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    Clinical Trial Results:
    A Randomized Phase 3 Study of Nivolumab Plus Ipilimumab or Nivolumab Combined With Fluorouracil Plus Cisplatin Versus Fluorouracil Plus Cisplatin in Subjects With Unresectable Advanced, Recurrent or Metastatic Previously Untreated Esophageal Squamous Cell Carcinoma

    Summary
    EudraCT number
    		 2016-001514-20
    Trial protocol
    		 CZ   ES   GB   PL   FR   DK   PT   IT   RO  
    Global end of trial date
    13 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jan 2026
    First version publication date
    23 Jan 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-648
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03143153
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium,
    Public contact
    Global Submission Management, Clinical Trials, Bristol-Myers Squibb International Corporation, mg-gsm-ct@bms.com
    Scientific contact
    Global Submission Management, Clinical Trials, Bristol-Myers Squibb International Corporation, Clinical.Trails@bms.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
    16 Feb 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to compare how long subjects with esophageal cancer live overall or live without disease progression after receiving nivolumab and ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jun 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 18
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Brazil: 50
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    China: 112
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Hong Kong: 9
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Japan: 395
    Country: Number of subjects enrolled
    Korea, Republic of: 63
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Peru: 7
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Romania: 26
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Taiwan: 94
    Country: Number of subjects enrolled
    Türkiye: 6
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    970
    EEA total number of subjects
    112
    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)
    518
    From 65 to 84 years
    449
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 970 participants randomized, 936 treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivolumab + Ipilimumab
    Arm description
    		 Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    No Treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    No Treatment

    Arm title
    		 Arm B: Nivolumab + Chemotherapy
    Arm description
    		 Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Arm C: Chemotherapy
    Arm description
    		 Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Arm A: Nivolumab + Ipilimumab Arm B: Nivolumab + Chemotherapy Arm C: Chemotherapy
    Started
    325
    321
    324
    Completed
    322
    310
    304
    Not completed
    3
    11
    20
         Participant withdrew consent
    -
    1
    12
         Other Reasons
    1
    2
    1
         Participant no longer meets study criteria
    -
    4
    2
         Adverse event unrelated to study drug
    1
    3
    1
         Disease Progression
    1
    1
    2
         Participant request to discontinue study treatment
    -
    -
    2
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivolumab + Ipilimumab
    Arm description
    		 Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 minutes infusion 1mg/kg

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg as 30 minutes infusion

    Arm title
    		 Arm B: Nivolumab + Chemotherapy
    Arm description
    		 Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg as 30 minutes infusion

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m² as a 30- to 120-minute infusion

    Investigational medicinal product name
    Flurouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    800 mg/m²/day as an IV continuous infusion

    Arm title
    		 Arm C: Chemotherapy
    Arm description
    		 Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m² as a 30- to 120-minute infusion

    Investigational medicinal product name
    Flurouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    800 mg/m²/day as an IV continuous infusion

    Number of subjects in period 2
    		Arm A: Nivolumab + Ipilimumab Arm B: Nivolumab + Chemotherapy Arm C: Chemotherapy
    Started
    322
    310
    304
    Completed
    28
    14
    0
    Not completed
    294
    296
    304
         Adverse event, serious fatal
    6
    4
    4
         Participant withdrew consent
    3
    4
    12
         Study drug toxicity
    59
    36
    38
         Other Reasons
    10
    10
    15
         Maximum clinical benefit
    1
    3
    4
         Pregnancy
    1
    -
    -
         Adverse event unrelated to study drug
    19
    26
    11
         Disease Progression
    182
    191
    199
         Participant request to discontinue study treatment
    13
    22
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Nivolumab + Ipilimumab
    Reporting group description
    		 Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.

    Reporting group title
    Arm B: Nivolumab + Chemotherapy
    Reporting group description
    		 Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.

    Reporting group title
    Arm C: Chemotherapy
    Reporting group description
    		 Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.

