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    Clinical Trial Results:
    A Phase 3, Randomized Study of Adjuvant Immunotherapy with Nivolumab Combined with Ipilimumab Versus Nivolumab Monotherapy after Complete Resection of Stage IIIb/c/d or Stage IV Melanoma (CheckMate 915: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 915)

    Summary
    EudraCT number
    		 2016-003729-41
    Trial protocol
    		 AT   DE   CZ   BE   ES   GB   PL   FR   GR   IT   Outside EU/EEA   RO  
    Global end of trial date
    02 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2021
    First version publication date
    12 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-915
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000117-PIP02-10 EMEA-001407-PIP01-12
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy, as measured by recurrence-free survival (RFS), provided by nivolumab plus ipilimumab versus nivolumab monotherapy in participants with completely resected stage IIIb/c/d or stage IV no evidence of disease (NED) melanoma (in all randomized participants with PD-L1 expression level < 1%. and all randomized participants)
    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 Apr 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 302
    Country: Number of subjects enrolled
    Austria: 24
    Country: Number of subjects enrolled
    Belgium: 38
    Country: Number of subjects enrolled
    Brazil: 52
    Country: Number of subjects enrolled
    Canada: 102
    Country: Number of subjects enrolled
    Czechia: 45
    Country: Number of subjects enrolled
    France: 202
    Country: Number of subjects enrolled
    Germany: 214
    Country: Number of subjects enrolled
    Greece: 45
    Country: Number of subjects enrolled
    Israel: 45
    Country: Number of subjects enrolled
    Italy: 216
    Country: Number of subjects enrolled
    New Zealand: 19
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Romania: 53
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Spain: 139
    Country: Number of subjects enrolled
    Switzerland: 40
    Country: Number of subjects enrolled
    United Kingdom: 89
    Country: Number of subjects enrolled
    United States: 176
    Worldwide total number of subjects
    1844
    EEA total number of subjects
    1007
    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)
    3
    Adults (18-64 years)
    1333
    From 65 to 84 years
    504
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1844 participants randomized and 1833 treated. Reasons not treated: 1 disease progression; 2 participants withdrew consent; 1 poor/non-compliance; 4 participants no longer met study criteria; 3 not reported

    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, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivo + Ipi
    Arm description
    		 Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-936558 Nivolumab Solution for Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg IV Q2W

    Investigational medicinal product name
    Ipilimumab Solution for Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/Kg IV Q6W

    Arm title
    		 Arm B: Nivo
    Arm description
    		 Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-936558 Nivolumab Solution for Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg IV Q2W

    Number of subjects in period 1
    		Arm A: Nivo + Ipi Arm B: Nivo
    Started
    920
    924
    Completed
    916
    917
    Not completed
    4
    7
         Disease progression
    -
    1
         Participant withdrew consent
    1
    1
         Not reported
    2
    1
         Participant no longer meets study criteria
    1
    3
         Poor/non-compliance
    -
    1
    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, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivo + Ipi
    Arm description
    		 Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab Solution for Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/Kg IV Q6W

    Investigational medicinal product name
    BMS-936558 Nivolumab Solution for Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg IV Q2W

    Arm title
    		 Arm B: Nivo
    Arm description
    		 Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-936558 Nivolumab Solution for Injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg IV Q2W

    Number of subjects in period 2
    		Arm A: Nivo + Ipi Arm B: Nivo
    Started
    916
    917
    Completed
    364
    561
    Not completed
    552
    356
         Disease progression
    166
    208
         Adverse Event unrelated to study drug
    15
    7
         Participant withdrew consent
    5
    10
         Study drug toxicity
    317
    104
         Participant no longer meets study criteria
    1
    3
         Other reasons
    12
    4
         Participant request to stop therapy
    33
    20
         Poor/non-compliance
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Nivo + Ipi
    Reporting group description
    		 Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)

    Reporting group title
    Arm B: Nivo
    Reporting group description
    		 Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49

    Reporting group values
    		 Arm A: Nivo + Ipi Arm B: Nivo Total
    Number of subjects
    		 920 924 1844
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 3 3
        Adults (18-64 years)
    		 662 671 1333
        From 65-84 years
    		 257 247 504
        85 years and over
    		 1 3 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 53.8 ( 14.6 ) 54.6 ( 13.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 405 387 792
        Male
    		 515 537 1052
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 907 911 1818
        Black or African American
    		 4 1 5
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 3 5 8
        Other
    		 6 6 12
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 22 22 44
        Not Hispanic or Latino
    		 359 376 735
        Unknown or Not Reported
    		 539 526 1065

