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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind Study of Nivolumab Monotherapy or Nivolumab Combined With Ipilimumab Versus Ipilimumab Monotherapy in Subjects With Previously Untreated Unresectable or Metastatic Melanoma

    Summary
    EudraCT number
    		 2012-005371-13
    Trial protocol
    		 BE   DE   IT   AT   FI   GB   IE   CZ   NL   ES   NO   DK   PL   SE  
    Global end of trial date
    19 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Apr 2025
    First version publication date
    19 Apr 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01844505
    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, mg-gsm-ct@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 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to show that Nivolumab and/or Nivolumab in combination with Ipilimumab will extend progression free survival and overall survival compared to Ipilimumab alone.
    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
    11 Jun 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 8 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 107
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Canada: 47
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Denmark: 24
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 64
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    Ireland: 27
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 100
    Country: Number of subjects enrolled
    Netherlands: 31
    Country: Number of subjects enrolled
    New Zealand: 8
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Switzerland: 23
    Country: Number of subjects enrolled
    United Kingdom: 93
    Country: Number of subjects enrolled
    United States: 207
    Worldwide total number of subjects
    945
    EEA total number of subjects
    444
    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)
    565
    From 65 to 84 years
    365
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    		 The "Completed" category in the Treatment Period stands for "Participant not continuing in the treatment period".

    Pre-assignment
    Screening details
    		 Participants were enrolled in 21 countries.

    Period 1
    Period 1 title
    Pre-Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab
    Arm description
    		 Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered once every 2 weeks (Q2W)

    Arm title
    		 Nivolumab + Ipilimumab
    Arm description
    		 Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered once every 3 weeks

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered once every 2 weeks (Q2W)

    Arm title
    		 Ipilimumab
    Arm description
    		 Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered once every 3 weeks

    Number of subjects in period 1
    		Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Started
    316
    314
    315
    Completed
    313
    313
    311
    Not completed
    3
    1
    4
         Not Treated
    3
    1
    4
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab
    Arm description
    		 Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered once every 2 weeks (Q2W)

    Arm title
    		 Nivolumab + Ipilimumab
    Arm description
    		 Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered once every 2 weeks (Q2W)

    Arm title
    		 Ipilimumab
    Arm description
    		 Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered once every 3 weeks

    Number of subjects in period 2
    		Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Started
    313
    313
    311
    Completed
    313
    313
    311

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity

    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity

    Reporting group title
    Ipilimumab
    Reporting group description
    		 Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses

    Reporting group values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab Total
    Number of subjects
    		 316 314 315 945
    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)
    		 198 185 182 565
        From 65-84 years
    		 111 125 129 365
        85 years and over
    		 7 4 4 15
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.7 ( 13.92 ) 59.3 ( 13.86 ) 60.8 ( 13.23 ) -
    Sex: Female, Male
    Units:
        Female
    		 114 108 113 335
        Male
    		 202 206 202 610
    Race/Ethnicity, Customized
    Units: Subjects
        WHITE
    		 308 310 303 921
        BLACK OR AFRICAN AMERICAN
    		 0 0 0 0
        ASIAN
    		 2 2 6 10
        AMERICAN INDIAN OR ALASKA NATIVE
    		 1 0 0 1
        NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER
    		 1 0 0 1
        OTHER
    		 4 2 5 11
        NOT REPORTED
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity

    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity

    Reporting group title
    Ipilimumab
    Reporting group description
    		 Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses
    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity

    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity

    Reporting group title
    Ipilimumab
    Reporting group description
    		 Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses

    Primary: Progression Free Survival (PFS) - Primary

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    End point title
    		 Progression Free Survival (PFS) - Primary
    End point description
    PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the Investigator, or death due to any cause, whichever occurred first. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. Participants treated beyond progression were considered to have progressive disease at the time of the initial progression event regardless of subsequent tumor response. Particpants who started anti-cancer therapy without a prior reported progression were censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy.
    End point type
    Primary
    End point timeframe
    From randomization until disease progression or death, whichever occurred first (assessed up to February 2015, approximately 20 months)
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316
    314
    315
    Units: months
        median (confidence interval 95%)
    6.87 (4.34 to 9.46)
    11.50 (8.90 to 16.72)
    2.89 (2.79 to 3.42)
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log Rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 99.5%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.76
    Statistical analysis title
    		 Analysis 2
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log Rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.42
    Confidence interval
         level
    		 99.5%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.57

    Primary: Overall Survival (OS)-Primary

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    End point title
    		 Overall Survival (OS)-Primary
    End point description
    OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive.
    End point type
    Primary
    End point timeframe
    From randomization to date of death (Assessed up to September 2016, approximately 39 months)
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [1]
    314 [2]
    315 [3]
    Units: months
        median (confidence interval 95%)
    99999 (29.08 to 99999)
    99999 (99999 to 99999)
    19.98 (17.08 to 24.61)
    Notes
    [1] - 99999 stands for Not Estimable
    [2] - 99999 stands for Not Estimable
    [3] - 99999 stands for Not Estimable
    Statistical analysis title
    		 Analysis 2
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.55
    Confidence interval
         level
    		 98%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.72
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 98%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.78

    Primary: Rate of Overall Survival

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    End point title
    		 Rate of Overall Survival [4]
    End point description
    OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive. The overall survival rate at time T (6, 12, or 24 months) was defined as the probability that a participant was alive at time T following randomization.
    End point type
    Primary
    End point timeframe
    24 months
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not required as per statistical design for those arms.
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316
    314
    315
    Units: Probability of survival at Time T
    number (confidence interval 95%)
        Rate of OS at 6 months
    0.85 (0.81 to 0.89)
    0.86 (0.81 to 0.89)
    0.82 (0.78 to 0.86)
        Rate of OS at 12 months
    0.74 (0.69 to 0.79)
    0.73 (0.68 to 0.78)
    0.67 (0.61 to 0.72)
        Rate of OS at 24 months
    0.59 (0.53 to 0.64)
    0.64 (0.59 to 0.69)
    0.45 (0.39 to 0.50)
    No statistical analyses for this end point

    Primary: Rate of Progression-Free Survival

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    End point title
    		 Rate of Progression-Free Survival [5]
    End point description
    PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the Investigator, or death due to any cause, whichever occurred first. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. Participants treated beyond progression were considered to have progressive disease at the time of the initial progression event regardless of subsequent tumor response. Participants who started anti-cancer therapy without a prior reported progression were censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy.
    End point type
    Primary
    End point timeframe
    24 months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Not required as per statistical design for those arms.
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316
    314
    315
    Units: Percentage of participants
    number (confidence interval 95%)
        Rate at 6 months
    0.52 (0.46 to 0.58)
    0.63 (0.57 to 0.68)
    0.28 (0.23 to 0.33)
        Rate at 12 months
    0.43 (0.37 to 0.49)
    0.50 (0.44 to 0.55)
    0.18 (0.14 to 0.22)
        Rate at 24 months
    0.37 (0.31 to 0.43)
    0.43 (0.37 to 0.48)
    0.12 (0.09 to 0.17)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the Investigator, or death due to any cause, whichever occurred first. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. Participants treated beyond progression were considered to have progressive disease at the time of the initial progression event regardless of subsequent tumor response. Participants who started anti-cancer therapy without a prior reported progression were censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression or death, whichever occurred first (assessed up to approximately 128 months)
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316
    314
    315
    Units: months
        median (confidence interval 95%)
    6.93 (5.13 to 10.18)
    11.50 (8.90 to 20.04)
    2.86 (2.79 to 3.09)
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 0.96

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive.
    End point type
    Secondary
    End point timeframe
    From randomization until death (assessed up to approximately 128 months)
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316
    314
    315
    Units: months
        median (confidence interval 95%)
    36.93 (28.25 to 58.71)
    71.92 (38.18 to 114.37)
    19.94 (16.85 to 24.61)
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.05

    Secondary: Objective Response Rate (ORR) per Investigator Assessment

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    End point title
    		 Objective Response Rate (ORR) per Investigator Assessment
    End point description
    The ORR was defined as the percentage of participants with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized participants for each arm. The BOR was defined as the best response designation, as determined by the Investigator, recorded between the date of randomization and the date of progression, as assessed by the Investigator per RECIST 1.1 or the date of subsequent anticancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever occurred first. For participants without evidence of RECIST 1.1 progression or subsequent anticancer therapy, all available response designations contributed to the BOR assessment. CR= Disappearance of all evidence of disease, confirmed by PET scan; PR= Regression of measureable disease and no new sites; Stable Disease (SD)= Failure to attain CR/PR or PD; Progressive Disease (PD)= Any new lesion or increase by >=50% of previously involved sites from nadir.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression or death, whichever occurred first (assessed up to approximately 128 months)
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316
    314
    315
    Units: Percentage of participants
        number (confidence interval 95%)
    44.9 (39.4 to 50.6)
    58.3 (52.6 to 63.8)
    19.0 (14.9 to 23.8)
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.49
         upper limit
    		 5.16
    Statistical analysis title
    		 Analysis 2
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.38
         upper limit
    		 9.22
    Statistical analysis title
    		 Analysis 6
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference of Objective Response Rates
    Point estimate
    13.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.7
         upper limit
    		 20.7
    Statistical analysis title
    		 Analysis 4
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference of Objective Response Rates
    Point estimate
    39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 32.2
         upper limit
    		 45.9
    Statistical analysis title
    		 Analysis 5
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.26
         upper limit
    		 2.42
    Statistical analysis title
    		 Analysis 3
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference of Objective Response Rates
    Point estimate
    26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 19.1
         upper limit
    		 32.8

