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    Clinical Trial Results:
    A Phase III Study of BBI-608 in combination with 5-Fluorouracil, Leucovorin, Irinotecan (FOLFIRI) in Adult Patients with Previously Treated Metastatic Colorectal Cancer (CRC)

    Summary
    EudraCT number
    		 2016-001627-31
    Trial protocol
    		 DE   NL   BE   CZ   ES   IT  
    Global end of trial date
    11 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jul 2022
    First version publication date
    17 Jul 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CanStem303C
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02753127
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sumitomo Pharma Oncology, Inc.
    Sponsor organisation address
    84 Waterford Drive, Marlborough, United States, 01752
    Public contact
    Clinical Trial Office, Sumitomo Pharma Oncology, Inc. , +1 6176746800, CanStem303C@bostonbiomedical.com
    Scientific contact
    Clinical Trial Office, Sumitomo Pharma Oncology, Inc. , +1 6176746800, CanStem303C@bostonbiomedical.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
    19 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To compare overall survival (OS) in the General Population patients treated with BBI-608 plus biweekly FOLFIRI (Arm 1) versus biweekly FOLFIRI (Arm 2) • To compare OS in the pSTAT3-positive (pSTAT3(+)) Subpopulation patients treated with BBI-608 plus biweekly FOLFIRI (Arm 1) versus biweekly FOLFIRI (Arm 2)
    Protection of trial subjects
    The study was conducted in accordance with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) Guidelines, and applicable local laws and national regulations relevant to the use of new therapeutic agents in the country of conduct. Patients who could not given informed consent (i.e. mentally incompetent persons, or those physically incapacitated such as comatose persons) were not recruited to this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 37
    Country: Number of subjects enrolled
    Spain: 136
    Country: Number of subjects enrolled
    Belgium: 40
    Country: Number of subjects enrolled
    Czechia: 37
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Italy: 51
    Country: Number of subjects enrolled
    Australia: 60
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    China: 121
    Country: Number of subjects enrolled
    Hong Kong: 12
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Japan: 126
    Country: Number of subjects enrolled
    Korea, Republic of: 83
    Country: Number of subjects enrolled
    Singapore: 17
    Country: Number of subjects enrolled
    United States: 412
    Worldwide total number of subjects
    1253
    EEA total number of subjects
    368
    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)
    796
    From 65 to 84 years
    456
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 1253 participants were randomized globally between October 2016 and March 2019.

    Pre-assignment
    Screening details
    		 Baseline evaluations were performed for all patients <14 days prior to randomization to determine study eligibility. A total of 1717 screenings were recorded

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Napabucasin + FOLFIRI ± Bevacizumab
    Arm description
    		 Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Napabucasin
    Investigational medicinal product code
    Other name
    BBI608, BBI-608
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Napabucasin was administered orally, twice daily, with doses separated by approximately 12 hours. Napabucasin administration began 2-5 days prior to the first FOLFIRI with Bevacizumab infusion.

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    5-FU 400 mg/m2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion. This regimen will be repeated on Day 1 of every 14-day cycle.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 400 mg/m2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion. This regimen will be repeated on Day 1 of every 14-day cycle.

    Investigational medicinal product name
    leucovorin
    Investigational medicinal product code
    Other name
    Levoleucovorin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 400 mg/m2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion. This regimen will be repeated on Day 1 of every 14-day cycle.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab (5 mg/kg) infusion should start at least 2 hours following the first dose of BBI-608 starting on Cycle 1 Day 1 and will be administered every 2 weeks.

    Arm title
    		 FOLFIRI ± Bevacizumab
    Arm description
    		 Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intracavernous use
    Dosage and administration details
    5-FU 400 mg/m2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion. This regimen will be repeated on Day 1 of every 14-day cycle.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 400 mg/m2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion. This regimen will be repeated on Day 1 of every 14-day cycle.

    Investigational medicinal product name
    leucovorin
    Investigational medicinal product code
    Other name
    Levoleucovorin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 400 mg/m2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion. This regimen will be repeated on Day 1 of every 14-day cycle.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Bevacizumab (5 mg/kg) infusion should start at least 2 hours following the first dose of BBI-608 starting on Cycle 1 Day 1 and will be administered every 2 weeks.

    Number of subjects in period 1
    		Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab
    Started
    624
    629
    Completed
    571
    561
    Not completed
    53
    68
         Consent withdrawn by subject
    37
    47
         Hospice
    -
    2
         Unknown
    3
    8
         Lost to follow-up
    13
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Napabucasin + FOLFIRI ± Bevacizumab
    Reporting group description
    		 Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle.

    Reporting group title
    FOLFIRI ± Bevacizumab
    Reporting group description
    		 Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle.