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Nivo + Ipi
    Reporting group description
    		 Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)

    Reporting group title
    Arm B: Nivo
    Reporting group description
    		 Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49
    Reporting group title
    Arm A: Nivo + Ipi
    Reporting group description
    		 Arm A: nivolumab 240 mg IV Q2 weeks plus ipilimumab 1 mg/kg IV Q6 weeks (for 1 year of study drug treatment)

    Reporting group title
    Arm B: Nivo
    Reporting group description
    		 Arm B: nivolumab 480 mg IV Q4 weeks (for 1 year of study drug treatment) with nivolumab placebo on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, & 47 and ipilimumab placebo on Weeks 1, 7, 13, 19, 25, 31, 37, 43, & 49

    Primary: Recurrence-free Survival (RFS) - all randomized participants

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    End point title
    		 Recurrence-free Survival (RFS) - all randomized participants
    End point description
    RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median values based on Kaplan-Meier Estimates.
    End point type
    Primary
    End point timeframe
    From randomization to Study Completion Date (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    918
    922
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Hazard Ratio RFS - all randomized
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    1840
    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
    		 0.78
         upper limit
    		 1.04

    Primary: Recurrence-free Survival (RFS) - all randomized participants with PD-L1 expression level < 1%

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    End point title
    		 Recurrence-free Survival (RFS) - all randomized participants with PD-L1 expression level < 1%
    End point description
    RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates. PD-L1 expression levels based on Interactive Response Technology (IRT).
    End point type
    Primary
    End point timeframe
    From randomization to Study Completion Date (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    347
    350
    Units: Months
        median (confidence interval 95%)
    33.15 (22.21 to 99999)
    27.63 (19.81 to 99999)
    Statistical analysis title
    		 Hazard Ratio RFS - all randomized with PD-L1 <1%
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    697
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.14

    Secondary: Overall Survival (OS) - all randomized participants

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    End point title
    		 Overall Survival (OS) - all randomized participants
    End point description
    OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.
    End point type
    Secondary
    End point timeframe
    From randomization to date of death (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    918
    922
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Hazard Ratio OS - all randomized
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    1840
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.32

    Secondary: Overall Survival (OS) - all randomized participants with PD-L1 expression level < 1%

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    End point title
    		 Overall Survival (OS) - all randomized participants with PD-L1 expression level < 1%
    End point description
    OS is defined as the time between the date of randomization and the date of death. Median based on Kaplan-Meier Estimates.
    End point type
    Secondary
    End point timeframe
    From randomization to date of death (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    347
    350
    Units: Months
        median (confidence interval 95%)
    99999 (41.72 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Hazard Ratio OS - all randomized with PD-L1 <1%
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    697
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.73

    Secondary: Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression

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    End point title
    		 Recurrence-free Survival (RFS) by Baseline Tumor PD-L1 Expression
    End point description
    RFS was defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma (including melanoma in situ), or death (from any cause), whichever occurred first. Median based on Kaplan-Meier Estimates. PD-L1 expression levels based on clinical database.
    End point type
    Secondary
    End point timeframe
    From randomization to Study Completion Date (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    920
    924
    Units: Months
    median (confidence interval 95%)
        < 1% Tumor PD-L1 Expression
    33.18 (22.21 to 99999)
    25.33 (19.81 to 99999)
        ≥ 1% Tumor PD-L1 Expression
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        ≥ 5% Tumor PD-L1 Expression
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        < 5% Tumor PD-L1 Expression
    99999 (31.18 to 99999)
    99999 (27.63 to 99999)
        Non-quantifiable Tumor PD-L1 Expression
    99999 (22.41 to 99999)
    99999 (10.87 to 99999)
    Statistical analysis title
    		 HR - tumor PD-L1 < 1%
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    1844
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.14
    Notes
    [1] - < 1% Tumor PD-L1 Expression
    Statistical analysis title
    		 HR - tumor PD-L1 >= 1%
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    1844
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.18
    Notes
    [2] - >= 1% Tumor PD-L1 Expression
    Statistical analysis title
    		 HR - tumor PD-L1 >= 5%
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    1844
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.34
    Notes
    [3] - >= 5% Tumor PD-L1 Expression
    Statistical analysis title
    		 HR - tumor PD-L1 < 5%
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    1844
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.1
    Notes
    [4] - < 5% Tumor PD-L1 Expression
    Statistical analysis title
    		 HR - tumor PD-L1 not quantifiable
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Nivo
    Number of subjects included in analysis
    1844
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.51
    Notes
    [5] - Non-quantifiable Tumor PD-L1 Expression