    Reporting group values
    		 Arm A: Nivolumab + Ipilimumab Arm B: Nivolumab + Chemotherapy Arm C: Chemotherapy Total
    Number of subjects
    		 325 321 324 970
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 185 167 166 518
        From 65-84 years
    		 140 151 158 449
        85 years and over
    		 0 3 0 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.2 ( 9.1 ) 63.1 ( 9.2 ) 63.3 ( 8.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 56 68 49 173
        Male
    		 269 253 275 797
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 79 85 84 248
        Black or African American
    		 4 1 6 11
        American Indian or Alaska Native
    		 1 2 1 4
        Asian Indian
    		 1 4 3 8
        Chinese
    		 71 74 70 215
        Japanese
    		 131 126 137 394
        Asian Other
    		 28 23 17 68
        Other
    		 10 6 6 22

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Nivolumab + Ipilimumab
    Reporting group description
    		 Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.

    Reporting group title
    Arm B: Nivolumab + Chemotherapy
    Reporting group description
    		 Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.

    Reporting group title
    Arm C: Chemotherapy
    Reporting group description
    		 Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.
    Reporting group title
    Arm A: Nivolumab + Ipilimumab
    Reporting group description
    		 Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.

    Reporting group title
    Arm B: Nivolumab + Chemotherapy
    Reporting group description
    		 Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.

    Reporting group title
    Arm C: Chemotherapy
    Reporting group description
    		 Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.

    Primary: Overall Survival (OS) in participants with tumor cell PD-L1

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    End point title
    		 Overall Survival (OS) in participants with tumor cell PD-L1
    End point description
    Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.
    End point type
    Primary
    End point timeframe
    From the date of randomization to up to the date of death (up to approximately 20 months)
    End point values
    		 Arm A: Nivolumab + Ipilimumab Arm B: Nivolumab + Chemotherapy Arm C: Chemotherapy
    Number of subjects analysed
    158
    158
    157
    Units: Months
        median (confidence interval 95%)
    13.70 (11.24 to 17.02)
    15.44 (11.93 to 19.52)
    9.07 (7.69 to 9.95)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy.
    Comparison groups
    Arm A: Nivolumab + Ipilimumab v Arm C: Chemotherapy
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 98.6%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.9
    Notes
    [1] - Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy.
    Comparison groups
    Arm A: Nivolumab + Ipilimumab v Arm C: Chemotherapy
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.84
    Notes
    [2] - Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
    Comparison groups
    Arm B: Nivolumab + Chemotherapy v Arm C: Chemotherapy
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 99.5%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.8
    Notes
    [3] - Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
    Comparison groups
    Arm B: Nivolumab + Chemotherapy v Arm C: Chemotherapy
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.71
    Notes
    [4] - Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT.

    Primary: Progression-free survival (PFS) as assessed by BICR in participants with tumor cell PD-L1

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    End point title
    		 Progression-free survival (PFS) as assessed by BICR in participants with tumor cell PD-L1
    End point description
    Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
    End point type
    Primary
    End point timeframe
    From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 9 months)
    End point values
    		 Arm A: Nivolumab + Ipilimumab Arm B: Nivolumab + Chemotherapy Arm C: Chemotherapy
    Number of subjects analysed
    158
    158
    157
    Units: Months
        median (confidence interval 95%)
    4.04 (2.40 to 4.93)
    6.93 (5.68 to 8.34)
    4.44 (2.89 to 5.82)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
    Comparison groups
    Arm A: Nivolumab + Ipilimumab v Arm C: Chemotherapy
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8958 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 98.5%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.43
    Notes
    [5] - Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
    Comparison groups
    Arm B: Nivolumab + Chemotherapy v Arm C: Chemotherapy
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0023 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.86
    Notes
    [6] - Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
    Comparison groups
    Arm B: Nivolumab + Chemotherapy v Arm C: Chemotherapy
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0023 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 98.5%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.92
    Notes
    [7] - Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
    Comparison groups
    Arm A: Nivolumab + Ipilimumab v Arm C: Chemotherapy
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8958 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.34
    Notes
    [8] - Log-rank test stratified by ECOG Performance Status (0 vs 1), number of organs with metastases (<= 1 vs. >= 2) as recorded in IRT