    Reporting group values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Total
    Number of subjects
    		 624 629 1253
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 393 403 796
        From 65-84 years
    		 231 225 456
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 61.0 (26 to 84) 61.0 (21 to 86) -
    Gender categorical
    Units: Subjects
        Female
    		 240 254 494
        Male
    		 384 375 759
    Subject analysis sets

    Subject analysis set title
    Intent-to-Treat Analysis Set in the General Population, Arm 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who were randomized to Arm1 to receive napabucasin administered orally, twice daily in combination with FOLFIRI ± Bevacizumab

    Subject analysis set title
    Intent-to-Treat Analysis Set in the General Population, Arm 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who were randomized to Arm 2 to receive FOLFIRI ± Bevacizumab

    Subject analysis set title
    Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who were randomized to Arm 1 to receive napabucasin administered orally, twice daily in combination with Napabucasin + FOLFIRI ± Bevacizumab and were assessed to have positive pSTAT3 status based on their biomarker data.

    Subject analysis set title
    Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who were randomized to Arm 2 to receive FOLFIRI ± Bevacizumab and were assessed to have positive pSTAT3 status based on their biomarker data.

    Subject analysis set title
    Safety Analysis Set in the General Population (SAS-GP) Arm 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who were randomized to Arm1 to receive napabucasin administered orally, twice daily in combination with FOLFIRI ± Bevacizumab and received at least 1 dose of study drug (BBI-608 and/or FOLFIRI).

    Subject analysis set title
    Safety Analysis Set in the General Population (SAS-GP) Arm 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who were randomized to Arm 2 to receive FOLFIRI ± Bevacizumab and received at least 1 dose of FOLFIRI.

    Subject analysis set title
    QoL Analysis Set in the General Population (QoL-GP), Arm 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who were randomized to Arm 1 to receive napabucasin administered orally, twice daily in combination with Napabucasin + FOLFIRI ± Bevacizumab and have at least 1 QoL assessment in the General Population. QoL-GP will be used for QoL endpoint analysis in the General Population. QoL assessments from 14 days prior to randomization and afterward are considered.

    Subject analysis set title
    QoL Analysis Set in the General Population (QoL-GP), Arm 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who were randomized to Arm 2 to receive FOLFIRI ± Bevacizumab and have at least 1 QoL assessment in the General Population. QoL-GP will be used for QoL endpoint analysis in the General Population. QoL assessments from 14 days prior to randomization and afterward are considered.

    Subject analysis sets values
    		 Intent-to-Treat Analysis Set in the General Population, Arm 1 Intent-to-Treat Analysis Set in the General Population, Arm 2 Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2 Safety Analysis Set in the General Population (SAS-GP) Arm 1 Safety Analysis Set in the General Population (SAS-GP) Arm 2 QoL Analysis Set in the General Population (QoL-GP), Arm 1 QoL Analysis Set in the General Population (QoL-GP), Arm 2
    Number of subjects
    624
    629
    275
    272
    622
    610
    622
    626
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    393
    403
    181
    171
    392
    391
    392
    401
        From 65-84 years
    231
    225
    94
    101
    230
    218
    230
    224
        85 years and over
    0
    1
    0
    0
    0
    1
    0
    1
    Age continuous
    Units: years
        median (full range (min-max))
    61.0 (26 to 84)
    61.0 (21 to 86)
    61.0 (26 to 81)
    60.0 (21 to 83)
    Gender categorical
    Units: Subjects
        Female
    240
    254
    105
    124
        Male
    384
    375
    170
    148

    End points

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    End points reporting groups
    Reporting group title
    Napabucasin + FOLFIRI ± Bevacizumab
    Reporting group description
    		 Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. This regimen will be repeated on Day 1 of every 14 day cycle.

    Reporting group title
    FOLFIRI ± Bevacizumab
    Reporting group description
    		 Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle.

    Subject analysis set title
    Intent-to-Treat Analysis Set in the General Population, Arm 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who were randomized to Arm1 to receive napabucasin administered orally, twice daily in combination with FOLFIRI ± Bevacizumab

    Subject analysis set title
    Intent-to-Treat Analysis Set in the General Population, Arm 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who were randomized to Arm 2 to receive FOLFIRI ± Bevacizumab

    Subject analysis set title
    Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who were randomized to Arm 1 to receive napabucasin administered orally, twice daily in combination with Napabucasin + FOLFIRI ± Bevacizumab and were assessed to have positive pSTAT3 status based on their biomarker data.

    Subject analysis set title
    Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants who were randomized to Arm 2 to receive FOLFIRI ± Bevacizumab and were assessed to have positive pSTAT3 status based on their biomarker data.

    Subject analysis set title
    Safety Analysis Set in the General Population (SAS-GP) Arm 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who were randomized to Arm1 to receive napabucasin administered orally, twice daily in combination with FOLFIRI ± Bevacizumab and received at least 1 dose of study drug (BBI-608 and/or FOLFIRI).