    Secondary: Time to Next-Line Therapies - all randomized participants

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    End point title
    		 Time to Next-Line Therapies - all randomized participants
    End point description
    Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date.
    End point type
    Secondary
    End point timeframe
    From randomization to start of next therapy or second next therapy (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    920
    924
    Units: Months
    median (confidence interval 95%)
        Time to next therapy
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Time to second next therapy
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Next-Line Therapies - all randomized participants with PD-L1 expression level < 1%

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    End point title
    		 Time to Next-Line Therapies - all randomized participants with PD-L1 expression level < 1%
    End point description
    Time to next therapy was defined as the time from the date of randomization to the start date of next systemic therapy. Participants who did not receive next treatment were censored at the last known alive date. Time to second next therapy was defined as the time from the date of randomization to the start date of second next systemic therapy. Participants who did not receive second next treatment were censored at the last known alive date
    End point type
    Secondary
    End point timeframe
    From randomization to start of next therapy or second next therapy (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    349
    351
    Units: Months
    median (confidence interval 95%)
        Time to next therapy
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Time to second next therapy
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time From Next Therapy to Second Next Therapy - all randomized participants

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    End point title
    		 Time From Next Therapy to Second Next Therapy - all randomized participants
    End point description
    Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.
    End point type
    Secondary
    End point timeframe
    From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    81
    81
    Units: Months
        median (full range (min-max))
    4.60 (0.8 to 23.7)
    4.80 (0.0 to 27.7)
    No statistical analyses for this end point

    Secondary: Time From Next Therapy to Second Next Therapy - all randomized participants with PD-L1 expression level < 1%

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    End point title
    		 Time From Next Therapy to Second Next Therapy - all randomized participants with PD-L1 expression level < 1%
    End point description
    Time from next treatment to second next treatment was defined as the time from the start date of next systemic therapy to start date of second next systemic therapy. No censoring rules were applied here as analysis was only performed for the subset of participants who received second next treatment.
    End point type
    Secondary
    End point timeframe
    From start of first next systemic therapy to start of second next systemic therapy (up to approximately 28 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    35
    46
    Units: Months
        median (full range (min-max))
    4.44 (0.8 to 23.7)
    5.04 (0.9 to 27.7)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) on next-line therapy - all randomized participants

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    End point title
    		 Progression-free survival (PFS) on next-line therapy - all randomized participants
    End point description
    PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.
    End point type
    Secondary
    End point timeframe
    From randomization to progression event (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    920
    924
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) on next-line therapy - all randomized participants with PD-L1 expression level < 1%

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    End point title
    		 Progression-free survival (PFS) on next-line therapy - all randomized participants with PD-L1 expression level < 1%
    End point description
    PFS2 was defined as the time from randomization to the progression date on next-line systemic therapy or the end date of next-line systemic therapy (if progression date not available) or death from any cause (if both progression date and end date not available), and to last known alive date in case of no event (ie, censoring), meaning either (1) no subsequent systemic therapy and no death OR (2) subsequent systemic therapy but no progression date nor end date available and no death.
    End point type
    Secondary
    End point timeframe
    From randomization to progression event (up to approximately 45 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Nivo
    Number of subjects analysed
    349
    351
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (35.94 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to 30 days after last dose
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Nivolumab Monotherapy
    Reporting group description
    		 Nivolumab Monotherapy: Subjects were infused 480 mg of Nivolumab for 30 minutes on Day 1 of each treatment cycle every 4 weeks for one year

    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Nivolumab + Ipilimumab: Subjects were infused 240 milligram (mg) of Nivolumab for 30 minutes on Day 1 every 2 weeks plus Ipilimumab 1 mg/kg for 30 minutes every 6 weeks for one year