    Secondary: Overall Survival (OS) in all randomized participants

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    End point title
    		 Overall Survival (OS) in all randomized participants
    End point description
    Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the subject was known to be alive.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to up to the date of death (up to approximately 88 months)
    End point values
    		 Arm A: Nivolumab + Ipilimumab Arm B: Nivolumab + Chemotherapy Arm C: Chemotherapy
    Number of subjects analysed
    325
    321
    324
    Units: Months
        median (confidence interval 95%)
    12.747 (11.269 to 15.474)
    13.207 (11.105 to 15.671)
    10.710 (9.396 to 12.090)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
    Comparison groups
    Arm B: Nivolumab + Chemotherapy v Arm C: Chemotherapy
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.92
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
    Comparison groups
    Arm A: Nivolumab + Ipilimumab v Arm C: Chemotherapy
    Number of subjects included in analysis
    649
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.92

    Secondary: Progression-free survival (PFS) in all randomized participants as assessed by BICR

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    End point title
    		 Progression-free survival (PFS) in all randomized participants as assessed by BICR
    End point description
    Progression-free survival (PFS) is defined as the time from randomization to the date of the first documented progressive disease (PD) per Blinded Independent Central Review (BICR) or death due to any cause. Participants who die without a reported prior PD per BICR (and die without start of subsequent therapy) will be considered to have progressed on the date of death. Participants who did not have documented PD per BICR per RECIST1.1 criteria and who did not die, will be censored at the date of the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on-study tumor assessments and did not die (or died after initiation of the subsequent anti-cancer therapy) will be censored at the randomization date. Participants who started any subsequent anti-cancer therapy without a prior reported PD per BICR will be censored at the last tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to up to the date of the first documented disease progression or death (up to approximately 88 months)
    End point values
    		 Arm A: Nivolumab + Ipilimumab Arm B: Nivolumab + Chemotherapy Arm C: Chemotherapy
    Number of subjects analysed
    325
    321
    324
    Units: Months
        median (confidence interval 95%)
    2.891 (2.661 to 4.172)
    5.782 (5.520 to 6.998)
    5.618 (4.304 to 5.914)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is Arm B: Nivolumab + Chemotherapy over Arm C: Chemotherapy
    Comparison groups
    Arm B: Nivolumab + Chemotherapy v Arm C: Chemotherapy
    Number of subjects included in analysis
    645
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is Arm A: Nivolumab + Ipilimumab over Arm C: Chemotherapy
    Comparison groups
    Arm A: Nivolumab + Ipilimumab v Arm C: Chemotherapy
    Number of subjects included in analysis
    649
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 1.5

    Secondary: Objective Response Rate (ORR) as assessed by BICR

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    End point title
    		 Objective Response Rate (ORR) as assessed by BICR
    End point description
    Objective response rate (ORR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation as determined by BICR, recorded between the date of randomization and the date of objectively documented progression (per RECIST 1.1) or the date of subsequent anti-cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurs first. Partial response is defined as at least a 30% decrease in the sum of diameters of target lesions. Complete response is defined as the disappearance of all target lesions and the reduction of any pathological lymph nodes to <10 mm.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to up to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to 88 months)
    End point values
    		 Arm A: Nivolumab + Ipilimumab Arm B: Nivolumab + Chemotherapy Arm C: Chemotherapy
    Number of subjects analysed
    325
    321
    324
    Units: Percentage of participants
    number (confidence interval 95%)
        Participants with baseline PD-L1 status < 1%
    20.1 (14.3 to 27.1)
    41.7 (34.1 to 49.7)
    33.7 (26.6 to 41.5)
        Participants with baseline PD-L1 status >= 1%
    35.4 (28.0 to 43.4)
    53.2 (45.1 to 61.1)
    19.9 (13.9 to 27.0)
        Participants with baseline PD-L1 status < 5%
    22.3 (16.7 to 28.6)
    44.8 (37.8 to 51.9)
    30.9 (24.7 to 37.7)
        Participants with baseline PD-L1 status >= 5%
    36.7 (28.1 to 45.9)
    51.7 (42.4 to 60.9)
    20.0 (13.1 to 28.5)
        Participants with baseline PD-L1 status < 10%
    23.3 (17.9 to 29.5)
    46.1 (39.4 to 53.0)
    29.3 (23.5 to 35.8)
        Participants with baseline PD-L1 status >= 10%
    36.9 (27.6 to 47.0)
    50.0 (39.9 to 60.1)
    21.6 (13.9 to 31.2)
        Participants with baseline PD-L1 missing
    33.3 (0.8 to 90.6)
    99999 (99999 to 99999)
    0.0 (0.0 to 84.2)
        All randomized participants
    27.4 (22.6 to 32.6)
    47.4 (41.8 to 53.0)
    26.9 (22.1 to 32.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All cause mortality was collected till 88 months and Serious and Non-Serious AEs from first dose (Day 1) to 100 days post last dose (up to 43 months)
    Adverse event reporting additional description
    All cause mortality was collected for all the randomized participants and serious and non-serious adverse events were collected for treated population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Arm A: Nivolumab + Ipilimumab
    Reporting group description
    		 Participants will receive treatment with nivolumab 3 mg/kg as a 30-minute infusion every 2 weeks and ipilimumab as a 30-minute infusion 1 mg/kg every 6 weeks.