    Secondary: Progression-Free Survival based on PD-L1 Expression Level

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    End point title
    		 Progression-Free Survival based on PD-L1 Expression Level
    End point description
    PD-L1 expression was defined as the percent of tumor cells demonstrating plasma membrane PD-L1 staining of any intensity using an IHC assay. Tumor biopsy specimens without measurable PD-L1 expression were classified as indeterminate if the staining was hampered for reasons attributed to the biology of the specimen and not because of improper specimen preparation or handling. Missing specimens, specimens that were not optimally collected (ie not evaluable), and all other specimens were classified as unknown. Participants must have been classified as PD-L1 >=5% or PD-L1 <5% per a verified IHC assay, or as indeterminate (ie not unknown), in order to be randomized.
    End point type
    Secondary
    End point timeframe
    From randomization until disease progression or death from any cause, whichever occurs first (Assessed up to September 2016, approximately 39 months)
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [6]
    314 [7]
    315 [8]
    Units: months
    median (confidence interval 95%)
        PD-L1 < 1% (n=117, 123, 113)
    2.83 (2.76 to 5.39)
    11.17 (6.93 to 26.68)
    2.76 (2.66 to 2.86)
        PD-L1 >= 1% (n= 171, 155, 164)
    16.20 (8.11 to 27.66)
    16.72 (9.72 to 99999)
    3.48 (2.83 to 4.17)
        PD-L1 < 5% (n= 208, 210, 202)
    5.32 (2.96 to 6.87)
    11.17 (8.31 to 22.18)
    2.83 (2.76 to 3.02)
        PD-L1 >= 5% (n= 80, 68, 75)
    22.34 (9.46 to 99999)
    22.11 (9.72 to 99999)
    3.94 (2.79 to 4.21)
        PD-L1 < 10% (n= 229, 232, 223)
    5.62 (3.09 to 8.87)
    11.10 (8.02 to 18.14)
    2.83 (2.76 to 3.02)
        PD-L1 >= 10% (n= 59, 46, 54)
    21.98 (9.07 to 99999)
    99999 (13.96 to 99999)
    4.11 (2.79 to 5.59)
        PD-L1 Indeterminate/ Not Evaluable (n= 28, 36, 38)
    2.99 (2.66 to 6.93)
    6.93 (2.79 to 20.04)
    2.83 (2.60 to 6.41)
    Notes
    [6] - 99999 stands for Not Estimable
    [7] - 99999 stands for Not Estimable
    [8] - 99999 stands for Not Estimable
    Statistical analysis title
    		 Analysis 3
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.87
    Statistical analysis title
    		 Analysis 4
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.59
    Statistical analysis title
    		 Analysis 2
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.54
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.85
    Statistical analysis title
    		 Analysis 7
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.71
    Statistical analysis title
    		 Analysis 8
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.53
    Statistical analysis title
    		 Analysis 9
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.94
    Statistical analysis title
    		 Analysis 10
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.6
    Statistical analysis title
    		 Analysis 11
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.54
    Statistical analysis title
    		 Analysis 12
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.38
    Statistical analysis title
    		 Analysis 13
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.67
    Statistical analysis title
    		 Analysis 14
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.54
    Statistical analysis title
    		 Analysis 5
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.53
    Statistical analysis title
    		 Analysis 6
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.21
    Statistical analysis title
    		 Analysis 18
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.09
    Statistical analysis title
    		 Analysis 17
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.49
    Statistical analysis title
    		 Analysis 16
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.73
    Statistical analysis title
    		 Analysis 15
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.01
    Statistical analysis title
    		 Analysis 19
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.52
    Statistical analysis title
    		 Analysis 20
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.89
    Statistical analysis title
    		 Analysis 21
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.09

    Secondary: Overall Survival based on PD-L1 Expression Level

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    End point title
    		 Overall Survival based on PD-L1 Expression Level
    End point description
    OS was defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS was censored on the last date the participant was known to be alive.
    End point type
    Secondary
    End point timeframe
    From randomization until date of death (Assessed up to September 2016, approximately 39 months)
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [9]
    314 [10]
    315 [11]
    Units: months
    median (confidence interval 95%)
        PD-L1 < 1% (n=117, 123, 113)
    23.46 (13.01 to 99999)
    99999 (26.45 to 99999)
    18.56 (13.67 to 23.20)
        PD-L1 >= 1% (n= 171, 155, 164)
    85.09 (39.00 to 99999)
    82.30 (39.06 to 99999)
    21.49 (16.85 to 29.08)
        PD-L1 < 5% (n= 208, 210, 202)
    35.94 (23.06 to 59.24)
    65.94 (32.72 to 114.37)
    18.40 (13.70 to 22.51)
        PD-L1 >= 5% (n= 80, 68, 75)
    64.51 (33.64 to 99999)
    104.97 (39.06 to 99999)
    28.88 (18.10 to 44.16)
        PD-L1 < 10% (n= 229, 232, 223)
    36.93 (23.46 to 80.85)
    70.74 (34.83 to 107.89)
    18.56 (14.98 to 23.03)
        PD-L1 >= 10% (n= 59, 46, 54)
    43.63 (31.24 to 99999)
    99999 (39.06 to 99999)
    29.08 (17.45 to 46.55)
        PD-L1 Indeterminate/ Not Evaluable (n= 28, 36, 38)
    23.89 (11.76 to 99999)
    99999 (21.39 to 99999)
    18.73 (8.41 to 30.00)
    Notes
    [9] - 99999 stands for Not Estimable
    [10] - 99999 stands for Not Estimable
    [11] - 99999 stands for Not Estimable
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.05
    Statistical analysis title
    		 Analysis 2
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.81
    Statistical analysis title
    		 Analysis 12
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.53
    Statistical analysis title
    		 Analysis 11
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.91
    Statistical analysis title
    		 Analysis 10
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.91
    Statistical analysis title
    		 Analysis 9
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.08
    Statistical analysis title
    		 Analysis 8
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.66
    Statistical analysis title
    		 Analysis 7
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.78
    Statistical analysis title
    		 Analysis 6
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.31
    Statistical analysis title
    		 Analysis 5
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.67
    Statistical analysis title
    		 Analysis 3
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.04
    Statistical analysis title
    		 Analysis 4
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.68
    Statistical analysis title
    		 Analysis 18
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    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
    		 0.45
         upper limit
    		 1.32
    Statistical analysis title
    		 Analysis 17
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.91
    Statistical analysis title
    		 Analysis 16
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.1
    Statistical analysis title
    		 Analysis 15
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.14
    Statistical analysis title
    		 Analysis 21
    Comparison groups
    Nivolumab v Nivolumab + Ipilimumab
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.39
    Statistical analysis title
    		 Analysis 13
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.75
    Statistical analysis title
    		 Analysis 20
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.91
    Statistical analysis title
    		 Analysis 19
    Comparison groups
    Nivolumab v Ipilimumab
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.34
    Statistical analysis title
    		 Analysis 14
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.68

    Secondary: Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status

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    End point title
    		 Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status
    End point description
    Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 5, 7, 11, 13, 17, 19, 23, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 133, 139, 145, 151 and 157
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [12]
    314 [13]
    315 [14]
    Units: Points on EORTC scale
    arithmetic mean (standard deviation)
        Week 5 (n= 233, 183, 221)
    -2.8 ( 15.74 )
    -4.3 ( 21.38 )
    -3.1 ( 17.24 )
        Week 7 (n= 239, 183, 218)
    -2.6 ( 16.89 )
    -5.0 ( 20.60 )
    -4.3 ( 18.07 )
        Week 11 (n= 201, 112, 163)
    -2.0 ( 18.10 )
    -2.4 ( 21.99 )
    -6.2 ( 18.73 )
        Week 13 (n= 195, 106, 130)
    -1.9 ( 16.44 )
    -3.8 ( 21.21 )
    -5.5 ( 20.27 )
        Week 17 (n= 158, 84, 104)
    -1.6 ( 19.73 )
    -6.0 ( 22.01 )
    -6.1 ( 16.80 )
        Week 19 (n= 164, 96, 98)
    -0.8 ( 18.30 )
    -0.8 ( 21.70 )
    -5.4 ( 19.52 )
        Week 23 (n= 134, 86, 75)
    -2.8 ( 19.44 )
    -2.6 ( 22.00 )
    -3.7 ( 16.28 )
        Week 25 (n= 144, 97, 75)
    1.3 ( 17.39 )
    -3.3 ( 17.70 )
    -4.2 ( 16.52 )
        Week 31 (n= 123, 92, 51)
    2.5 ( 17.40 )
    1.5 ( 21.47 )
    2.0 ( 15.51 )
        Week 37 (n= 116, 88, 48)
    3.2 ( 18.44 )
    -0.2 ( 21.18 )
    -1.9 ( 15.11 )
        Week 43 (n= 103, 74, 44)
    3.5 ( 18.28 )
    -0.5 ( 23.04 )
    -0.9 ( 15.59 )
        Week 49 (n= 97, 70, 40)
    2.7 ( 16.52 )
    0.6 ( 21.95 )
    -0.4 ( 15.78 )
        Week 55 (n= 86, 66, 34)
    1.8 ( 14.26 )
    -2.4 ( 22.01 )
    0.7 ( 13.03 )
        Week 61 (n= 85, 61, 31)
    1.6 ( 16.29 )
    -3.6 ( 20.78 )
    0.8 ( 11.25 )
        Week 67 (n= 76, 61, 29)
    2.1 ( 17.49 )
    -2.9 ( 21.35 )
    -6.6 ( 15.17 )
        Week 73 (n= 67, 54, 19)
    0.1 ( 19.11 )
    -4.5 ( 21.76 )
    -3.5 ( 16.97 )
        Week 79 (n= 67, 54, 21)
    -0.1 ( 14.40 )
    -4.8 ( 20.51 )
    -0.8 ( 14.65 )
        Week 85 (n= 68, 51, 18)
    2.8 ( 16.64 )
    -3.3 ( 22.37 )
    0.0 ( 10.69 )
        Week 91 (n= 62, 53, 16)
    0.9 ( 17.08 )
    -3.9 ( 20.78 )
    0.5 ( 12.72 )
        Week 97 (n= 58, 49, 17)
    0.9 ( 17.01 )
    -5.1 ( 23.06 )
    -2.9 ( 12.13 )
        Week 103 (n= 53, 46, 17)
    2.2 ( 17.61 )
    -9.8 ( 19.03 )
    0.0 ( 13.50 )
        Week 109 (n= 44, 39, 14)
    2.8 ( 16.56 )
    -3.8 ( 23.17 )
    -2.4 ( 14.03 )
        Week 115 (n= 44, 36, 17)
    0.6 ( 15.50 )
    -6.9 ( 22.76 )
    -0.5 ( 11.59 )
        Week 121 (n= 44, 39, 16)
    1.1 ( 19.90 )
    -1.5 ( 19.20 )
    -3.1 ( 15.18 )
        Week 127 (n= 47, 36, 17)
    0.9 ( 20.06 )
    -1.9 ( 22.37 )
    1.5 ( 12.92 )
        Week 133 (n= 29, 31, 11)
    3.2 ( 20.70 )
    -2.4 ( 25.11 )
    3.8 ( 13.10 )
        Week 139 (n= 20, 19, 6)
    0.0 ( 18.73 )
    -4.4 ( 17.43 )
    5.6 ( 15.52 )
        Week 145 (n= 14, 14, 6)
    0.6 ( 25.42 )
    -8.9 ( 8.93 )
    -4.2 ( 17.28 )
        Week 151 (n= 7, 7, 1)
    3.6 ( 9.45 )
    -13.1 ( 9.45 )
    8.3 ( 99999 )
        Week 157 (n= 1, 3, 0)
    0.0 ( 99999 )
    -16.7 ( 8.33 )
    99999 ( 99999 )
    Notes
    [12] - 99999 stands for Not Estimable
    [13] - 99999 stands for Not Estimable
    [14] - 99999 stands for Not Estimable
    No statistical analyses for this end point