    Serious adverse events
    		 Nivolumab Monotherapy Nivolumab + Ipilimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    185 / 917 (20.17%)
    308 / 916 (33.62%)
         number of deaths (all causes)
    121
    122
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    22 / 917 (2.40%)
    13 / 916 (1.42%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 917 (0.11%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 917 (0.22%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    6 / 917 (0.65%)
    6 / 916 (0.66%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Marginal zone lymphoma
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melanoma recurrent
         subjects affected / exposed
    1 / 917 (0.11%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to breast
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 917 (0.11%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastasis
         subjects affected / exposed
    1 / 917 (0.11%)
    4 / 916 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    2 / 917 (0.22%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloma
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 917 (0.22%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Recurrent cancer
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    10 / 917 (1.09%)
    8 / 916 (0.87%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 917 (0.11%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 917 (0.11%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 917 (0.00%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granuloma
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lithiasis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 917 (0.11%)
    9 / 916 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    1 / 917 (0.11%)
    6 / 916 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic spasm
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated pneumonitis
         subjects affected / exposed
    0 / 917 (0.00%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 917 (0.22%)
    8 / 916 (0.87%)
         occurrences causally related to treatment / all
    2 / 2
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Depression
         subjects affected / exposed
    2 / 917 (0.22%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    3 / 917 (0.33%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 917 (0.00%)
    4 / 916 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory distress
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiomegaly
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 917 (0.00%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Autoimmune neuropathy
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery dissection
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 917 (0.33%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningism
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Miller Fisher syndrome
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    3 / 917 (0.33%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Orbital myositis
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    2 / 917 (0.22%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 917 (0.11%)
    8 / 916 (0.87%)
         occurrences causally related to treatment / all
    1 / 1
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    4 / 917 (0.44%)
    21 / 916 (2.29%)
         occurrences causally related to treatment / all
    4 / 4
    23 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 917 (0.55%)
    17 / 916 (1.86%)
         occurrences causally related to treatment / all
    4 / 5
    17 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epigastric discomfort
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 917 (0.11%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    3 / 917 (0.33%)
    15 / 916 (1.64%)
         occurrences causally related to treatment / all
    2 / 3
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 917 (0.22%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal fibrosis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 917 (0.00%)
    11 / 916 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis sclerosing
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    2 / 917 (0.22%)
    5 / 916 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 917 (0.00%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 917 (0.00%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodular regenerative hyperplasia
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive liver disease
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 917 (0.22%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 917 (0.33%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    2 / 917 (0.22%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    1 / 917 (0.11%)
    8 / 916 (0.87%)
         occurrences causally related to treatment / all
    1 / 1
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperparathyroidism primary
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 917 (0.00%)
    5 / 916 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    6 / 917 (0.65%)
    18 / 916 (1.97%)
         occurrences causally related to treatment / all
    6 / 6
    19 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 917 (0.11%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytic hypophysitis
         subjects affected / exposed
    0 / 917 (0.00%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Primary adrenal insufficiency
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 917 (0.11%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis acute
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyrotoxic crisis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 917 (0.11%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis-like syndrome
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adrenalitis
         subjects affected / exposed
    2 / 917 (0.22%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 917 (0.22%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter colitis
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 917 (0.44%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    2 / 917 (0.22%)
    4 / 916 (0.44%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    3 / 917 (0.33%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes oesophagitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected bite
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 917 (0.11%)
    3 / 916 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Picornavirus infection
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 917 (0.11%)
    8 / 916 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    2 / 917 (0.22%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 917 (0.22%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 917 (0.11%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fulminant type 1 diabetes mellitus
