toxicity
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 58 (1.72%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    7
    1
    5
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Dermal cyst
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Erythema nodosum
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    5 / 436 (1.15%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    3 / 64 (4.69%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    6
    0
    5
    0
    0
    0
    0
    2
    3
    0
    1
    Rosacea
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Urticaria
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    3 / 64 (4.69%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    5
    0
    5
    0
    0
    0
    0
    1
    5
    0
    1
    Acne
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    2
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    4
    Blister
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    Hand dermatitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    5 / 293 (1.71%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    5
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hair texture abnormal
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    2 / 293 (0.68%)
    1 / 143 (0.70%)
    9 / 436 (2.06%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    1
    9
    1
    0
    0
    0
    4
    2
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    17 / 293 (5.80%)
    4 / 143 (2.80%)
    17 / 436 (3.90%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    1 / 64 (1.56%)
    2 / 34 (5.88%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    25
    4
    19
    0
    0
    0
    0
    1
    1
    4
    0
    Renal colic
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    16 / 293 (5.46%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    17
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    24 / 293 (8.19%)
    1 / 143 (0.70%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    3 / 64 (4.69%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    32
    1
    1
    0
    0
    0
    0
    0
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 40 (45.00%)
    3 / 58 (5.17%)
    50 / 293 (17.06%)
    8 / 143 (5.59%)
    14 / 436 (3.21%)
    3 / 18 (16.67%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    4 / 98 (4.08%)
    8 / 64 (12.50%)
    3 / 34 (8.82%)
    5 / 11 (45.45%)
         occurrences all number
    30
    6
    67
    10
    16
    5
    1
    0
    0
    4
    8
    5
    5
    Back pain
         subjects affected / exposed
    5 / 40 (12.50%)
    6 / 58 (10.34%)
    22 / 293 (7.51%)
    9 / 143 (6.29%)
    13 / 436 (2.98%)
    2 / 18 (11.11%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    5 / 64 (7.81%)
    3 / 34 (8.82%)
    3 / 11 (27.27%)
         occurrences all number
    5
    6
    32
    9
    14
    2
    0
    0
    0
    3
    5
    3
    4
    Bone pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    6 / 293 (2.05%)
    0 / 143 (0.00%)
    4 / 436 (0.92%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    6
    0
    4
    1
    0
    0
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    5 / 293 (1.71%)
    0 / 143 (0.00%)
    9 / 436 (2.06%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    1
    5
    0
    9
    0
    0
    1
    0
    0
    1
    0
    0
    Muscle tightness
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    5 / 293 (1.71%)
    2 / 143 (1.40%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    6
    2
    5
    0
    0
    0
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    6 / 40 (15.00%)
    4 / 58 (6.90%)
    15 / 293 (5.12%)
    3 / 143 (2.10%)
    8 / 436 (1.83%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    5 / 98 (5.10%)
    5 / 64 (7.81%)
    2 / 34 (5.88%)
    1 / 11 (9.09%)
         occurrences all number
    8
    4
    17
    3
    12
    1
    0
    0
    0
    9
    5
    3
    1
    Pain in extremity
         subjects affected / exposed
    7 / 40 (17.50%)
    1 / 58 (1.72%)
    13 / 293 (4.44%)
    8 / 143 (5.59%)
    15 / 436 (3.44%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    5 / 64 (7.81%)
    2 / 34 (5.88%)
    0 / 11 (0.00%)
         occurrences all number
    10
    1
    18
    9
    19
    0
    0
    0
    0
    3
    6
    2
    0
    Osteoporosis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    2 / 143 (1.40%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    6 / 436 (1.38%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    0
    0
    0
    1
    1
    0
    2
    Osteoporotic fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    5 / 293 (1.71%)
    3 / 143 (2.10%)
    3 / 436 (0.69%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    5
    3
    3
    2
    0
    0
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 58 (3.45%)
    5 / 293 (1.71%)
    2 / 143 (1.40%)
    4 / 436 (0.92%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    2 / 64 (3.13%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    3
    2
    6
    2
    4
    1
    0
    0
    0
    0
    2
    1
    0
    Eye infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    6 / 40 (15.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    8
    0
    3
    1
    0
    0
    0
    0
    0
    0
    0
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    15 / 293 (5.12%)
    10 / 143 (6.99%)
    15 / 436 (3.44%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    3 / 64 (4.69%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    21
    12
    17
    1
    0
    1
    0
    3
    4
    1
    1
    Onychomycosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    2 / 143 (1.40%)
    2 / 436 (0.46%)
    2 / 18 (11.11%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    4
    2
    2
    2