    Reporting group title
    Arm C: Chemotherapy
    Reporting group description
    		 Participants will receive treatment with fluorouracil 800 mg/m²/day as an IV continuous infusion from Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.

    Reporting group title
    Arm B: Nivolumab + Chemotherapy
    Reporting group description
    		 Participants will receive treatment with nivolumab 240 mg as a 30-minute infusion on Day 1 and Day 15, fluorouracil 800 mg/m²/day as an IV continuous infusion on Day 1 through Day 5 (for 5 days), and cisplatin 80 mg/m² as a 30- to 120-minute infusion on Day 1 of 4-week cycle.

    Serious adverse events
    		 Arm A: Nivolumab + Ipilimumab Arm C: Chemotherapy Arm B: Nivolumab + Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    243 / 322 (75.47%)
    174 / 304 (57.24%)
    226 / 310 (72.90%)
         number of deaths (all causes)
    267
    266
    262
         number of deaths resulting from adverse events
    85
    75
    82
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adult T-cell lymphoma/leukaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    3 / 322 (0.93%)
    1 / 304 (0.33%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    59 / 322 (18.32%)
    65 / 304 (21.38%)
    61 / 310 (19.68%)
         occurrences causally related to treatment / all
    0 / 59
    0 / 66
    0 / 63
         deaths causally related to treatment / all
    0 / 49
    0 / 58
    0 / 49
    Lipoma
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopharyngeal cancer
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenoma
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone marrow
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Tumour compression
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases to kidney
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour fistulisation
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    3 / 304 (0.99%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 322 (0.31%)
    4 / 304 (1.32%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Poor venous access
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 322 (0.62%)
    3 / 304 (0.99%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Internal haemorrhage
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 304 (0.66%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Oesophageal operation
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Assisted suicide
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 322 (1.55%)
    1 / 304 (0.33%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site discharge
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    5 / 322 (1.55%)
    0 / 304 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
    Mucosal inflammation
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 304 (0.66%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 322 (0.62%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
    Feeling cold
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 322 (0.93%)
    1 / 304 (0.33%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nodule
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    14 / 322 (4.35%)
    7 / 304 (2.30%)
    7 / 310 (2.26%)
         occurrences causally related to treatment / all
    6 / 17
    1 / 7
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 322 (0.31%)
    2 / 304 (0.66%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    Polyp
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 322 (1.55%)
    2 / 304 (0.66%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 304 (0.66%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mediastinal disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    5 / 322 (1.55%)
    2 / 304 (0.66%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 322 (1.24%)
    1 / 304 (0.33%)
    5 / 310 (1.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 322 (0.62%)
    3 / 304 (0.99%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    13 / 322 (4.04%)
    1 / 304 (0.33%)
    6 / 310 (1.94%)
         occurrences causally related to treatment / all
    13 / 13
    0 / 1
    9 / 9
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Stridor
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheal stenosis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheal fistula
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Depression
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Logorrhoea
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patient-device incompatibility
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adjusted calcium increased
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    3 / 322 (0.93%)
    1 / 304 (0.33%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood calcium increased