    Secondary: Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning

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    End point title
    		 Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Social Functioning
    End point description
    Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 5, 7, 11, 13, 17, 19, 23, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 133, 139, 145, 151 and 157
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [15]
    314 [16]
    315 [17]
    Units: Points on EORTC scale
    arithmetic mean (standard deviation)
        Week 5 (n= 233, 183, 221)
    -1.2 ( 21.99 )
    -4.6 ( 21.76 )
    -1.6 ( 21.59 )
        Week 7 (n= 239, 183, 218)
    -0.1 ( 20.58 )
    -5.8 ( 21.81 )
    -0.2 ( 21.79 )
        Week 11 (n= 201, 112, 163)
    -0.6 ( 22.32 )
    -5.1 ( 22.02 )
    -3.4 ( 21.53 )
        Week 13 (n= 195, 106, 130)
    0.6 ( 22.73 )
    -3.6 ( 20.57 )
    -2.2 ( 24.41 )
        Week 17 (n= 158, 84, 104)
    -0.9 ( 22.28 )
    -4.4 ( 25.10 )
    -2.9 ( 18.06 )
        Week 19 (n= 164, 96, 98)
    1.4 ( 21.40 )
    -1.7 ( 23.13 )
    -1.3 ( 24.71 )
        Week 23 (n= 134, 86, 75)
    -0.1 ( 19.87 )
    -1.2 ( 23.40 )
    -4.2 ( 21.94 )
        Week 25 (n= 144, 97, 75)
    1.2 ( 19.77 )
    -3.4 ( 21.37 )
    -1.3 ( 25.23 )
        Week 31 (n= 123, 92, 51)
    3.5 ( 16.84 )
    0.2 ( 20.30 )
    3.6 ( 22.68 )
        Week 37 (n= 116, 88, 48)
    1.6 ( 18.12 )
    1.1 ( 22.71 )
    3.1 ( 18.40 )
        Week 43 (n= 103, 74, 44)
    -0.2 ( 20.68 )
    2.9 ( 21.43 )
    4.2 ( 22.77 )
        Week 49 (n= 97, 70, 40)
    2.4 ( 17.35 )
    3.1 ( 19.92 )
    6.3 ( 18.37 )
        Week 55 (n= 86, 66, 34)
    0.6 ( 19.21 )
    0.0 ( 21.68 )
    5.9 ( 17.83 )
        Week 61 (n= 85, 61, 31)
    2.7 ( 16.44 )
    -0.5 ( 22.76 )
    5.9 ( 17.51 )
        Week 67 (n= 76, 61, 29)
    1.8 ( 16.46 )
    -0.8 ( 24.80 )
    -2.3 ( 17.66 )
        Week 73 (n= 67, 54, 19)
    1.5 ( 17.58 )
    -2.5 ( 17.85 )
    -8.8 ( 18.73 )
        Week 79 (n= 67, 54, 21)
    1.2 ( 14.01 )
    -3.4 ( 24.31 )
    0.8 ( 3.64 )
        Week 85 (n= 68, 51, 18)
    1.0 ( 13.77 )
    -7.5 ( 21.68 )
    -1.9 ( 7.86 )
        Week 91 (n= 62, 53, 16)
    -0.8 ( 17.96 )
    -5.7 ( 24.23 )
    1.0 ( 4.17 )
        Week 97 (n= 58, 49, 17)
    -0.3 ( 16.95 )
    -2.7 ( 22.14 )
    0.0 ( 0.00 )
        Week 103 (n= 53, 46, 17)
    -0.6 ( 17.28 )
    -4.3 ( 22.62 )
    -1.0 ( 4.04 )
        Week 109 (n= 44, 39, 14)
    4.2 ( 15.72 )
    -2.6 ( 20.43 )
    -3.6 ( 9.65 )
        Week 115 (n= 44, 36, 17)
    3.8 ( 18.63 )
    -2.3 ( 25.56 )
    0.0 ( 5.89 )
        Week 121 (n= 44, 39, 16)
    3.4 ( 19.88 )
    -3.0 ( 25.33 )
    -1.0 ( 4.17 )
        Week 127 (n= 47, 36, 17)
    3.5 ( 18.37 )
    -2.3 ( 22.24 )
    2.0 ( 5.54 )
        Week 133 (n= 29, 31, 11)
    0.6 ( 15.74 )
    -2.2 ( 26.44 )
    3.0 ( 10.05 )
        Week 139 (n= 20, 19, 6)
    4.2 ( 10.64 )
    -4.4 ( 19.12 )
    2.8 ( 16.39 )
        Week 145 (n= 14, 14, 6)
    -8.3 ( 26.75 )
    -11.9 ( 16.57 )
    2.8 ( 16.39 )
        Week 151 (n= 7, 7, 1)
    7.1 ( 23.29 )
    -9.5 ( 16.27 )
    0 ( 99999 )
        Week 157 (n= 1, 3, 0)
    0.0 ( 99999 )
    -22.2 ( 19.25 )
    99999 ( 99999 )
    Notes
    [15] - 99999 stands for Not Estimable
    [16] - 99999 stands for Not Estimable
    [17] - 99999 stands for Not Estimable
    No statistical analyses for this end point