    Subject analysis set title
    Safety Analysis Set in the General Population (SAS-GP) Arm 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who were randomized to Arm 2 to receive FOLFIRI ± Bevacizumab and received at least 1 dose of FOLFIRI.

    Subject analysis set title
    QoL Analysis Set in the General Population (QoL-GP), Arm 1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who were randomized to Arm 1 to receive napabucasin administered orally, twice daily in combination with Napabucasin + FOLFIRI ± Bevacizumab and have at least 1 QoL assessment in the General Population. QoL-GP will be used for QoL endpoint analysis in the General Population. QoL assessments from 14 days prior to randomization and afterward are considered.

    Subject analysis set title
    QoL Analysis Set in the General Population (QoL-GP), Arm 2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All participants who were randomized to Arm 2 to receive FOLFIRI ± Bevacizumab and have at least 1 QoL assessment in the General Population. QoL-GP will be used for QoL endpoint analysis in the General Population. QoL assessments from 14 days prior to randomization and afterward are considered.

    Primary: Overall Survival (OS) General population

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    End point title
    		 Overall Survival (OS) General population
    End point description
    Overall survival was defined as the time from randomization until death from any cause. Patients who are alive at the time of the interim or the final analyses or who have become lost to follow-up will be censored on the date the patient was last known to be alive.
    End point type
    Primary
    End point timeframe
    Randomization to Date of Death from any cause or database cutoff date (28 Apr 2020) (Approximately 43 months)
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Intent-to-Treat Analysis Set in the General Population, Arm 1 Intent-to-Treat Analysis Set in the General Population, Arm 2
    Number of subjects analysed
    624
    629
    624
    629
    Units: Months
        median (confidence interval 95%)
    14.29 (13.34 to 15.70)
    13.83 (12.42 to 15.28)
    14.29 (13.34 to 15.7)
    13.83 (12.42 to 15.28)
    Statistical analysis title
    		 Statistical Test of Hypothesis
    Comparison groups
    Napabucasin + FOLFIRI ± Bevacizumab v FOLFIRI ± Bevacizumab
    Number of subjects included in analysis
    1253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3629
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.976
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.854
         upper limit
    		 1.117

    Primary: Overall Survival pSTAT3(+) Subpopulation patients

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    End point title
    		 Overall Survival pSTAT3(+) Subpopulation patients
    End point description
    Overall survival was defined as the time from randomization until death from any cause. Patients who are alive at the time of the interim or the final analyses or who have become lost to follow-up will be censored on the date the patient was last known to be alive.
    End point type
    Primary
    End point timeframe
    Randomization to Date of Death from any cause or database cutoff date (28 Apr 2020) (Approximately 43 months)
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Number of subjects analysed
    275
    272
    275
    272
    Units: Months
        median (confidence interval 95%)
    13.17 (11.30 to 15.31)
    12.12 (11.24 to 14.06)
    13.17 (11.30 to 15.31)
    12.12 (11.24 to 14.06)
    Statistical analysis title
    		 Statistical Test of Hypothesis, pSTAT3(+)
    Comparison groups
    Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 v Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Number of subjects included in analysis
    547
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3782
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.969
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.797
         upper limit
    		 1.179

    Secondary: Progression Free Survival (pSTAT3(+) Subpopulation patients)

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    End point title
    		 Progression Free Survival (pSTAT3(+) Subpopulation patients)
    End point description
    PFS is defined as the time from randomization to the first objective documentation of disease progression per RECIST 1.1 (PD) or death, whichever comes first.
    End point type
    Secondary
    End point timeframe
    Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Number of subjects analysed
    275
    272
    275
    272
    Units: Months
        median (confidence interval 95%)
    5.39 (4.14 to 5.62)
    5.55 (4.44 to 5.91)
    5.39 (4.14 to 5.62)
    5.55 (4.44 to 5.91)
    Statistical analysis title
    		 Statistical Test of Hypothesis, pSTAT3(+)
    Comparison groups
    Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 v Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Number of subjects included in analysis
    547
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7434
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.064
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.883
         upper limit
    		 1.283

    Secondary: Progression Free Survival (General population)

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    End point title
    		 Progression Free Survival (General population)
    End point description
    PFS is defined as the time from randomization to the first objective documentation of disease progression per RECIST 1.1 (PD) or death, whichever comes first.
    End point type
    Secondary
    End point timeframe
    Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Intent-to-Treat Analysis Set in the General Population, Arm 1 Intent-to-Treat Analysis Set in the General Population, Arm 2
    Number of subjects analysed
    624
    629
    624
    629
    Units: Months
        median (confidence interval 95%)
    5.55 (5.39 to 5.78)
    5.62 (5.45 to 6.34)
    5.55 (5.39 to 5.78)
    5.62 (5.45 to 6.34)
    Statistical analysis title
    		 Statistical Test of Hypothesis, General population
    Comparison groups
    Napabucasin + FOLFIRI ± Bevacizumab v FOLFIRI ± Bevacizumab
    Number of subjects included in analysis
    1253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7307
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.917
         upper limit
    		 1.18