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram Q wave abnormal
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cortisol decreased
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 304 (0.66%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urine output decreased
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrio-oesophageal fistula
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heat illness
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Stoma site discharge
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation oesophagitis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    5 / 322 (1.55%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site pain
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 322 (0.31%)
    2 / 304 (0.66%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 322 (0.31%)
    3 / 304 (0.99%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriospasm coronary
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 322 (0.62%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain stem haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated encephalopathy
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated encephalitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stupor
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 322 (1.86%)
    7 / 304 (2.30%)
    5 / 310 (1.61%)
         occurrences causally related to treatment / all
    0 / 6
    2 / 8
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 322 (1.86%)
    5 / 304 (1.64%)
    7 / 310 (2.26%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 5
    4 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye pain
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vogt-Koyanagi-Harada disease
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 322 (0.31%)
    2 / 304 (0.66%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 322 (0.31%)
    2 / 304 (0.66%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 322 (1.55%)
    3 / 304 (0.99%)
    7 / 310 (2.26%)
         occurrences causally related to treatment / all
    2 / 5
    3 / 3
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 322 (0.62%)
    1 / 304 (0.33%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    4 / 322 (1.24%)
    0 / 304 (0.00%)
    5 / 310 (1.61%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aorto-oesophageal fistula
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric fistula
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    12 / 322 (3.73%)
    16 / 304 (5.26%)
    21 / 310 (6.77%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 20
    1 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 322 (1.55%)
    2 / 304 (0.66%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Haematemesis
         subjects affected / exposed
    2 / 322 (0.62%)
    2 / 304 (0.66%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 304 (0.66%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    2 / 322 (0.62%)
    5 / 304 (1.64%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 5
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal mass
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal haemorrhage
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    0 / 322 (0.00%)
    3 / 304 (0.99%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal motility disorder
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    3 / 322 (0.93%)
    5 / 304 (1.64%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    4 / 322 (1.24%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagomediastinal fistula
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal-pulmonary fistula
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    3 / 322 (0.93%)
    13 / 304 (4.28%)
    9 / 310 (2.90%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 13
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Oesophageal pain
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Rectal perforation
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    6 / 310 (1.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 322 (1.24%)
    2 / 304 (0.66%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 322 (1.55%)
    12 / 304 (3.95%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    4 / 6
    9 / 12
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    9 / 322 (2.80%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    8 / 9
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 322 (0.62%)
    4 / 304 (1.32%)
    9 / 310 (2.90%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
    Hydronephrosis
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 322 (0.00%)
    2 / 304 (0.66%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    8 / 322 (2.48%)