    Secondary: Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning

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    End point title
    		 Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning
    End point description
    Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 5, 7, 11, 13, 17, 19, 23, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 133, 139, 145, 151 and 157
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [18]
    314 [19]
    315 [20]
    Units: Points on EORTC scale
    arithmetic mean (standard deviation)
        Week 5 (n= 233, 183, 221)
    0.1 ( 12.28 )
    -2.1 ( 16.49 )
    -0.2 ( 13.99 )
        Week 7 (n= 239, 183, 218)
    -1.7 ( 12.80 )
    -3.6 ( 16.26 )
    -1.5 ( 13.36 )
        Week 11 (n= 201, 112, 163)
    -1.7 ( 13.27 )
    -0.1 ( 16.67 )
    -4.7 ( 15.33 )
        Week 13 (n= 195, 106, 130)
    -0.9 ( 13.45 )
    -0.3 ( 14.36 )
    -2.3 ( 14.64 )
        Week 17 (n= 158, 84, 104)
    -0.9 ( 12.79 )
    -3.6 ( 19.37 )
    -2.4 ( 13.43 )
        Week 19 (n= 164, 96, 98)
    -1.9 ( 13.99 )
    -1.0 ( 17.07 )
    -2.2 ( 13.39 )
        Week 23 (n= 134, 86, 75)
    -0.6 ( 13.31 )
    -4.5 ( 21.61 )
    -5.6 ( 14.58 )
        Week 25 (n= 144, 97, 75)
    -1.2 ( 12.72 )
    -4.8 ( 20.26 )
    -2.4 ( 12.46 )
        Week 31 (n= 123, 92, 51)
    1.1 ( 12.40 )
    -1.6 ( 17.13 )
    -3.3 ( 12.48 )
        Week 37 (n= 116, 88, 48)
    1.6 ( 11.42 )
    -2.8 ( 17.91 )
    -5.6 ( 15.88 )
        Week 43 (n= 103, 74, 44)
    -1.6 ( 15.40 )
    -2.9 ( 13.89 )
    0.0 ( 11.37 )
        Week 49 (n= 97, 70, 40)
    -1.2 ( 12.32 )
    -1.2 ( 15.10 )
    0.4 ( 12.22 )
        Week 55 (n= 86, 66, 34)
    0.4 ( 13.52 )
    -2.8 ( 14.79 )
    -2.5 ( 12.40 )
        Week 61 (n= 85, 61, 31)
    0.0 ( 14.09 )
    -1.6 ( 15.12 )
    -3.2 ( 15.76 )
        Week 67 (n= 76, 61, 29)
    -1.3 ( 13.27 )
    -3.0 ( 17.35 )
    -7.5 ( 16.42 )
        Week 73 (n= 67, 54, 19)
    -2.2 ( 11.20 )
    -4.9 ( 19.86 )
    -6.1 ( 11.40 )
        Week 79 (n= 67, 54, 21)
    -0.2 ( 12.48 )
    -4.6 ( 20.58 )
    -4.8 ( 13.06 )
        Week 85 (n= 68, 51, 18)
    -1.5 ( 12.79 )
    -4.2 ( 17.90 )
    -2.8 ( 13.10 )
        Week 91 (n= 62, 53, 16)
    -0.5 ( 12.06 )
    -4.7 ( 19.44 )
    -1.0 ( 9.56 )
        Week 97 (n= 58, 49, 17)
    -3.2 ( 14.12 )
    -3.7 ( 13.72 )
    -2.0 ( 10.00 )
        Week 103 (n= 53, 46, 17)
    -2.5 ( 15.81 )
    -5.8 ( 23.63 )
    -5.9 ( 15.52 )
        Week 109 (n= 44, 39, 14)
    1.1 ( 10.42 )
    -3.8 ( 19.29 )
    -1.2 ( 7.91 )
        Week 115 (n= 44, 36, 17)
    0.4 ( 9.84 )
    -3.7 ( 15.49 )
    -2.0 ( 10.00 )
        Week 121 (n= 44, 39, 16)
    -1.1 ( 14.56 )
    -7.7 ( 15.22 )
    -1.0 ( 9.56 )
        Week 127 (n= 47, 36, 17)
    -2.8 ( 17.83 )
    -3.2 ( 13.10 )
    -1.0 ( 13.78 )
        Week 133 (n= 29, 31, 11)
    -4.6 ( 22.67 )
    -3.8 ( 13.41 )
    1.5 ( 8.99 )
        Week 139 (n= 20, 19, 6)
    -3.3 ( 6.84 )
    -6.1 ( 11.40 )
    5.6 ( 8.61 )
        Week 145 (n= 14, 14, 6)
    -11.9 ( 29.55 )
    -4.8 ( 12.10 )
    -5.6 ( 17.21 )
        Week 151 (n= 7, 7, 1)
    -2.4 ( 11.50 )
    -7.1 ( 13.11 )
    16.7 ( 99999 )
        Week 157 (n= 1, 3, 0)
    0.0 ( 99999 )
    -11.1 ( 9.62 )
    99999 ( 99999 )
    Notes
    [18] - 99999 stands for Not Estimable
    [19] - 99999 stands for Not Estimable
    [20] - 99999 stands for Not Estimable
    No statistical analyses for this end point

    Secondary: Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning

    		 Close Top of page
    End point title
    		 Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Emotional Functioning
    End point description
    Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 5, 7, 11, 13, 17, 19, 23, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 133, 139, 145, 151 and 157
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [21]
    314 [22]
    315 [23]
    Units: Points on EORTC scale
    arithmetic mean (standard deviation)
        Week 5 (n= 233, 183, 221)
    4.6 ( 15.91 )
    2.5 ( 16.44 )
    3.7 ( 17.21 )
        Week 7 (n= 239, 183, 218)
    4.0 ( 16.82 )
    2.0 ( 18.10 )
    3.1 ( 17.39 )
        Week 11 (n= 201, 112, 163)
    5.3 ( 14.84 )
    3.7 ( 15.57 )
    2.0 ( 18.89 )
        Week 13 (n= 195, 106, 130)
    3.8 ( 15.99 )
    4.3 ( 17.53 )
    2.9 ( 18.03 )
        Week 17 (n= 158, 84, 104)
    5.6 ( 16.54 )
    4.2 ( 18.81 )
    4.9 ( 15.86 )
        Week 19 (n= 164, 96, 98)
    5.8 ( 16.26 )
    6.2 ( 19.01 )
    6.5 ( 18.27 )
        Week 23 (n= 134, 86, 75)
    6.1 ( 17.04 )
    4.5 ( 20.20 )
    3.7 ( 18.85 )
        Week 25 (n= 144, 97, 75)
    6.6 ( 16.31 )
    2.1 ( 19.69 )
    5.9 ( 17.15 )
        Week 31 (n= 123, 92, 51)
    8.3 ( 15.57 )
    4.7 ( 15.64 )
    9.2 ( 16.69 )
        Week 37 (n= 116, 88, 48)
    9.6 ( 15.60 )
    6.8 ( 17.98 )
    5.9 ( 16.75 )
        Week 43 (n= 103, 74, 44)
    6.7 ( 18.89 )
    7.5 ( 18.36 )
    6.1 ( 14.86 )
        Week 49 (n= 97, 70, 40)
    5.8 ( 18.61 )
    7.1 ( 19.67 )
    8.1 ( 15.50 )
        Week 55 (n= 86, 66, 34)
    8.1 ( 18.57 )
    8.3 ( 16.79 )
    12.3 ( 15.11 )
        Week 61 (n= 85, 61, 31)
    7.9 ( 18.54 )
    7.9 ( 22.69 )
    9.9 ( 14.82 )
        Week 67 (n= 76, 61, 29)
    7.8 ( 19.97 )
    7.1 ( 20.52 )
    3.7 ( 15.36 )
        Week 73 (n= 67, 54, 19)
    8.0 ( 18.66 )
    4.5 ( 18.29 )
    4.8 ( 10.51 )
        Week 79 (n= 67, 54, 21)
    7.6 ( 19.56 )
    2.9 ( 23.36 )
    6.7 ( 10.41 )
        Week 85 (n= 68, 51, 18)
    6.4 ( 16.55 )
    3.3 ( 21.09 )
    7.9 ( 12.61 )
        Week 91 (n= 62, 53, 16)
    9.1 ( 17.77 )
    4.7 ( 20.25 )
    3.6 ( 12.53 )
        Week 97 (n= 58, 49, 17)
    5.3 ( 17.78 )
    3.9 ( 21.05 )
    3.9 ( 14.47 )
        Week 103 (n= 53, 46, 17)
    6.6 ( 19.50 )
    1.4 ( 23.46 )
    4.4 ( 12.88 )
        Week 109 (n= 44, 39, 14)
    8.3 ( 17.33 )
    4.1 ( 22.61 )
    12.5 ( 11.20 )
        Week 115 (n= 44, 36, 17)
    8.1 ( 21.15 )
    6.0 ( 21.23 )
    10.3 ( 10.84 )
        Week 121 (n= 44, 39, 16)
    8.3 ( 20.01 )
    4.5 ( 21.36 )
    9.4 ( 7.98 )
        Week 127 (n= 47, 36, 17)
    10.6 ( 17.61 )
    7.2 ( 21.19 )
    8.3 ( 13.50 )
        Week 133 (n= 29, 31, 11)
    7.5 ( 19.46 )
    8.3 ( 19.48 )
    9.1 ( 7.87 )
        Week 139 (n= 20, 19, 6)
    9.6 ( 11.87 )
    9.2 ( 16.87 )
    11.1 ( 10.09 )
        Week 145 (n= 14, 14, 6)
    2.4 ( 18.32 )
    6.0 ( 15.82 )
    11.1 ( 10.09 )
        Week 151 (n= 7, 7, 1)
    17.9 ( 16.27 )
    -2.4 ( 22.93 )
    16.7 ( 99999 )
        Week 157 (n= 1, 3, 0)
    16.7 ( 99999 )
    -11.1 ( 17.35 )
    99999 ( 99999 )
    Notes
    [21] - 99999 stands for Not Estimable
    [22] - 99999 stands for Not Estimable
    [23] - 99999 stands for Not Estimable
    No statistical analyses for this end point