    Secondary: Disease Control Rate (DCR) (General population)

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    End point title
    		 Disease Control Rate (DCR) (General population)
    End point description
    DCR is defined as the percentage of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1. The primary estimate of DCR will be based on patients with measurable disease by RECIST 1.1 at randomization
    End point type
    Secondary
    End point timeframe
    Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Intent-to-Treat Analysis Set in the General Population, Arm 1 Intent-to-Treat Analysis Set in the General Population, Arm 2
    Number of subjects analysed
    593
    609
    593
    609
    Units: Percentage
        number (confidence interval 95%)
    69.6 (65.8 to 73.3)
    69.1 (65.3 to 72.8)
    69.6 (65.8 to 73.3)
    69.1 (65.3 to 72.8)
    Statistical analysis title
    		 Statistical Test of Hypothesis, General population
    Comparison groups
    Napabucasin + FOLFIRI ± Bevacizumab v FOLFIRI ± Bevacizumab
    Number of subjects included in analysis
    1202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4797
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 rate difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9
         upper limit
    		 5.2

    Secondary: Disease Control Rate (DCR) (pSTAT3(+) Subpopulation patients)

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    End point title
    		 Disease Control Rate (DCR) (pSTAT3(+) Subpopulation patients)
    End point description
    DCR is defined as the percentage of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1. The primary estimate of DCR will be based on patients with measurable disease by RECIST 1.1 at randomization
    End point type
    Secondary
    End point timeframe
    Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Number of subjects analysed
    268
    266
    268
    266
    Units: percentage of participants
        number (confidence interval 95%)
    67.2 (61.2 to 72.8)
    70.3 (64.4 to 75.7)
    67.2 (61.2 to 72.8)
    70.3 (64.4 to 75.7)
    Statistical analysis title
    		 Statistical Test of Hypothesis, pSTAT3(+)
    Comparison groups
    Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 v Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.783
    Method
    		 Z test
    Parameter type
    		 rate difference
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 4.7

    Secondary: Objective Response Rate (ORR) (General population)

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    End point title
    		 Objective Response Rate (ORR) (General population)
    End point description
    ORR is defined as the proportion of patients with a documented complete response and partial response (CR + PR) based on RECIST 1.1. The primary estimate for ORR will be based on patients with measurable disease by RECIST 1.1 at randomization.
    End point type
    Secondary
    End point timeframe
    Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Intent-to-Treat Analysis Set in the General Population, Arm 1 Intent-to-Treat Analysis Set in the General Population, Arm 2
    Number of subjects analysed
    593
    609
    593
    609
    Units: percentage of participants
        number (confidence interval 95%)
    13.8 (11.2 to 16.9)
    14.6 (11.9 to 17.7)
    13.8 (11.2 to 16.9)
    14.6 (11.9 to 17.7)
    Statistical analysis title
    		 Statistical Test of Hypothesis, General population
    Comparison groups
    Napabucasin + FOLFIRI ± Bevacizumab v FOLFIRI ± Bevacizumab
    Number of subjects included in analysis
    1202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6776
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 rate difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 3

    Secondary: Objective Response Rate (ORR) (pSTAT3(+) Subpopulation patients)

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    End point title
    		 Objective Response Rate (ORR) (pSTAT3(+) Subpopulation patients)
    End point description
    ORR is defined as the proportion of patients with a documented complete response and partial response (CR + PR) based on RECIST 1.1. The primary estimate for ORR will be based on patients with measurable disease by RECIST 1.1 at randomization.
    End point type
    Secondary
    End point timeframe
    Randomization to Date of Death or until the date of first documented objective disease progression or database cutoff date (28 Apr 2020) (Approximately 43 months)
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Number of subjects analysed
    268
    266
    268
    266
    Units: percentage of participants
        number (confidence interval 95%)
    11.9 (8.3 to 16.4)
    13.9 (10.0 to 18.7)
    11.9 (8.3 to 16.4)
    13.9 (10.0 to 18.7)
    Statistical analysis title
    		 Statistical Test of Hypothesis, pSTAT3(+)
    Comparison groups
    Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 1 v Intent-to-Treat Analysis Set in the pSTAT3(+) , Arm 2
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7513
    Method
    		 Z test
    Parameter type
    		 rate difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.7
         upper limit
    		 3.7

    Secondary: Mean Change From Baseline for Global Health Status at Time 2 (Cycle 5 Day 1).