    0 / 304 (0.00%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    7 / 8
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorder
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    6 / 322 (1.86%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    7 / 322 (2.17%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    3 / 322 (0.93%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated arthritis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 322 (0.62%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 322 (0.00%)
    3 / 304 (0.99%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bacterial infection
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis bacterial
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 322 (0.62%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 322 (0.00%)
    3 / 304 (0.99%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    32 / 322 (9.94%)
    20 / 304 (6.58%)
    33 / 310 (10.65%)
         occurrences causally related to treatment / all
    0 / 35
    2 / 23
    6 / 40
         deaths causally related to treatment / all
    0 / 6
    1 / 3
    1 / 6
    Pneumonia aspiration
         subjects affected / exposed
    12 / 322 (3.73%)
    8 / 304 (2.63%)
    6 / 310 (1.94%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 8
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    4 / 322 (1.24%)
    2 / 304 (0.66%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    Sepsis
         subjects affected / exposed
    4 / 322 (1.24%)
    3 / 304 (0.99%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Stoma site cellulitis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethritis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 322 (0.31%)
    2 / 304 (0.66%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Decreased appetite
         subjects affected / exposed
    9 / 322 (2.80%)
    7 / 304 (2.30%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    2 / 9
    2 / 7
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    9 / 322 (2.80%)
    6 / 304 (1.97%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    3 / 10
    4 / 6
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fulminant type 1 diabetes mellitus
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    5 / 322 (1.55%)
    4 / 304 (1.32%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    4 / 322 (1.24%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 322 (0.00%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 322 (0.00%)
    1 / 304 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    6 / 322 (1.86%)
    4 / 304 (1.32%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    6 / 7
    4 / 5
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    2 / 304 (0.66%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 322 (0.31%)
    0 / 304 (0.00%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    2 / 322 (0.62%)
    0 / 304 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 322 (0.31%)
    1 / 304 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Nivolumab + Ipilimumab Arm C: Chemotherapy Arm B: Nivolumab + Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    301 / 322 (93.48%)
    288 / 304 (94.74%)
    307 / 310 (99.03%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    18 / 322 (5.59%)
    19 / 304 (6.25%)
    15 / 310 (4.84%)
         occurrences all number
    19
    19
    18
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 322 (2.80%)
    22 / 304 (7.24%)
    24 / 310 (7.74%)
         occurrences all number
    15
    25
    37
    Hypotension
         subjects affected / exposed
    11 / 322 (3.42%)
    16 / 304 (5.26%)
    13 / 310 (4.19%)
         occurrences all number
    11
    19
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    56 / 322 (17.39%)
    63 / 304 (20.72%)
    83 / 310 (26.77%)
         occurrences all number
    69
    98
    121
    Asthenia
         subjects affected / exposed
    25 / 322 (7.76%)
    26 / 304 (8.55%)
    24 / 310 (7.74%)
         occurrences all number
    29
    38
    52
    Infusion site extravasation
         subjects affected / exposed
    6 / 322 (1.86%)
    20 / 304 (6.58%)
    15 / 310 (4.84%)
         occurrences all number
    6
    28
    24
    Malaise
         subjects affected / exposed
    27 / 322 (8.39%)
    55 / 304 (18.09%)
    59 / 310 (19.03%)
         occurrences all number
    36
    85
    108
    Pyrexia
         subjects affected / exposed
    76 / 322 (23.60%)
    48 / 304 (15.79%)
    65 / 310 (20.97%)
         occurrences all number
    131
    59
    84
    Oedema peripheral
         subjects affected / exposed
    32 / 322 (9.94%)
    25 / 304 (8.22%)
    45 / 310 (14.52%)
         occurrences all number
    37
    52
    67
    Mucosal inflammation
         subjects affected / exposed