         subjects affected / exposed
    1 / 917 (0.11%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 917 (0.33%)
    4 / 916 (0.44%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 917 (0.22%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Steroid diabetes
         subjects affected / exposed
    0 / 917 (0.00%)
    2 / 916 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    2 / 917 (0.22%)
    0 / 916 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 917 (0.00%)
    1 / 916 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nivolumab Monotherapy Nivolumab + Ipilimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    882 / 917 (96.18%)
    894 / 916 (97.60%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    46 / 917 (5.02%)
    42 / 916 (4.59%)
         occurrences all number
    73
    58
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    143 / 917 (15.59%)
    159 / 916 (17.36%)
         occurrences all number
    271
    284
    Fatigue
         subjects affected / exposed
    334 / 917 (36.42%)
    339 / 916 (37.01%)
         occurrences all number
    505
    503
    Influenza like illness
         subjects affected / exposed
    45 / 917 (4.91%)
    56 / 916 (6.11%)
         occurrences all number
    60
    72
    Pyrexia
         subjects affected / exposed
    79 / 917 (8.62%)
    112 / 916 (12.23%)
         occurrences all number
    94
    142
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    166 / 917 (18.10%)
    160 / 916 (17.47%)
         occurrences all number
    216
    214
    Dyspnoea
         subjects affected / exposed
    65 / 917 (7.09%)
    66 / 916 (7.21%)
         occurrences all number
    72
    85
    Oropharyngeal pain
         subjects affected / exposed
    43 / 917 (4.69%)
    50 / 916 (5.46%)
         occurrences all number
    48
    55
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    46 / 917 (5.02%)
    30 / 916 (3.28%)
         occurrences all number
    56
    34
    Insomnia
         subjects affected / exposed
    68 / 917 (7.42%)
    78 / 916 (8.52%)
         occurrences all number
    79
    91
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    81 / 917 (8.83%)
    129 / 916 (14.08%)
         occurrences all number
    129
    239
    Amylase increased
         subjects affected / exposed
    33 / 917 (3.60%)
    79 / 916 (8.62%)
         occurrences all number
    60
    142
    Aspartate aminotransferase increased
         subjects affected / exposed
    66 / 917 (7.20%)
    107 / 916 (11.68%)
         occurrences all number
    92
    159
    Blood creatine phosphokinase increased
         subjects affected / exposed
    50 / 917 (5.45%)
    54 / 916 (5.90%)
         occurrences all number
    67
    75
    Lipase increased
         subjects affected / exposed
    52 / 917 (5.67%)
    115 / 916 (12.55%)
         occurrences all number
    95
    240
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    45 / 917 (4.91%)
    56 / 916 (6.11%)
         occurrences all number
    80
    87
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    60 / 917 (6.54%)
    62 / 916 (6.77%)
         occurrences all number
    73
    78
    Headache
         subjects affected / exposed
    207 / 917 (22.57%)
    266 / 916 (29.04%)
         occurrences all number
    336
    420
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    77 / 917 (8.40%)
    99 / 916 (10.81%)
         occurrences all number
    105
    131
    Abdominal pain upper
         subjects affected / exposed
    35 / 917 (3.82%)
    54 / 916 (5.90%)
         occurrences all number
    42
    67
    Constipation
         subjects affected / exposed
    87 / 917 (9.49%)
    98 / 916 (10.70%)
         occurrences all number
    112
    124
    Diarrhoea
         subjects affected / exposed
    301 / 917 (32.82%)
    327 / 916 (35.70%)
         occurrences all number
    521
    595
    Dry mouth
         subjects affected / exposed
    87 / 917 (9.49%)
    95 / 916 (10.37%)
         occurrences all number
    94
    108
    Nausea
         subjects affected / exposed
    180 / 917 (19.63%)
    213 / 916 (23.25%)
         occurrences all number
    270
    308
    Vomiting
         subjects affected / exposed
    73 / 917 (7.96%)
    95 / 916 (10.37%)
         occurrences all number
    99
    119
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    236 / 917 (25.74%)
    337 / 916 (36.79%)
         occurrences all number
    324
    507
    Rash
         subjects affected / exposed
    229 / 917 (24.97%)
    254 / 916 (27.73%)
         occurrences all number
    342
    374
    Vitiligo
         subjects affected / exposed
    55 / 917 (6.00%)
    46 / 916 (5.02%)
         occurrences all number
    63
    49
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    6 / 917 (0.65%)
    48 / 916 (5.24%)
         occurrences all number
    8
    52
    Hyperthyroidism
         subjects affected / exposed
    98 / 917 (10.69%)
    179 / 916 (19.54%)
         occurrences all number
    115
    211
    Hypophysitis
         subjects affected / exposed
    10 / 917 (1.09%)
    84 / 916 (9.17%)
         occurrences all number
    10
    94
    Hypothyroidism
         subjects affected / exposed
    134 / 917 (14.61%)
    208 / 916 (22.71%)
         occurrences all number
    161
    253
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    205 / 917 (22.36%)
    158 / 916 (17.25%)
         occurrences all number
    356
    253
    Back pain
         subjects affected / exposed
    92 / 917 (10.03%)
    89 / 916 (9.72%)
         occurrences all number
    115
    108
    Myalgia
         subjects affected / exposed
    80 / 917 (8.72%)
    90 / 916 (9.83%)
         occurrences all number
    106
    114
    Pain in extremity
         subjects affected / exposed
    50 / 917 (5.45%)
    44 / 916 (4.80%)
         occurrences all number
    70
    55
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    100 / 917 (10.91%)
    108 / 916 (11.79%)
         occurrences all number
    129
    152
    Upper respiratory tract infection
         subjects affected / exposed
    82 / 917 (8.94%)
    67 / 916 (7.31%)
         occurrences all number
    114
    82
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    60 / 917 (6.54%)
    104 / 916 (11.35%)
         occurrences all number
    79
    125
    Hyperglycaemia
         subjects affected / exposed
    46 / 917 (5.02%)
    45 / 916 (4.91%)
         occurrences all number
    68
    66

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2017
    Study design changes
    11 Mar 2019
    Statistical analysis design modifications

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

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