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    End point title
    		 Mean Change From Baseline for Global Health Status at Time 2 (Cycle 5 Day 1).
    End point description
    The Quality of Life (QoL) of patients will be assessed using European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ-C30) (EORTC QLQ-30) while the patient remains on study treatment (FOLFIRI with or without BBI-608). EORTC QLQ-30 is used to assess the overall quality of life in cancer patients using 28 questions with a 4 point scale. (1 'Not at all' to 4'Very Much'); 2 questions use a 7-point sale (1 'Very Poor' to 7 'Excellent'). Scores are averaged and transformed to 0-100 scale; higher overall score = better quality of life.
    End point type
    Secondary
    End point timeframe
    From baseline at Time 2 (Cycle 5 Day 1), approximately 57 days
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab QoL Analysis Set in the General Population (QoL-GP), Arm 1 QoL Analysis Set in the General Population (QoL-GP), Arm 2
    Number of subjects analysed
    376
    341
    376
    341
    Units: score on a scale
        median (standard deviation)
    -7.07 ± 21.936
    -5.45 ± 20.607
    -7.07 ± 21.936
    -5.45 ± 20.607
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline for Global Health Status at Time 4 (Cycle 9 Day 1).

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    End point title
    		 Mean Change From Baseline for Global Health Status at Time 4 (Cycle 9 Day 1).
    End point description
    The Quality of Life (QoL) of patients will be assessed using European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ-C30) (EORTC QLQ-30) while the patient remains on study treatment (FOLFIRI with or without BBI-608). EORTC QLQ-30 is used to assess the overall quality of life in cancer patients using 28 questions with a 4 point scale. (1 'Not at all' to 4'Very Much'); 2 questions use a 7-point sale (1 Very Poor' to 7 'Excellent'). Scores are averaged and transformed to 0-100 scale; higher overall score = better quality of life.
    End point type
    Secondary
    End point timeframe
    From baseline at time 4 (Cycle 9 Day 1), approximately 113 days
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab QoL Analysis Set in the General Population (QoL-GP), Arm 1 QoL Analysis Set in the General Population (QoL-GP), Arm 2
    Number of subjects analysed
    370
    360
    370
    360
    Units: score on a scale
        median (standard deviation)
    -7.70 ± 21.932
    -5.58 ± 21.590
    -7.70 ± 21.936
    -5.58 ± 21.590
    No statistical analyses for this end point

    Secondary: Number of Patients With Adverse Events in the General Population

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    End point title
    		 Number of Patients With Adverse Events in the General Population
    End point description
    All patients who have received at least one dose of either BBI-608 or FOLFIRI will be included in the safety analysis according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.0. The incidence of adverse events will be summarized by type of adverse event and severity.
    End point type
    Secondary
    End point timeframe
    All adverse event are collected from date of signed informed consent until 30 days after protocol treatment discontinuation. Outcome followed until study discontinuation up to 4 years
    End point values
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab
    Number of subjects analysed
    622
    610
    Units: Participants
    619
    602
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse event are collected from date of signed informed consent until 30 days after protocol treatment discontinuation. Outcome followed until study discontinuation.
    Adverse event reporting additional description
    All adverse event are collected from date of signed informed consent until 30 days after protocol treatment discontinuation. Outcome followed until study discontinuation up to 4 years. All cause mortality is analyzed in the ITT population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Napabucasin + FOLFIRI ± Bevacizumab
    Reporting group description
    		 -

    Reporting group title
    FOLFIRI ± Bevacizumab
    Reporting group description
    		 -