    4 / 322 (1.24%)
    30 / 304 (9.87%)
    37 / 310 (11.94%)
         occurrences all number
    4
    41
    70
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    14 / 322 (4.35%)
    16 / 304 (5.26%)
    14 / 310 (4.52%)
         occurrences all number
    15
    18
    17
    Pneumonitis
         subjects affected / exposed
    17 / 322 (5.28%)
    6 / 304 (1.97%)
    20 / 310 (6.45%)
         occurrences all number
    17
    6
    21
    Hiccups
         subjects affected / exposed
    12 / 322 (3.73%)
    63 / 304 (20.72%)
    53 / 310 (17.10%)
         occurrences all number
    15
    124
    115
    Dyspnoea
         subjects affected / exposed
    24 / 322 (7.45%)
    11 / 304 (3.62%)
    14 / 310 (4.52%)
         occurrences all number
    27
    11
    20
    Cough
         subjects affected / exposed
    40 / 322 (12.42%)
    37 / 304 (12.17%)
    44 / 310 (14.19%)
         occurrences all number
    52
    42
    51
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    33 / 322 (10.25%)
    40 / 304 (13.16%)
    54 / 310 (17.42%)
         occurrences all number
    37
    48
    63
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    12 / 322 (3.73%)
    61 / 304 (20.07%)
    75 / 310 (24.19%)
         occurrences all number
    20
    131
    188
    Lymphocyte count decreased
         subjects affected / exposed
    8 / 322 (2.48%)
    9 / 304 (2.96%)
    16 / 310 (5.16%)
         occurrences all number
    14
    13
    39
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 322 (0.00%)
    9 / 304 (2.96%)
    20 / 310 (6.45%)
         occurrences all number
    0
    11
    24
    Blood creatinine increased
         subjects affected / exposed
    13 / 322 (4.04%)
    40 / 304 (13.16%)
    41 / 310 (13.23%)
         occurrences all number
    17
    60
    71
    Blood alkaline phosphatase increased
         subjects affected / exposed
    19 / 322 (5.90%)
    10 / 304 (3.29%)
    22 / 310 (7.10%)
         occurrences all number
    23
    11
    24
    Aspartate aminotransferase increased
         subjects affected / exposed
    48 / 322 (14.91%)
    12 / 304 (3.95%)
    28 / 310 (9.03%)
         occurrences all number
    61
    17
    32
    Platelet count decreased
         subjects affected / exposed
    13 / 322 (4.04%)
    36 / 304 (11.84%)
    46 / 310 (14.84%)
         occurrences all number
    18
    73
    95
    Alanine aminotransferase increased
         subjects affected / exposed
    44 / 322 (13.66%)
    13 / 304 (4.28%)
    26 / 310 (8.39%)
         occurrences all number
    60
    18
    35
    Weight decreased
         subjects affected / exposed
    43 / 322 (13.35%)
    35 / 304 (11.51%)
    41 / 310 (13.23%)
         occurrences all number
    51
    44
    51
    Weight increased
         subjects affected / exposed
    6 / 322 (1.86%)
    14 / 304 (4.61%)
    25 / 310 (8.06%)
         occurrences all number
    8
    25
    41
    White blood cell count decreased
         subjects affected / exposed
    12 / 322 (3.73%)
    41 / 304 (13.49%)
    58 / 310 (18.71%)
         occurrences all number
    30
    70
    141
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 322 (8.07%)
    16 / 304 (5.26%)
    27 / 310 (8.71%)
         occurrences all number
    29
    17
    33
    Dizziness
         subjects affected / exposed
    17 / 322 (5.28%)
    29 / 304 (9.54%)
    18 / 310 (5.81%)
         occurrences all number
    19
    38
    31
    Dysgeusia
         subjects affected / exposed
    10 / 322 (3.11%)
    19 / 304 (6.25%)
    23 / 310 (7.42%)
         occurrences all number
    10
    25
    30
    Peripheral sensory neuropathy
         subjects affected / exposed
    5 / 322 (1.55%)
    28 / 304 (9.21%)
    31 / 310 (10.00%)
         occurrences all number
    7
    29
    32
    Neuropathy peripheral
         subjects affected / exposed
    2 / 322 (0.62%)
    15 / 304 (4.93%)
    22 / 310 (7.10%)
         occurrences all number
    2
    16
    26
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    6 / 322 (1.86%)
    23 / 304 (7.57%)
    38 / 310 (12.26%)
         occurrences all number
    12
    38
    70
    Anaemia
         subjects affected / exposed
    84 / 322 (26.09%)
    108 / 304 (35.53%)
    156 / 310 (50.32%)
         occurrences all number
    122
    168
    265
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    16 / 322 (4.97%)
    13 / 304 (4.28%)
    22 / 310 (7.10%)
         occurrences all number
    17
    16
    25
    Abdominal pain
         subjects affected / exposed
    22 / 322 (6.83%)
    18 / 304 (5.92%)
    23 / 310 (7.42%)
         occurrences all number
    24
    22
    29
    Constipation
         subjects affected / exposed
    87 / 322 (27.02%)
    138 / 304 (45.39%)
    142 / 310 (45.81%)