    Secondary: Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Role Functioning

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    End point title
    		 Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Role Functioning
    End point description
    Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 5, 7, 11, 13, 17, 19, 23, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 133, 139, 145, 151 and 157
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [24]
    314 [25]
    315 [26]
    Units: Points on EORTC scale
    arithmetic mean (standard deviation)
        Week 5 (n= 233, 183, 221)
    -4.1 ( 23.71 )
    -6.8 ( 24.90 )
    -4.4 ( 21.18 )
        Week 7 (n= 239, 183, 218)
    -3.6 ( 24.21 )
    -11.6 ( 28.25 )
    -4.9 ( 22.44 )
        Week 11 (n= 201, 112, 163)
    -3.2 ( 24.46 )
    -9.7 ( 28.97 )
    -6.1 ( 24.56 )
        Week 13 (n= 195, 106, 130)
    -3.1 ( 24.15 )
    -8.3 ( 25.33 )
    -6.9 ( 25.65 )
        Week 17 (n= 158, 84, 104)
    -3.2 ( 26.14 )
    -11.1 ( 27.05 )
    -6.3 ( 20.27 )
        Week 19 (n= 164, 96, 98)
    -1.3 ( 24.56 )
    -4.3 ( 25.04 )
    -6.1 ( 24.80 )
        Week 23 (n= 134, 86, 75)
    -2.6 ( 25.76 )
    -6.4 ( 24.14 )
    -8.4 ( 24.56 )
        Week 25 (n= 144, 97, 75)
    0.7 ( 21.13 )
    -7.7 ( 23.70 )
    -7.8 ( 23.78 )
        Week 31 (n= 123, 92, 51)
    -0.7 ( 21.38 )
    -3.1 ( 24.82 )
    -3.9 ( 23.24 )
        Week 37 (n= 116, 88, 48)
    1.6 ( 22.94 )
    -3.2 ( 26.37 )
    -3.1 ( 21.92 )
        Week 43 (n= 103, 74, 44)
    1.0 ( 20.85 )
    -3.4 ( 26.46 )
    -1.1 ( 19.49 )
        Week 49 (n= 97, 70, 40)
    1.7 ( 20.62 )
    -1.2 ( 21.67 )
    -2.1 ( 21.08 )
        Week 55 (n= 86, 66, 34)
    1.6 ( 20.07 )
    -4.8 ( 21.03 )
    1.0 ( 16.89 )
        Week 61 (n= 85, 61, 31)
    0.4 ( 19.58 )
    -3.0 ( 24.82 )
    1.1 ( 21.05 )
        Week 67 (n= 76, 61, 29)
    0.7 ( 19.33 )
    -4.6 ( 25.84 )
    -1.7 ( 17.45 )
        Week 73 (n= 67, 54, 19)
    0.5 ( 19.24 )
    -5.6 ( 26.70 )
    -0.9 ( 17.10 )
        Week 79 (n= 67, 54, 21)
    -0.7 ( 18.45 )
    -8.3 ( 27.99 )
    -2.4 ( 12.12 )
        Week 85 (n= 68, 51, 18)
    -2.2 ( 16.26 )
    -9.8 ( 28.90 )
    0.9 ( 12.09 )
        Week 91 (n= 62, 53, 16)
    1.1 ( 22.76 )
    -10.7 ( 29.25 )
    2.1 ( 13.44 )
        Week 97 (n= 58, 49, 17)
    0.6 ( 23.77 )
    -7.5 ( 26.80 )
    0.0 ( 13.18 )
        Week 103 (n= 53, 46, 17)
    -0.6 ( 26.95 )
    -9.8 ( 23.46 )
    2.0 ( 10.00 )
        Week 109 (n= 44, 39, 14)
    1.1 ( 21.98 )
    -5.6 ( 22.73 )
    4.8 ( 10.19 )
        Week 115 (n= 44, 36, 17)
    1.1 ( 22.27 )
    -10.6 ( 28.77 )
    2.0 ( 11.61 )
        Week 121 (n= 44, 39, 16)
    0.4 ( 28.41 )
    -8.1 ( 26.73 )
    2.1 ( 14.75 )
        Week 127 (n= 47, 36, 17)
    1.4 ( 24.03 )
    -6.0 ( 26.17 )
    1.0 ( 7.15 )
        Week 133 (n= 29, 31, 11)
    1.1 ( 34.48 )
    -4.3 ( 24.33 )
    -1.5 ( 11.68 )
        Week 139 (n= 20, 19, 6)
    -5.8 ( 9.79 )
    -8.8 ( 18.73 )
    8.3 ( 13.94 )
        Week 145 (n= 14, 14, 6)
    -6.0 ( 34.96 )
    -10.7 ( 16.80 )
    0.0 ( 23.57 )
        Week 151 (n= 7, 7, 1)
    7.1 ( 26.97 )
    -14.3 ( 17.82 )
    0.0 ( 99999 )
        Week 157 (n= 1, 3, 0)
    0.0 ( 99999 )
    -11.1 ( 19.25 )
    99999 ( 99999 )
    Notes
    [24] - 99999 stands for Not Estimable
    [25] - 99999 stands for Not Estimable
    [26] - 99999 stands for Not Estimable
    No statistical analyses for this end point

    Secondary: Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning

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    End point title
    		 Mean change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Physical Functioning
    End point description
    Health Related Quality of Life was assessed using the EORTC QLQ-C30 questionnaire Version 3. With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 5, 7, 11, 13, 17, 19, 23, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 133, 139, 145, 151 and 157
    End point values
    		 Nivolumab Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    316 [27]
    314 [28]
    315 [29]
    Units: Points on EORTC scale
    arithmetic mean (standard deviation)
        Week 5 (n= 233, 183, 221)
    -2.6 ( 13.62 )
    -4.9 ( 14.52 )
    -5.2 ( 14.09 )
        Week 7 (n= 239, 183, 218)
    -2.4 ( 14.53 )
    -5.3 ( 14.92 )
    -5.1 ( 14.69 )
        Week 11 (n= 201, 112, 163)
    -2.4 ( 16.14 )
    -5.6 ( 13.76 )
    -6.3 ( 14.72 )
        Week 13 (n= 195, 106, 130)
    -1.7 ( 15.79 )
    -4.3 ( 14.11 )
    -5.0 ( 17.47 )
        Week 17 (n= 158, 84, 104)
    -1.4 ( 15.82 )
    -6.7 ( 17.27 )
    -3.7 ( 13.46 )
        Week 19 (n= 164, 96, 98)
    0.4 ( 14.14 )
    -3.7 ( 14.34 )
    -4.3 ( 17.70 )
        Week 23 (n= 134, 86, 75)
    0.9 ( 13.87 )
    -4.0 ( 15.59 )
    -5.5 ( 15.04 )
        Week 25 (n= 144, 97, 75)
    1.4 ( 11.02 )
    -4.2 ( 14.28 )
    -3.6 ( 16.19 )
        Week 31 (n= 123, 92, 51)
    1.9 ( 11.60 )
    -2.4 ( 12.91 )
    -2.9 ( 14.62 )
        Week 37 (n= 116, 88, 48)
    2.1 ( 13.57 )
    -0.8 ( 13.00 )
    -2.2 ( 13.71 )
        Week 43 (n= 103, 74, 44)
    1.9 ( 13.16 )
    -0.5 ( 13.55 )
    -1.7 ( 12.71 )
        Week 49 (n= 97, 70, 40)
    1.3 ( 12.08 )
    -0.1 ( 12.97 )
    0.2 ( 12.31 )
        Week 55 (n= 86, 66, 34)
    1.8 ( 11.68 )
    -2.9 ( 13.24 )
    0.2 ( 10.57 )
        Week 61 (n= 85, 61, 31)
    0.2 ( 11.65 )
    -2.1 ( 13.91 )
    -0.2 ( 11.35 )
        Week 67 (n= 76, 61, 29)
    0.9 ( 12.44 )
    -1.7 ( 13.22 )
    -3.9 ( 10.62 )
        Week 73 (n= 67, 54, 19)
    0.5 ( 14.38 )
    -3.5 ( 11.27 )
    -3.9 ( 7.80 )
        Week 79 (n= 67, 54, 21)
    -1.7 ( 7.99 )
    -4.3 ( 17.09 )
    -1.3 ( 6.54 )
        Week 85 (n= 68, 51, 18)
    -1.6 ( 12.86 )
    -3.5 ( 12.88 )
    -2.6 ( 6.11 )
        Week 91 (n= 62, 53, 16)
    -0.4 ( 13.27 )
    -4.2 ( 14.45 )
    0.0 ( 0.00 )
        Week 97 (n= 58, 49, 17)
    -0.4 ( 13.79 )
    -4.4 ( 16.53 )
    -0.8 ( 4.00 )
        Week 103 (n= 53, 46, 17)
    -1.5 ( 17.18 )
    -5.4 ( 15.63 )
    -2.4 ( 7.05 )
        Week 109 (n= 44, 39, 14)
    1.7 ( 14.74 )
    -1.2 ( 13.92 )
    -1.0 ( 3.56 )
        Week 115 (n= 44, 36, 17)
    0.2 ( 14.20 )
    -2.0 ( 15.10 )
    -0.8 ( 3.23 )
        Week 121 (n= 44, 39, 16)
    -0.3 ( 15.77 )
    -3.4 ( 13.58 )
    -2.5 ( 5.37 )
        Week 127 (n= 47, 36, 17)
    1.2 ( 17.21 )
    -3.0 ( 16.75 )
    -2.4 ( 5.75 )
        Week 133 (n= 29, 31, 11)
    0.2 ( 23.33 )
    0.4 ( 14.40 )
    -2.4 ( 6.16 )
        Week 139 (n= 20, 19, 6)
    0.4 ( 7.94 )
    -3.9 ( 11.40 )
    -3.3 ( 5.58 )
        Week 145 (n= 14, 14, 6)
    -1.4 ( 27.94 )
    -6.7 ( 9.06 )
    -6.7 ( 8.43 )
        Week 151 (n= 7, 7, 1)
    8.6 ( 17.52 )
    -9.5 ( 12.68 )
    0.0 ( 99999 )
        Week 157 (n= 1, 3, 0)
    0.0 ( 99999 )
    -17.8 ( 25.24 )
    99999 ( 99999 )
    Notes
    [27] - 99999 stands for Not Estimable
    [28] - 99999 stands for Not Estimable
    [29] - 99999 stands for Not Estimable
    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 from date of randomization till death due to any cause (up to approximately 128 months) and Serious and Other Adverse events were collected from first dose till 30 days after last dose (up to approximately 128 months).
    Adverse event reporting additional description
    All cause mortality data was collected for all the randomized participants and serious and other adverse events were collected for all the treated participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    NIVOLUMAB
    Reporting group description
    		 Nivolumab monotherapy 3 mg/kg intravenous (IV) once every 2 weeks (Q2W) until disease progression or unacceptable toxicity

    Reporting group title
    NIVOLUMAB+IPILIMUMAB
    Reporting group description
    		 Nivolumab 1 mg/kg IV combined with Ipilimumab 3 mg/kg IV once every 3 weeks (Q3W) for 4 doses followed by nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity

    Reporting group title
    IPILIMUMAB
    Reporting group description
    		 Ipilimumab monotherapy 3 mg/kg IV Q3W for a total of 4 doses