    Serious adverse events
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    234 / 622 (37.62%)
    201 / 610 (32.95%)
         number of deaths (all causes)
    507
    499
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant Ascites
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases To Kidney
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases To Liver
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases To Lung
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary Tumour Benign
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon Cancer Metastatic
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases To Heart
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases To Peritoneum
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Pain
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 622 (0.96%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    3 / 6
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    2 / 622 (0.32%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic Shock
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian Vein Thrombosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous Thrombosis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Tumour Excision
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    18 / 622 (2.89%)
    16 / 610 (2.62%)
         occurrences causally related to treatment / all
    5 / 18
    5 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    17 / 622 (2.73%)
    15 / 610 (2.46%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 15
         deaths causally related to treatment / all
    0 / 12
    0 / 11
    General Physical Health Deterioration
         subjects affected / exposed
    5 / 622 (0.80%)
    5 / 610 (0.82%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Asthenia
         subjects affected / exposed
    4 / 622 (0.64%)
    4 / 610 (0.66%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 622 (0.64%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Mucosal Inflammation
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal Toxicity
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 622 (0.16%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    12 / 622 (1.93%)
    9 / 610 (1.48%)
         occurrences causally related to treatment / all
    5 / 12
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    5 / 622 (0.80%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 622 (0.48%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    2 / 622 (0.32%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infiltration
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Artery Thrombosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device Dislocation
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis In Device
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood Bilirubin Increased
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    2 / 622 (0.32%)
    8 / 610 (1.31%)
         occurrences causally related to treatment / all
    2 / 2
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Necrosis Marker Increased
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Uric Acid Increased
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Related Reaction
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma Site Haemorrhage
         subjects affected / exposed
    2 / 622 (0.32%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Stoma Complication
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma Complication
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    3 / 622 (0.48%)
    4 / 610 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac Failure
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Fibrillation
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 622 (0.32%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered State Of Consciousness
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior Sagittal Sinus Thrombosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Disorder
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 622 (1.45%)
    4 / 610 (0.66%)
         occurrences causally related to treatment / all
    5 / 9
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Marrow Failure
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    8 / 622 (1.29%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    8 / 8
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 622 (0.64%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 622 (0.48%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated Intravascular Coagulation
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    39 / 622 (6.27%)
    19 / 610 (3.11%)
         occurrences causally related to treatment / all
    37 / 39
    18 / 19
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Abdominal Pain
         subjects affected / exposed
    17 / 622 (2.73%)
    16 / 610 (2.62%)
         occurrences causally related to treatment / all
    8 / 17
    5 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    10 / 622 (1.61%)
    15 / 610 (2.46%)
         occurrences causally related to treatment / all
    1 / 10
    2 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Small Intestinal Obstruction
         subjects affected / exposed
    10 / 622 (1.61%)
    12 / 610 (1.97%)
         occurrences causally related to treatment / all
    1 / 10
    1 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vomiting
         subjects affected / exposed
    10 / 622 (1.61%)
    8 / 610 (1.31%)
         occurrences causally related to treatment / all
    9 / 10
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nausea
         subjects affected / exposed
    9 / 622 (1.45%)
    4 / 610 (0.66%)
         occurrences causally related to treatment / all
    8 / 9
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    4 / 622 (0.64%)
    8 / 610 (1.31%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 622 (0.48%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    3 / 622 (0.48%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestinal Obstruction
         subjects affected / exposed
    3 / 622 (0.48%)
    4 / 610 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    3 / 622 (0.48%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colitis
         subjects affected / exposed
    2 / 622 (0.32%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Varices Haemorrhage
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Hernia Obstructive
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea Haemorrhagic
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Disorder
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Inflammation
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Perforation
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Toxicity
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia Strangulated
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestinal Stenosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction Gastric
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Distension
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Perforation
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Ulcer Perforation
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mouth Ulceration
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis Intestinalis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 622 (0.48%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile Duct Obstruction
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder Necrosis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Function Abnormal
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice Cholestatic
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile Duct Stenosis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Injury
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    7 / 622 (1.13%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    2 / 7
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Prerenal Failure
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal Failure
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydroureter
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Obstruction
         subjects affected / exposed
    0 / 622 (0.00%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    3 / 622 (0.48%)
    4 / 610 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture Pain
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis Of Jaw
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    7 / 622 (1.13%)
    10 / 610 (1.64%)
         occurrences causally related to treatment / all
    4 / 7
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Urinary Tract Infection
         subjects affected / exposed
    6 / 622 (0.96%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 622 (0.64%)
    8 / 610 (1.31%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Anal Abscess
         subjects affected / exposed
    2 / 622 (0.32%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 622 (0.32%)
    2 / 610 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 622 (0.32%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Infection
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Sepsis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Infection
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic Abscess
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis Infectious
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected Dermal Cyst
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nosocomial Infection
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal Abscess
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar Abscess
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Influenzal
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas Bronchitis
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Abscess