    0
    0
    0
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    4 / 436 (0.92%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    4
    1
    0
    0
    0
    0
    0
    1
    0
    Paronychia
         subjects affected / exposed
    5 / 40 (12.50%)
    1 / 58 (1.72%)
    2 / 293 (0.68%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    13
    1
    2
    1
    0
    0
    0
    0
    0
    0
    0
    0
    8
    Rhinitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    5 / 293 (1.71%)
    3 / 143 (2.10%)
    15 / 436 (3.44%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    1 / 64 (1.56%)
    3 / 34 (8.82%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    5
    3
    15
    0
    0
    0
    0
    2
    1
    3
    0
    Tracheitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 58 (0.00%)
    12 / 293 (4.10%)
    2 / 143 (1.40%)
    12 / 436 (2.75%)
    2 / 18 (11.11%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    4 / 98 (4.08%)
    2 / 64 (3.13%)
    3 / 34 (8.82%)
    0 / 11 (0.00%)
         occurrences all number
    4
    0
    22
    2
    13
    2
    0
    0
    0
    5
    2
    3
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 58 (1.72%)
    12 / 293 (4.10%)
    4 / 143 (2.80%)
    22 / 436 (5.05%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    3 / 98 (3.06%)
    7 / 64 (10.94%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    13
    4
    26
    1
    0
    0
    0
    3
    10
    1
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    3 / 436 (0.69%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    3
    0
    0
    0
    0
    1
    2
    0
    1
    Vulvitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Device related infection
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 58 (1.72%)
    2 / 293 (0.68%)
    0 / 143 (0.00%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    1
    3
    0
    4
    0
    0
    0
    0
    1
    0
    0
    0
    Catheter site infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    0
    0
    0
    0
    0
    1
    Febrile infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    0
    0
    0
    1
    1
    Vascular device infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    2 / 436 (0.46%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    2
    0
    0
    0
    0
    0
    0
    0
    1
    Staphylococcal infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Anal abscess
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    1 / 143 (0.70%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    1
    4
    0
    0
    1
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 40 (20.00%)
    7 / 58 (12.07%)
    24 / 293 (8.19%)
    14 / 143 (9.79%)
    65 / 436 (14.91%)
    0 / 18 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    14 / 98 (14.29%)
    11 / 64 (17.19%)
    1 / 34 (2.94%)
    2 / 11 (18.18%)
         occurrences all number
    10
    8
    26
    15
    85
    0
    1
    0
    0
    17
    12
    1
    2
    Food craving
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    0 / 293 (0.00%)
    0 / 143 (0.00%)
    0 / 436 (0.00%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 58 (0.00%)
    5 / 293 (1.71%)
    2 / 143 (1.40%)
    22 / 436 (5.05%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    5 / 98 (5.10%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    6
    5
    29
    0
    0
    0
    0
    7
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    2 / 143 (1.40%)
    9 / 436 (2.06%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    1 / 64 (1.56%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    2
    4
    9
    1
    0
    0
    0
    0
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    5 / 293 (1.71%)
    6 / 143 (4.20%)
    12 / 436 (2.75%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    10
    10
    16
    1
    0
    0
    0
    1
    2
    0
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 40 (7.50%)
    7 / 58 (12.07%)
    6 / 293 (2.05%)
    8 / 143 (5.59%)
    35 / 436 (8.03%)
    1 / 18 (5.56%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    4 / 64 (6.25%)
    1 / 34 (2.94%)
    2 / 11 (18.18%)
         occurrences all number
    6
    8
    7
    9
    44
    1
    0
    1
    0
    2
    4
    1
    2
    Hypomagnesaemia
         subjects affected / exposed
    6 / 40 (15.00%)
    1 / 58 (1.72%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    6
    2
    4
    0
    1
    0
    0
    0
    0
    1
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 58 (0.00%)
    2 / 293 (0.68%)
    3 / 143 (2.10%)
    4 / 436 (0.92%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    2 / 98 (2.04%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    2
    3
    4
    0
    0
    0
    0
    2
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 58 (1.72%)
    1 / 293 (0.34%)
    1 / 143 (0.70%)
    0 / 436 (0.00%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    0 / 64 (0.00%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    1 / 143 (0.70%)
    1 / 436 (0.23%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 98 (1.02%)
    0 / 64 (0.00%)
    1 / 34 (2.94%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    5
    2
    1
    0
    0
    0
    0
    1
    0
    1
    2
    Dehydration
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 58 (0.00%)
    4 / 293 (1.37%)
    0 / 143 (0.00%)
    5 / 436 (1.15%)
    0 / 18 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 98 (0.00%)
    2 / 64 (3.13%)
    0 / 34 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    4
    0
    5
    0
    0
    0
    0
    0
    2
    0
    2

    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.

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

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