    Serious adverse events
    		 NIVOLUMAB NIVOLUMAB+IPILIMUMAB IPILIMUMAB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    187 / 313 (59.74%)
    249 / 313 (79.55%)
    205 / 311 (65.92%)
         number of deaths (all causes)
    191
    172
    241
         number of deaths resulting from adverse events
    55
    51
    61
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoid cystic carcinoma of salivary gland
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Basal cell carcinoma
         subjects affected / exposed
    8 / 313 (2.56%)
    3 / 313 (0.96%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    0 / 311 (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
    Desmoid tumour
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Infected metastasis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Intestinal metastasis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Malignant melanoma
         subjects affected / exposed
    4 / 313 (1.28%)
    0 / 313 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Malignant neoplasm progression
         subjects affected / exposed
    54 / 313 (17.25%)
    38 / 313 (12.14%)
    61 / 311 (19.61%)
         occurrences causally related to treatment / all
    0 / 60
    0 / 43
    0 / 66
         deaths causally related to treatment / all
    0 / 41
    0 / 29
    0 / 45
    Metastasis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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 spine
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Tumour haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Squamous cell carcinoma of skin
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
    0 / 311 (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
    Squamous cell carcinoma
         subjects affected / exposed
    9 / 313 (2.88%)
    2 / 313 (0.64%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Prostate cancer
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
    0 / 311 (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
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    3 / 313 (0.96%)
    1 / 313 (0.32%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases to meninges
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (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
    Tumour pain
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    1 / 311 (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
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Hypotension
         subjects affected / exposed
    1 / 313 (0.32%)
    4 / 313 (1.28%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Embolism
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Inferior vena caval occlusion
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Lymphorrhoea
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Orthostatic hypotension
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (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
    Deep vein thrombosis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    General disorders and administration site conditions
    Hyperthermia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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 physical health deterioration
         subjects affected / exposed
    3 / 313 (0.96%)
    10 / 313 (3.19%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 3
    4 / 15
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    0 / 1
    Fatigue
         subjects affected / exposed
    2 / 313 (0.64%)
    6 / 313 (1.92%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Chills
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Chest pain
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
    0 / 311 (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
    Catheter site discharge
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Asthenia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Accidental death
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Inflammation
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    4 / 313 (1.28%)
    30 / 313 (9.58%)
    12 / 311 (3.86%)
         occurrences causally related to treatment / all
    1 / 6
    14 / 32
    6 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Pain
         subjects affected / exposed
    3 / 313 (0.96%)
    4 / 313 (1.28%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Mucosal inflammation
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Malaise
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    1 / 311 (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
    Influenza like illness
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nodule
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Sudden death
         subjects affected / exposed
    2 / 313 (0.64%)
    2 / 313 (0.64%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Ejaculation failure
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Pleural effusion
         subjects affected / exposed
    3 / 313 (0.96%)
    3 / 313 (0.96%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 infiltration
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Lung disorder
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Laryngospasm
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Interstitial lung disease
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Haemoptysis
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    0 / 311 (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
    Hepatic hydrothorax
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Dyspnoea
         subjects affected / exposed
    3 / 313 (0.96%)
    7 / 313 (2.24%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Tonsillar disorder
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Stridor
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 failure
         subjects affected / exposed
    2 / 313 (0.64%)
    3 / 313 (0.96%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    3 / 313 (0.96%)
    11 / 313 (3.51%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 11
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Pulmonary mass
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Pneumonitis
         subjects affected / exposed
    3 / 313 (0.96%)
    8 / 313 (2.56%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    2 / 3
    9 / 9
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Psychotic disorder
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Mental status changes
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Delusion
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Delirium
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 313 (0.32%)
    4 / 313 (1.28%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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 loosening
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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 breakage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    1 / 311 (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
    Investigations
    General physical condition abnormal
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Cortisol decreased
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (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
    Liver function test increased
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 313 (0.32%)
    3 / 313 (0.96%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 313 (0.00%)
    3 / 313 (0.96%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Transaminases increased
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Concussion
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Fall
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Femur fracture
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Hip fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Infusion related reaction
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Ligament sprain
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Multiple fractures
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Osteoradionecrosis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Post procedural complication
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Procedural pneumothorax
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Radius fracture
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Skin laceration
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Skull fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 compression fracture
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 retention postoperative
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Toxicity to various agents
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Tibia fracture
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Spinal fracture
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    1 / 311 (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 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    Bradycardia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Atrioventricular block
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Atrial flutter
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 313 (0.64%)
    4 / 313 (1.28%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Acute coronary syndrome
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Cardiac failure chronic
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Myocardial infarction
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    1 / 311 (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
    Coronary artery disease
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Cor pulmonale
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Cardiomyopathy
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Cardiac tamponade
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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 failure congestive
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Sinus tachycardia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Facial paralysis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Hemiparesis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Encephalopathy
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Diabetic coma
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Ataxia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Epilepsy
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (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
    Lethargy
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    1 / 311 (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
    Hydrocephalus
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Medullary compression syndrome
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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 motor neuropathy
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Paraparesis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Neuropathy peripheral
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Neuralgia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Nervous system disorder
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Nerve compression
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Polyneuropathy
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Seizure
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 313 (0.00%)
    3 / 313 (0.96%)
    0 / 311 (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
    Syncope
         subjects affected / exposed
    3 / 313 (0.96%)
    4 / 313 (1.28%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Spinal cord compression
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    1 / 311 (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
    Spinal claudication
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Somnolence
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Sensory disturbance
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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 and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 313 (1.60%)
    4 / 313 (1.28%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bicytopenia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Anaemia of chronic disease
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Lymphadenitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Haemolytic anaemia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Eosinophilia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Febrile neutropenia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Lymphadenopathy
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Microcytic anaemia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Thrombocytopenia
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normocytic anaemia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Neutropenia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (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
    Uveitis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Anal fistula
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    2 / 313 (0.64%)
    2 / 313 (0.64%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    1 / 311 (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
    Chronic gastritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Abdominal pain lower
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    6 / 313 (1.92%)
    5 / 313 (1.60%)
    7 / 311 (2.25%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Abdominal distension
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Autoimmune pancreatitis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Enteritis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Enterocolitis
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Gastritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 313 (1.28%)
    1 / 313 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Colitis
         subjects affected / exposed
    6 / 313 (1.92%)
    33 / 313 (10.54%)
    29 / 311 (9.32%)
         occurrences causally related to treatment / all
    3 / 7
    38 / 38
    34 / 36
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    Constipation
         subjects affected / exposed
    3 / 313 (0.96%)
    5 / 313 (1.60%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    8 / 313 (2.56%)
    40 / 313 (12.78%)
    26 / 311 (8.36%)
         occurrences causally related to treatment / all
    2 / 9
    39 / 46
    28 / 32