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal Abscess
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 622 (0.16%)
    4 / 610 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Urosepsis
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Abscess
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Wall Abscess
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess Jaw
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess Rupture
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal Infection
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coccidioidomycosis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Epididymitis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal Sepsis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lower Respiratory Tract
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising Fasciitis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic Herpes Zoster
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Abscess
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Infection
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoas Abscess
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Sepsis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 622 (0.00%)
    4 / 610 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyonephrosis
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Streptococcal Bacteraemia
         subjects affected / exposed
    0 / 622 (0.00%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    15 / 622 (2.41%)
    9 / 610 (1.48%)
         occurrences causally related to treatment / all
    12 / 15
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypokalaemia
         subjects affected / exposed
    5 / 622 (0.80%)
    6 / 610 (0.98%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased Appetite
         subjects affected / exposed
    4 / 622 (0.64%)
    3 / 610 (0.49%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure To Thrive
         subjects affected / exposed
    1 / 622 (0.16%)
    1 / 610 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Hyperglycaemia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 622 (0.16%)
    0 / 610 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Napabucasin + FOLFIRI ± Bevacizumab FOLFIRI ± Bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    619 / 622 (99.52%)
    602 / 610 (98.69%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    58 / 622 (9.32%)
    65 / 610 (10.66%)
         occurrences all number
    114
    124
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    233 / 622 (37.46%)
    219 / 610 (35.90%)
         occurrences all number
    486
    465
    Asthenia
         subjects affected / exposed
    134 / 622 (21.54%)
    116 / 610 (19.02%)
         occurrences all number
    361
    291
    Pyrexia
         subjects affected / exposed
    106 / 622 (17.04%)
    89 / 610 (14.59%)
         occurrences all number
    163
    142
    Mucosal Inflammation
         subjects affected / exposed
    58 / 622 (9.32%)
    89 / 610 (14.59%)
         occurrences all number
    93
    205
    Oedema Peripheral
         subjects affected / exposed
    44 / 622 (7.07%)
    46 / 610 (7.54%)
         occurrences all number
    55
    57
    Malaise
         subjects affected / exposed
    42 / 622 (6.75%)
    34 / 610 (5.57%)
         occurrences all number
    103
    59
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    72 / 622 (11.58%)
    75 / 610 (12.30%)
         occurrences all number
    87
    103
    Epistaxis
         subjects affected / exposed
    60 / 622 (9.65%)
    79 / 610 (12.95%)
         occurrences all number
    78
    107
    Dyspnoea
         subjects affected / exposed
    55 / 622 (8.84%)
    46 / 610 (7.54%)
         occurrences all number
    69
    60
    Hiccups
         subjects affected / exposed
    41 / 622 (6.59%)
    29 / 610 (4.75%)
         occurrences all number
    49
    46
    Oropharyngeal Pain
         subjects affected / exposed
    19 / 622 (3.05%)
    33 / 610 (5.41%)
         occurrences all number
    21
    41
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    54 / 622 (8.68%)
    84 / 610 (13.77%)
         occurrences all number
    87
    100
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    149 / 622 (23.95%)
    176 / 610 (28.85%)
         occurrences all number
    440
    422
    Weight Decreased
         subjects affected / exposed
    106 / 622 (17.04%)
    54 / 610 (8.85%)
         occurrences all number
    146
    77
    White Blood Cell Count Decreased
         subjects affected / exposed
    87 / 622 (13.99%)
    109 / 610 (17.87%)
         occurrences all number
    325
    302
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    75 / 622 (12.06%)
    67 / 610 (10.98%)
         occurrences all number
    149
    119
    Alanine Aminotransferase Increased
         subjects affected / exposed
    67 / 622 (10.77%)
    57 / 610 (9.34%)
         occurrences all number
    130
    96
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    59 / 622 (9.49%)
    35 / 610 (5.74%)
         occurrences all number
    105
    56
    Platelet Count Decreased
         subjects affected / exposed
    42 / 622 (6.75%)
    47 / 610 (7.70%)
         occurrences all number
    96
    97
    Blood Bilirubin Increased
         subjects affected / exposed
    29 / 622 (4.66%)
    31 / 610 (5.08%)
         occurrences all number
    56
    51
    Nervous system disorders
    Headache
         subjects affected / exposed
    85 / 622 (13.67%)
    73 / 610 (11.97%)
         occurrences all number
    137
    104
    Dizziness
         subjects affected / exposed
    59 / 622 (9.49%)
    47 / 610 (7.70%)
         occurrences all number
    119
    63
    Dysgeusia
         subjects affected / exposed
    46 / 622 (7.40%)
    59 / 610 (9.67%)
         occurrences all number
    49
    69
    Neuropathy Peripheral
         subjects affected / exposed
    32 / 622 (5.14%)
    22 / 610 (3.61%)
         occurrences all number
    46
    27
    Cholinergic Syndrome
         subjects affected / exposed
    20 / 622 (3.22%)
    33 / 610 (5.41%)
         occurrences all number
    21
    74
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    151 / 622 (24.28%)
    147 / 610 (24.10%)
         occurrences all number
    427
    351
    Neutropenia
         subjects affected / exposed
    151 / 622 (24.28%)
    162 / 610 (26.56%)
         occurrences all number
    347
    390
    Thrombocytopenia
         subjects affected / exposed
    33 / 622 (5.31%)
    23 / 610 (3.77%)
         occurrences all number
    65
    38
    Leukopenia
         subjects affected / exposed
    31 / 622 (4.98%)
    42 / 610 (6.89%)
         occurrences all number
    80
    130
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    522 / 622 (83.92%)
    322 / 610 (52.79%)
         occurrences all number
    1940
    874
    Nausea
         subjects affected / exposed
    374 / 622 (60.13%)
    307 / 610 (50.33%)
         occurrences all number
    1012
    851
    Vomiting
         subjects affected / exposed
    252 / 622 (40.51%)
    177 / 610 (29.02%)
         occurrences all number
    660
    395
    Abdominal Pain
         subjects affected / exposed
    246 / 622 (39.55%)
    146 / 610 (23.93%)
         occurrences all number
    522
    218
    Constipation
         subjects affected / exposed
    126 / 622 (20.26%)
    173 / 610 (28.36%)
         occurrences all number
    176
    280
    Stomatitis
         subjects affected / exposed
    92 / 622 (14.79%)
    116 / 610 (19.02%)
         occurrences all number
    195
    198
    Abdominal Pain Upper
         subjects affected / exposed
    63 / 622 (10.13%)
    46 / 610 (7.54%)
         occurrences all number
    93
    66
    Dyspepsia
         subjects affected / exposed
    56 / 622 (9.00%)
    39 / 610 (6.39%)
         occurrences all number
    67
    64
    Abdominal Distension
         subjects affected / exposed
    34 / 622 (5.47%)
    31 / 610 (5.08%)
         occurrences all number
    42
    36
    Proctalgia
         subjects affected / exposed
    34 / 622 (5.47%)
    20 / 610 (3.28%)
         occurrences all number
    40
    25
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    133 / 622 (21.38%)
    159 / 610 (26.07%)
         occurrences all number
    163
    190
    Rash
         subjects affected / exposed
    31 / 622 (4.98%)
    41 / 610 (6.72%)
         occurrences all number
    38
    44
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    30 / 622 (4.82%)
    33 / 610 (5.41%)
         occurrences all number
    47
    47
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    70 / 622 (11.25%)
    4 / 610 (0.66%)
         occurrences all number
    74
    4
    Proteinuria
         subjects affected / exposed
    54 / 622 (8.68%)
    44 / 610 (7.21%)
         occurrences all number
    109
    87
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    74 / 622 (11.90%)
    82 / 610 (13.44%)
         occurrences all number
    93
    97
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    68 / 622 (10.93%)
    40 / 610 (6.56%)
         occurrences all number
    104
    65
    Upper Respiratory Tract Infection
         subjects affected / exposed
    44 / 622 (7.07%)
    43 / 610 (7.05%)
         occurrences all number
    51
    54
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    230 / 622 (36.98%)
    187 / 610 (30.66%)
         occurrences all number
    484
    375
    Hypokalaemia
         subjects affected / exposed
    103 / 622 (16.56%)
    55 / 610 (9.02%)
         occurrences all number
    191
    98
    Dehydration
         subjects affected / exposed
    47 / 622 (7.56%)
    29 / 610 (4.75%)
         occurrences all number
    74
    46
    Hypoalbuminaemia
         subjects affected / exposed
    33 / 622 (5.31%)
    29 / 610 (4.75%)
         occurrences all number
    70
    63