         occurrences all number
    104
    203
    216
    Diarrhoea
         subjects affected / exposed
    84 / 322 (26.09%)
    63 / 304 (20.72%)
    98 / 310 (31.61%)
         occurrences all number
    114
    116
    171
    Vomiting
         subjects affected / exposed
    53 / 322 (16.46%)
    60 / 304 (19.74%)
    77 / 310 (24.84%)
         occurrences all number
    68
    95
    132
    Stomatitis
         subjects affected / exposed
    34 / 322 (10.56%)
    75 / 304 (24.67%)
    100 / 310 (32.26%)
         occurrences all number
    43
    148
    197
    Nausea
         subjects affected / exposed
    88 / 322 (27.33%)
    172 / 304 (56.58%)
    207 / 310 (66.77%)
         occurrences all number
    119
    378
    452
    Dysphagia
         subjects affected / exposed
    39 / 322 (12.11%)
    31 / 304 (10.20%)
    42 / 310 (13.55%)
         occurrences all number
    44
    37
    52
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    17 / 322 (5.28%)
    1 / 304 (0.33%)
    3 / 310 (0.97%)
         occurrences all number
    22
    1
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    10 / 322 (3.11%)
    42 / 304 (13.82%)
    42 / 310 (13.55%)
         occurrences all number
    10
    42
    42
    Dry skin
         subjects affected / exposed
    18 / 322 (5.59%)
    12 / 304 (3.95%)
    13 / 310 (4.19%)
         occurrences all number
    19
    12
    13
    Pruritus
         subjects affected / exposed
    59 / 322 (18.32%)
    20 / 304 (6.58%)
    38 / 310 (12.26%)
         occurrences all number
    71
    21
    52
    Rash
         subjects affected / exposed
    75 / 322 (23.29%)
    22 / 304 (7.24%)
    43 / 310 (13.87%)
         occurrences all number
    100
    27
    52
    Rash maculo-papular
         subjects affected / exposed
    18 / 322 (5.59%)
    3 / 304 (0.99%)
    8 / 310 (2.58%)
         occurrences all number
    20
    3
    9
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    2 / 322 (0.62%)
    17 / 304 (5.59%)
    12 / 310 (3.87%)
         occurrences all number
    2
    21
    13
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    44 / 322 (13.66%)
    1 / 304 (0.33%)
    23 / 310 (7.42%)
         occurrences all number
    45
    1
    24
    Hyperthyroidism
         subjects affected / exposed
    20 / 322 (6.21%)
    1 / 304 (0.33%)
    7 / 310 (2.26%)
         occurrences all number
    22
    1
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    28 / 322 (8.70%)
    13 / 304 (4.28%)
    19 / 310 (6.13%)
         occurrences all number
    33
    15
    20
    Back pain
         subjects affected / exposed
    21 / 322 (6.52%)
    15 / 304 (4.93%)
    12 / 310 (3.87%)
         occurrences all number
    22
    15
    15
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    37 / 322 (11.49%)
    30 / 304 (9.87%)
    33 / 310 (10.65%)
         occurrences all number
    41
    32
    39
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    9 / 322 (2.80%)
    5 / 304 (1.64%)
    18 / 310 (5.81%)
         occurrences all number
    15
    8
    28
    Hypoalbuminaemia
         subjects affected / exposed
    34 / 322 (10.56%)
    20 / 304 (6.58%)
    25 / 310 (8.06%)
         occurrences all number
    54
    28
    34
    Hyperkalaemia
         subjects affected / exposed
    12 / 322 (3.73%)
    22 / 304 (7.24%)
    20 / 310 (6.45%)
         occurrences all number
    13
    33
    27
    Hypercalcaemia
         subjects affected / exposed
    11 / 322 (3.42%)
    9 / 304 (2.96%)
    20 / 310 (6.45%)
         occurrences all number
    13
    12
    24
    Decreased appetite
         subjects affected / exposed
    70 / 322 (21.74%)
    156 / 304 (51.32%)
    161 / 310 (51.94%)
         occurrences all number
    88
    296
    299
    Hypophosphataemia
         subjects affected / exposed
    14 / 322 (4.35%)
    4 / 304 (1.32%)
    17 / 310 (5.48%)
         occurrences all number
    16
    8
    19
    Hyponatraemia
         subjects affected / exposed
    32 / 322 (9.94%)
    36 / 304 (11.84%)
    55 / 310 (17.74%)
         occurrences all number
    48
    49
    77
    Hypokalaemia
         subjects affected / exposed
    34 / 322 (10.56%)
    30 / 304 (9.87%)
    44 / 310 (14.19%)
         occurrences all number
    55
    56
    70

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2016
    Expansion of the esophageal cohort into a 3-arm randomized Phase 3 study in first line squamous esophageal cancer. The study now includes a nivolumab plus chemotherapy arm (fluorouracil and cisplatin) and a chemotherapy alone arm in addition to the existing nivolumab and ipilimumab arm. The gastric cohort was removed.

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

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