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Dysphagia
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
    0 / 311 (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
    Lymphangiectasia intestinal
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Large intestine perforation
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 pseudo-obstruction
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 perforation
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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 paralytic
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Haematochezia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Mouth haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Nausea
         subjects affected / exposed
    2 / 313 (0.64%)
    9 / 313 (2.88%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    7 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Small intestinal perforation
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    3 / 313 (0.96%)
    2 / 313 (0.64%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Rectal prolapse
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Rectal haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (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
    Pancreatitis acute
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Pancreatitis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal pain
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 313 (0.64%)
    0 / 313 (0.00%)
    0 / 311 (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
    Volvulus
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Vomiting
         subjects affected / exposed
    3 / 313 (0.96%)
    11 / 313 (3.51%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 4
    7 / 14
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    1 / 311 (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
    Cholecystitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (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
    Hepatorenal failure
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Hepatomegaly
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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 acute
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Hepatitis
         subjects affected / exposed
    2 / 313 (0.64%)
    5 / 313 (1.60%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (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
    Cholelithiasis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    1 / 311 (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
    Cholecystitis chronic
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Autoimmune hepatitis
         subjects affected / exposed
    3 / 313 (0.96%)
    6 / 313 (1.92%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Portal hypertension
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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 hepatitis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (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
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 313 (0.32%)
    7 / 313 (2.24%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 313 (0.00%)
    5 / 313 (1.60%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Dermatomyositis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Vasculitic ulcer
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Toxic skin eruption
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Toxic epidermal necrolysis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Skin toxicity
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Skin oedema
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Skin lesion
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Skin burning sensation
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Diabetic foot
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Rash maculo-papular
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Pemphigoid
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Pruritus
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 313 (0.64%)
    2 / 313 (0.64%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 313 (0.64%)
    10 / 313 (3.19%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 10
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Glomerulonephritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Immune-mediated nephritis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Nephrolithiasis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    1 / 311 (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
    Lower urinary tract symptoms
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Nephropathy toxic
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Prerenal failure
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Renal colic
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    1 / 311 (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
    Renal failure
         subjects affected / exposed
    2 / 313 (0.64%)
    3 / 313 (0.96%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Renal mass
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Urinary retention
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Adrenal insufficiency
         subjects affected / exposed
    3 / 313 (0.96%)
    7 / 313 (2.24%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    3 / 3
    7 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal haemorrhage
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Endocrine disorder
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Thyroiditis
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Lymphocytic hypophysitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Hypothyroidism
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 313 (0.32%)
    3 / 313 (0.96%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 313 (0.32%)
    8 / 313 (2.56%)
    8 / 311 (2.57%)
         occurrences causally related to treatment / all
    1 / 1
    7 / 8
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 313 (0.00%)
    6 / 313 (1.92%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperparathyroidism
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Goitre
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Groin pain
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Flank pain
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Fibromyalgia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Chondrocalcinosis
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (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
    Bone pain
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Back pain
         subjects affected / exposed
    2 / 313 (0.64%)
    2 / 313 (0.64%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Arthritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Arthralgia
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Polymyositis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Polyarthritis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Pathological fracture
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    1 / 311 (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 / 1
    Pain in extremity
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Myopathy
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Myalgia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Muscular weakness
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 313 (0.64%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Scleroderma
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Spinal pain
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Infections and infestations
    Biliary sepsis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Appendicitis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (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
    Anal abscess
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Bronchitis
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    1 / 311 (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
    Clostridium difficile infection
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium bacteraemia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Citrobacter sepsis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Cellulitis
         subjects affected / exposed
    3 / 313 (0.96%)
    3 / 313 (0.96%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Device related infection
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 313 (0.64%)
    1 / 313 (0.32%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Encephalitis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis intestinal perforated
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Diverticulitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    1 / 311 (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
    Escherichia sepsis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Febrile infection
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    1 / 311 (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
    Localised infection
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    2 / 313 (0.64%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    H1N1 influenza
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Groin abscess
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Gastrointestinal infection
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Gastroenteritis viral
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    0 / 311 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 313 (0.32%)
    3 / 313 (0.96%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Folliculitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Meningitis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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 syncytial virus infection
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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 tract infection
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (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
    Sepsis
         subjects affected / exposed
    5 / 313 (1.60%)
    3 / 313 (0.96%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    0 / 311 (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
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Peritonitis bacterial
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Peritonitis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Oral candidiasis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Pneumonia
         subjects affected / exposed
    3 / 313 (0.96%)
    9 / 313 (2.88%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Staphylococcal infection
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Streptococcal infection
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Tonsillitis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    2 / 313 (0.64%)
    3 / 313 (0.96%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Viral infection
         subjects affected / exposed
    0 / 313 (0.00%)
    1 / 313 (0.32%)
    0 / 311 (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
    Wound infection
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (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
    Septic shock
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Hypocalcaemia
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Hyperkalaemia
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Hyperglycaemia
         subjects affected / exposed
    1 / 313 (0.32%)
    7 / 313 (2.24%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 12
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Diabetes mellitus
         subjects affected / exposed
    1 / 313 (0.32%)
    1 / 313 (0.32%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 313 (0.00%)
    10 / 313 (3.19%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 12
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 313 (0.00%)
    2 / 313 (0.64%)
    0 / 311 (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
    Hypokalaemia
         subjects affected / exposed
    1 / 313 (0.32%)
    2 / 313 (0.64%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 313 (0.00%)
    3 / 313 (0.96%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metabolic acidosis
         subjects affected / exposed
    0 / 313 (0.00%)
    0 / 313 (0.00%)
    1 / 311 (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
    Steroid diabetes
         subjects affected / exposed
    1 / 313 (0.32%)
    0 / 313 (0.00%)
    0 / 311 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NIVOLUMAB NIVOLUMAB+IPILIMUMAB IPILIMUMAB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    302 / 313 (96.49%)
    302 / 313 (96.49%)
    302 / 311 (97.11%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    34 / 313 (10.86%)
    26 / 313 (8.31%)
    27 / 311 (8.68%)
         occurrences all number
    56
    54
    34
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    64 / 313 (20.45%)
    123 / 313 (39.30%)
    61 / 311 (19.61%)
         occurrences all number
    85
    191
    92
    Pain
         subjects affected / exposed
    18 / 313 (5.75%)
    23 / 313 (7.35%)
    29 / 311 (9.32%)
         occurrences all number
    20
    37
    30
    Oedema peripheral
         subjects affected / exposed
    39 / 313 (12.46%)
    39 / 313 (12.46%)
    45 / 311 (14.47%)
         occurrences all number
    44
    46
    51
    Influenza like illness
         subjects affected / exposed
    31 / 313 (9.90%)
    28 / 313 (8.95%)
    25 / 311 (8.04%)
         occurrences all number
    38
    41
    30
    Fatigue
         subjects affected / exposed
    159 / 313 (50.80%)
    168 / 313 (53.67%)
    140 / 311 (45.02%)
         occurrences all number
    210
    249
    185
    Chills
         subjects affected / exposed
    23 / 313 (7.35%)
    35 / 313 (11.18%)
    20 / 311 (6.43%)
         occurrences all number
    26
    40
    23
    Chest pain
         subjects affected / exposed
    19 / 313 (6.07%)
    12 / 313 (3.83%)
    13 / 311 (4.18%)
         occurrences all number
    20
    17
    14
    Asthenia
         subjects affected / exposed
    47 / 313 (15.02%)
    50 / 313 (15.97%)
    29 / 311 (9.32%)
         occurrences all number
    83
    61
    36
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    20 / 313 (6.39%)
    23 / 313 (7.35%)
    17 / 311 (5.47%)
         occurrences all number
    24
    30
    18