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jul 2016
    The protocol was amended to reflect requests from Regulatory Authority, update the frequency of collection of all safety blood samples
    06 Dec 2016
    The protocol was amended in response to a trial steering committee request to update the inclusion/exclusion criteria, correct errors and inconsistencies, and include clarifications.
    26 Jun 2017
    The protocol was amended to reflect requests from various Regulatory Authorities, update the inclusion/exclusion criteria, to include more updated safety data on BBI-60, correct errors and inconsistencies, and include clarifications.
    16 Feb 2018
    The protocol was amended for consistency with the most recent edition of the napabucasin Investigator's Brochure, to remove the efficacy analysis from the first interim analysis while keeping the futility analysis, to clarify sensitivity and subgroup analysis for overall survival, to remove the multiplicity adjustment for the secondary endpoints, to clarify the one-sided futility and efficacy boundaries for the interim analyses and the final analysis, to correct transcription errors, and to include other clarifications.
    25 Dec 2018
    The protocol was amended to update the study objectives, addition of a primary endpoint (overall survival) in the pSTAT3+ Subpopulation, reflect the addition of multiplicity adjustment strategy, include information on the Sponsor's blinding plan, implementation of an adaptive design allowing for futility stopping, patient population/hypothesis selection, and event count adjustment correct transcription errors, reflect the Sponsor's updated practices for AE reporting, and provide clarifications.
    25 Sep 2019
    The protocol was amended to specify the strategy of pSTAT3(+) Subpopulation, the pSTAT3(-) Subpopulation and pSTAT3(Unknown) Subpopulation, at the time of the interim analysis, preliminary data suggested cut slides were stable for up to 6 months. Other minor administrative and editorial changes were made throughout the amendment including typographical errors for consistency, clarification, and style.

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

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