    Nasal congestion
         subjects affected / exposed
    21 / 313 (6.71%)
    15 / 313 (4.79%)
    8 / 311 (2.57%)
         occurrences all number
    25
    17
    12
    Dyspnoea exertional
         subjects affected / exposed
    20 / 313 (6.39%)
    8 / 313 (2.56%)
    14 / 311 (4.50%)
         occurrences all number
    23
    10
    16
    Dyspnoea
         subjects affected / exposed
    47 / 313 (15.02%)
    72 / 313 (23.00%)
    43 / 311 (13.83%)
         occurrences all number
    54
    90
    51
    Cough
         subjects affected / exposed
    100 / 313 (31.95%)
    82 / 313 (26.20%)
    69 / 311 (22.19%)
         occurrences all number
    155
    115
    96
    Pneumonitis
         subjects affected / exposed
    6 / 313 (1.92%)
    17 / 313 (5.43%)
    7 / 311 (2.25%)
         occurrences all number
    8
    21
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    44 / 313 (14.06%)
    51 / 313 (16.29%)
    42 / 311 (13.50%)
         occurrences all number
    52
    60
    43
    Depression
         subjects affected / exposed
    12 / 313 (3.83%)
    21 / 313 (6.71%)
    9 / 311 (2.89%)
         occurrences all number
    15
    24
    10
    Anxiety
         subjects affected / exposed
    11 / 313 (3.51%)
    24 / 313 (7.67%)
    19 / 311 (6.11%)
         occurrences all number
    15
    26
    21
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    25 / 313 (7.99%)
    69 / 313 (22.04%)
    18 / 311 (5.79%)
         occurrences all number
    33
    89
    21
    Amylase increased
         subjects affected / exposed
    23 / 313 (7.35%)
    33 / 313 (10.54%)
    17 / 311 (5.47%)
         occurrences all number
    59
    38
    37
    Aspartate aminotransferase increased
         subjects affected / exposed
    25 / 313 (7.99%)
    61 / 313 (19.49%)
    19 / 311 (6.11%)
         occurrences all number
    30
    80
    20
    Blood alkaline phosphatase increased
         subjects affected / exposed
    14 / 313 (4.47%)
    19 / 313 (6.07%)
    8 / 311 (2.57%)
         occurrences all number
    15
    22
    9
    Blood creatinine increased
         subjects affected / exposed
    7 / 313 (2.24%)
    25 / 313 (7.99%)
    15 / 311 (4.82%)
         occurrences all number
    8
    31
    22
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 313 (2.24%)
    16 / 313 (5.11%)
    10 / 311 (3.22%)
         occurrences all number
    7
    21
    10
    Lipase increased
         subjects affected / exposed
    35 / 313 (11.18%)
    51 / 313 (16.29%)
    21 / 311 (6.75%)
         occurrences all number
    88
    67
    61
    Weight decreased
         subjects affected / exposed
    28 / 313 (8.95%)
    42 / 313 (13.42%)
    26 / 311 (8.36%)
         occurrences all number
    29
    46
    27
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    6 / 313 (1.92%)
    16 / 313 (5.11%)
    13 / 311 (4.18%)
         occurrences all number
    6
    18
    13
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    23 / 313 (7.35%)
    18 / 313 (5.75%)
    17 / 311 (5.47%)
         occurrences all number
    24
    18
    18
    Headache
         subjects affected / exposed
    79 / 313 (25.24%)
    82 / 313 (26.20%)
    78 / 311 (25.08%)
         occurrences all number
    98
    157
    103
    Dizziness
         subjects affected / exposed
    33 / 313 (10.54%)
    43 / 313 (13.74%)
    30 / 311 (9.65%)
         occurrences all number
    45
    53
    37
    Dysgeusia
         subjects affected / exposed
    17 / 313 (5.43%)
    18 / 313 (5.75%)
    8 / 311 (2.57%)
         occurrences all number
    20
    19
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    35 / 313 (11.18%)
    41 / 313 (13.10%)
    43 / 311 (13.83%)
         occurrences all number
    39
    56
    52
    Eye disorders
    Vision blurred
         subjects affected / exposed
    18 / 313 (5.75%)
    18 / 313 (5.75%)
    15 / 311 (4.82%)
         occurrences all number
    20
    21
    18
    Dry eye
         subjects affected / exposed
    17 / 313 (5.43%)
    12 / 313 (3.83%)
    8 / 311 (2.57%)
         occurrences all number
    19
    13
    8
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    17 / 313 (5.43%)
    9 / 313 (2.88%)
    13 / 311 (4.18%)
         occurrences all number
    21
    12
    16
    Abdominal pain
         subjects affected / exposed
    62 / 313 (19.81%)
    59 / 313 (18.85%)
    68 / 311 (21.86%)
         occurrences all number
    77
    82
    89
    Abdominal pain upper
         subjects affected / exposed
    24 / 313 (7.67%)
    24 / 313 (7.67%)
    25 / 311 (8.04%)
         occurrences all number
    24
    27
    31
    Colitis
         subjects affected / exposed
    9 / 313 (2.88%)
    21 / 313 (6.71%)
    15 / 311 (4.82%)
         occurrences all number
    9
    22
    17
    Constipation
         subjects affected / exposed
    69 / 313 (22.04%)
    63 / 313 (20.13%)
    77 / 311 (24.76%)
         occurrences all number
    91
    97
    98
    Diarrhoea
         subjects affected / exposed
    122 / 313 (38.98%)
    168 / 313 (53.67%)
    147 / 311 (47.27%)
         occurrences all number
    247
    405
    277
    Dyspepsia
         subjects affected / exposed
    17 / 313 (5.43%)
    12 / 313 (3.83%)
    14 / 311 (4.50%)
         occurrences all number
    26
    17
    14
    Dry mouth
         subjects affected / exposed
    28 / 313 (8.95%)
    34 / 313 (10.86%)
    17 / 311 (5.47%)
         occurrences all number
    31
    41
    17
    Vomiting
         subjects affected / exposed
    69 / 313 (22.04%)
    99 / 313 (31.63%)
    60 / 311 (19.29%)
         occurrences all number
    92
    161
    79
    Nausea
         subjects affected / exposed
    105 / 313 (33.55%)
    136 / 313 (43.45%)
    104 / 311 (33.44%)
         occurrences all number
    170
    232
    158
    Gastrooesophageal reflux disease
         subjects affected / exposed
    19 / 313 (6.07%)
    13 / 313 (4.15%)
    14 / 311 (4.50%)
         occurrences all number
    20
    19
    15
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    25 / 313 (7.99%)
    16 / 313 (5.11%)
    14 / 311 (4.50%)
         occurrences all number
    32
    18
    14
    Dry skin
         subjects affected / exposed
    28 / 313 (8.95%)
    30 / 313 (9.58%)
    19 / 311 (6.11%)
         occurrences all number
    29
    35
    21
    Actinic keratosis
         subjects affected / exposed
    17 / 313 (5.43%)
    2 / 313 (0.64%)
    1 / 311 (0.32%)
         occurrences all number
    21
    2
    1
    Vitiligo
         subjects affected / exposed
    38 / 313 (12.14%)
    29 / 313 (9.27%)
    17 / 311 (5.47%)
         occurrences all number
    43
    31
    17
    Rash maculo-papular
         subjects affected / exposed
    22 / 313 (7.03%)
    44 / 313 (14.06%)
    43 / 311 (13.83%)
         occurrences all number
    26
    55
    57
    Rash
         subjects affected / exposed
    101 / 313 (32.27%)
    111 / 313 (35.46%)
    84 / 311 (27.01%)
         occurrences all number
    145
    159
    104
    Pruritus
         subjects affected / exposed
    92 / 313 (29.39%)
    126 / 313 (40.26%)
    135 / 311 (43.41%)
         occurrences all number
    151
    200
    167
    Hyperhidrosis
         subjects affected / exposed
    12 / 313 (3.83%)
    22 / 313 (7.03%)
    11 / 311 (3.54%)
         occurrences all number
    13
    29
    11
    Skin lesion
         subjects affected / exposed
    20 / 313 (6.39%)
    11 / 313 (3.51%)
    9 / 311 (2.89%)
         occurrences all number
    24
    12
    10
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    4 / 313 (1.28%)
    16 / 313 (5.11%)
    7 / 311 (2.25%)
         occurrences all number
    4
    17
    7
    Hyperthyroidism
         subjects affected / exposed
    18 / 313 (5.75%)
    30 / 313 (9.58%)
    3 / 311 (0.96%)
         occurrences all number
    20
    34
    11
    Hypophysitis
         subjects affected / exposed
    5 / 313 (1.60%)
    20 / 313 (6.39%)
    9 / 311 (2.89%)
         occurrences all number
    5
    20
    11
    Hypothyroidism
         subjects affected / exposed
    38 / 313 (12.14%)
    68 / 313 (21.73%)
    17 / 311 (5.47%)
         occurrences all number
    41
    70
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    87 / 313 (27.80%)
    79 / 313 (25.24%)
    78 / 311 (25.08%)
         occurrences all number
    121
    125
    87
    Back pain
         subjects affected / exposed
    58 / 313 (18.53%)
    46 / 313 (14.70%)
    53 / 311 (17.04%)
         occurrences all number
    74
    56
    61
    Groin pain
         subjects affected / exposed
    17 / 313 (5.43%)
    5 / 313 (1.60%)
    8 / 311 (2.57%)
         occurrences all number
    19
    5
    8
    Muscle spasms
         subjects affected / exposed
    22 / 313 (7.03%)
    16 / 313 (5.11%)
    16 / 311 (5.14%)
         occurrences all number
    24
    19
    17
    Muscular weakness
         subjects affected / exposed
    13 / 313 (4.15%)
    22 / 313 (7.03%)
    12 / 311 (3.86%)
         occurrences all number
    16
    25
    13
    Musculoskeletal chest pain
         subjects affected / exposed
    16 / 313 (5.11%)
    13 / 313 (4.15%)
    16 / 311 (5.14%)
         occurrences all number
    19
    13
    24
    Myalgia
         subjects affected / exposed
    34 / 313 (10.86%)
    33 / 313 (10.54%)
    23 / 311 (7.40%)
         occurrences all number
    36
    43
    26
    Neck pain
         subjects affected / exposed
    15 / 313 (4.79%)
    18 / 313 (5.75%)
    12 / 311 (3.86%)
         occurrences all number
    21
    18
    13
    Pain in extremity
         subjects affected / exposed
    49 / 313 (15.65%)
    38 / 313 (12.14%)
    43 / 311 (13.83%)
         occurrences all number
    57
    40
    48
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    16 / 313 (5.11%)
    14 / 313 (4.47%)
    5 / 311 (1.61%)
         occurrences all number
    20
    25
    6
    Rhinitis
         subjects affected / exposed
    20 / 313 (6.39%)
    26 / 313 (8.31%)
    10 / 311 (3.22%)
         occurrences all number
    24
    30
    10
    Nasopharyngitis
         subjects affected / exposed
    43 / 313 (13.74%)
    34 / 313 (10.86%)
    29 / 311 (9.32%)
         occurrences all number
    66
    57
    39
    Influenza
         subjects affected / exposed
    16 / 313 (5.11%)
    20 / 313 (6.39%)
    8 / 311 (2.57%)
         occurrences all number
    19
    24
    8
    Conjunctivitis
         subjects affected / exposed
    5 / 313 (1.60%)
    19 / 313 (6.07%)
    6 / 311 (1.93%)
         occurrences all number
    7
    21
    6
    Upper respiratory tract infection
         subjects affected / exposed
    32 / 313 (10.22%)
    28 / 313 (8.95%)
    17 / 311 (5.47%)
         occurrences all number
    47
    68
    29
    Urinary tract infection
         subjects affected / exposed
    16 / 313 (5.11%)
    23 / 313 (7.35%)
    9 / 311 (2.89%)
         occurrences all number
    31
    35
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    76 / 313 (24.28%)
    97 / 313 (30.99%)
    76 / 311 (24.44%)
         occurrences all number
    94
    140
    89
    Dehydration
         subjects affected / exposed
    7 / 313 (2.24%)
    24 / 313 (7.67%)
    17 / 311 (5.47%)
         occurrences all number
    8
    31
    22
    Hyperglycaemia
         subjects affected / exposed
    9 / 313 (2.88%)
    18 / 313 (5.75%)
    17 / 311 (5.47%)
         occurrences all number
    10
    20
    25
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 313 (1.92%)
    16 / 313 (5.11%)
    9 / 311 (2.89%)
         occurrences all number
    7
    19
    9
    Hypokalaemia
         subjects affected / exposed
    12 / 313 (3.83%)
    37 / 313 (11.82%)
    15 / 311 (4.82%)
         occurrences all number
    16
    42
    21
    Hyponatraemia
         subjects affected / exposed
    7 / 313 (2.24%)
    25 / 313 (7.99%)
    14 / 311 (4.50%)
         occurrences all number
    8
    32
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Aug 2013
    The main purpose of the first global amendment is to add a recommendation to perform an optional tumor biopsy when assessing whether to treat beyond progression per a Health Authority request. This biopsy can be used to assess the impact of treatment on relevant melanoma biomarkers including BRAF mutation status and investigate potential mechanisms of resistance to immunotherapeutic agents.
    27 Jun 2014
    The main purpose of Amendment 06 is to change the secondary objective to add PFS as a co-primary objective. Additional modification are as described below: Revise Research Hypothesis, Study Rationale, Primary Endpoints to include PFS as a co-primary objective/endpoint. Add rationale for inclusion of PFS as a co-primary endpoint. Revise statistical section 8 to include analyses related to PFS.
    16 Jan 2015
    The main purpose of Amendment 07 is to add the collection of radiographic images for review by an independent radiological review committee. No other changes are included in this amendment.
    19 May 2015
    The purpose of this amendment is to allow for future collection of survival status outside of the protocol-defined windows if necessary, correct errors and update Appendix 5 Methodsof Contraception as well as SAE reporting language.
    12 Oct 2016
    The main purpose of this protocol amendment is necessary following a recent update to the Nivolumab Investigator’s Brochure version 15, Erratum 01, includingthose related to the use of contraceptives, and updatedAppendix 5. Additionally, updated Tumor Assessment scan frequencyin the Follow-up and Survival phase.
    20 Oct 2017
    Prior to implementation of this amendment, following completion of the primary efficacy analysis, maintenance of the blind was no longer required for study purposes and all subjects were unblinded.The purpose of this amendment is to provide instructions for unblinded subjects remaining on study treatment or in follow-up.
    17 May 2021
    The purpose of Protocol Amendment 08 is to extend the studyfor about an additional 2.5 years, to yield a total study duration of approximately 10 years.As a consequence, data associated with the primary, secondary, and exploratory efficacy outcomes will continue to be collected on case report forms. In addition, protocol clarifications and/or updates are provided.EQ-5D questionnaires after study drug discontinuation will be collected for up to 7.5 years since randomization.

    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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