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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind Study of Nivolumab Monotherapy or Nivolumab Combined with Ipilimumab vs Placebo in Participants with Localized Renal Cell Carcinoma Who Underwent Radical or Partial Nephrectomy and Who Are at High Risk of Relapse CheckMate 914: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 914

    Summary
    EudraCT number
    		 2016-004502-34
    Trial protocol
    		 AT   DE   BE   CZ   NL   GB   FR   ES   IT   RO  
    Global end of trial date
    01 Feb 2024

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Nov 2024
    First version publication date
    10 Aug 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-914
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03138512
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A: To compare disease-free survival (DFS) per Blinded Independent Central Review (BICR) of nivolumab combined with ipilimumab versus placebo infusions in participants with localized RCC, with a predominantly clear cell histology who have undergone a nephrectomy. Part B: To compare disease-free survival (DFS) per Blinded Independent Central Review (BICR) of nivolumab versus placebo infusions in participants with localized renal cell carcinoma, with a predominantly clear cell histology who have undergone nephrectomy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Aug 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
    Argentina: 159
    Country: Number of subjects enrolled
    Australia: 85
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Brazil: 60
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    Chile: 30
    Country: Number of subjects enrolled
    China: 100
    Country: Number of subjects enrolled
    Colombia: 11
    Country: Number of subjects enrolled
    Czechia: 39
    Country: Number of subjects enrolled
    France: 163
    Country: Number of subjects enrolled
    Germany: 67
    Country: Number of subjects enrolled
    Italy: 93
    Country: Number of subjects enrolled
    Japan: 124
    Country: Number of subjects enrolled
    Mexico: 132
    Country: Number of subjects enrolled
    Netherlands: 30
    Country: Number of subjects enrolled
    Poland: 50
    Country: Number of subjects enrolled
    Romania: 19
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Türkiye: 10
    Country: Number of subjects enrolled
    United Kingdom: 72
    Country: Number of subjects enrolled
    United States: 248
    Worldwide total number of subjects
    1641
    EEA total number of subjects
    537
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1142
    From 65 to 84 years
    498
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Part A and B participants are separately randomized and treated.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Nivo + Ipi
    Arm description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is delayed).
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg

    Arm title
    		 Arm B: Placebo
    Arm description
    		 Placebo infusions at the same frequency of nivolumab and ipilimumab infusions.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ipilimumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% Sodium Chloride or 5% Dextrose Injection

    Investigational medicinal product name
    Nivolumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% Sodium Chloride or 5% Dextrose Injection

    Arm title
    		 Arm C: Nivo
    Arm description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab Placebo every 6 weeks (or every third nivolumab dose if dosing is delayed).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% Sodium Chloride or 5% Dextrose Injection

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg

    Number of subjects in period 1
    		Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Started
    611
    619
    411
    Randomized to Part A
    405 [1]
    411 [2]
    0 [3]
    Randomized to Part B
    206 [4]
    208 [5]
    411
    Completed
    608
    614
    408
    Not completed
    3
    5
    3
         Participant no longer meets study criteria
    1
    4
    3
         Other reasons
    1
    -
    -
         Participants withdrew consent
    1
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: CM914 had two Parts (A & B), which were consisted with 2 arms (O+Y versus Placebo) and 3 arms (O+Y, Placebo and Nivo mono).
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: CM914 had two Parts (A & B), which were consisted with 2 arms (O+Y versus Placebo) and 3 arms (O+Y, Placebo and Nivo mono).
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: CM914 had two Parts (A & B), which were consisted with 2 arms (O+Y versus Placebo) and 3 arms (O+Y, Placebo and Nivo mono).
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: CM914 had two Parts (A & B), which were consisted with 2 arms (O+Y versus Placebo) and 3 arms (O+Y, Placebo and Nivo mono).
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: CM914 had two Parts (A & B), which were consisted with 2 arms (O+Y versus Placebo) and 3 arms (O+Y, Placebo and Nivo mono).
    Period 2
    Period 2 title
    Treatment Part A
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm A: Nivo + Ipi
    Arm description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is delayed).
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg

    Arm title
    		 Arm B: Placebo
    Arm description
    		 Placebo infusions at the same frequency of nivolumab and ipilimumab infusions.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ipilimumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% Sodium Chloride or 5% Dextrose Injection

    Investigational medicinal product name
    Nivolumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% Sodium Chloride or 5% Dextrose Injection

    Number of subjects in period 2
    		Arm A: Nivo + Ipi Arm B: Placebo
    Started
    404
    407
    Completed
    229
    360
    Not completed
    175
    47
         Participant request to discontinue treatment
    9
    4
         Disease recurrence
    10
    20
         Participant withdrew consent
    2
    4
         Death
    1
    -
         Pregnancy
    -
    1
         Adverse event unrelated to study drug
    9
    4
         Other reasons
    11
    8
         Study Drug Toxicity
    132
    5
         Lost to follow-up
    -
    1
         Poor/non-compliance
    1
    -
    Period 3
    Period 3 title
    Treatment Part B
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm A: Nivo + Ipi
    Arm description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is delayed).
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg

    Arm title
    		 Arm B: Placebo
    Arm description
    		 Placebo infusions at the same frequency of nivolumab and ipilimumab infusions.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ipilimumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% Sodium Chloride or 5% Dextrose Injection

    Investigational medicinal product name
    Nivolumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% Sodium Chloride or 5% Dextrose Injection

    Arm title
    		 Arm C: Nivo
    Arm description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab Placebo every 6 weeks (or every third nivolumab dose if dosing is delayed).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab-Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.9% Sodium Chloride or 5% Dextrose Injection

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg

    Number of subjects in period 3
    		Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Started
    204
    207
    408
    Completed
    118
    182
    327
    Not completed
    86
    25
    81
         Disease recurrence
    6
    12
    10
         Participant withdrew consent
    1
    1
    2
         Death
    1
    -
    -
         Request to discontinue study treatment
    6
    4
    6
         Adverse event unrelated to study drug
    5
    2
    12
         Other reasons
    3
    1
    5
         Study Drug Toxicity
    63
    3
    45
         Lost to follow-up
    -
    1
    -
         Poor/non-compliance
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Nivo + Ipi
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is delayed).

    Reporting group title
    Arm B: Placebo
    Reporting group description
    		 Placebo infusions at the same frequency of nivolumab and ipilimumab infusions.

    Reporting group title
    Arm C: Nivo
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab Placebo every 6 weeks (or every third nivolumab dose if dosing is delayed).

    Reporting group values
    		 Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo Total
    Number of subjects
    		 611 619 411 1641
    Age Categorical
    Units: Participants
        Part A|< 65
    		 293 301 0 594
        Part B|< 65
    		 132 137 279 548
        Part A|>= 65 AND < 75
    		 93 91 0 184
        Part B|>= 65 AND < 75
    		 64 60 108 232
        Part A|>= 75 AND < 85
    		 19 19 0 38
        Part B|>= 75 AND < 85
    		 10 11 23 44
        Part A|>= 85
    		 0 0 0 0
        Part B|>= 85
    		 0 0 1 1
    Age Continuous
    All Randomized Part A Subjects Note: 0.99999 - N/A (No participants randomized to Arm C for Part A)
    Units: years
        arithmetic mean (standard deviation)
    		 57.9 ( 10.49 ) 57.3 ( 10.53 ) 0.99999 ( 0.99999 ) -
    Sex: Female, Male
    Units: Participants
        Part A|Female
    		 119 117 0 236
        Part B|Female
    		 59 67 106 232
        Part A|Male
    		 286 294 0 580
        Part B|Male
    		 147 141 305 593
    Race (NIH/OMB)
    Units: Subjects
        Part A|American Indian or Alaska Native
    		 0 3 0 3
        Part B|American Indian or Alaska Native
    		 5 3 14 22
        Part A|Asian
    		 93 65 0 158
        Part B|Asian
    		 20 26 50 96
        Part A|Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Part B|Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Part A|Black or African American
    		 3 6 0 9
        Part B|Black or African American
    		 0 1 4 5
        Part A|White
    		 303 322 0 625
        Part B|White
    		 173 169 331 673
        Part A|More than one race
    		 0 0 0 0
        Part B|More than one race
    		 0 0 0 0
        Part A|Unknown or Not Reported
    		 6 14 0 20
        Part B|Unknown or Not Reported
    		 8 9 12 29
    Ethnicity (NIH/OMB)
    Units: Subjects
        Part A|Hispanic or Latino
    		 41 44 0 85
        Part B|Hispanic or Latino
    		 26 34 67 127
        Part A|Not Hispanic or Latino
    		 189 197 0 386
        Part B|Not Hispanic or Latino
    		 93 79 157 329
        Part A|Unknown or Not Reported
    		 175 170 0 345
        Part B|Unknown or Not Reported
    		 87 95 187 369
    Age Continuous
    All Randomized Part B Subjects
    Units: Years
        arithmetic mean (standard deviation)
    		 58.6 ( 10.9 ) 58.1 ( 11.2 ) 58.0 ( 11.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Nivo + Ipi
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is delayed).

    Reporting group title
    Arm B: Placebo
    Reporting group description
    		 Placebo infusions at the same frequency of nivolumab and ipilimumab infusions.

    Reporting group title
    Arm C: Nivo
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab Placebo every 6 weeks (or every third nivolumab dose if dosing is delayed).
    Reporting group title
    Arm A: Nivo + Ipi
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is delayed).

    Reporting group title
    Arm B: Placebo
    Reporting group description
    		 Placebo infusions at the same frequency of nivolumab and ipilimumab infusions.
    Reporting group title
    Arm A: Nivo + Ipi
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is delayed).

    Reporting group title
    Arm B: Placebo
    Reporting group description
    		 Placebo infusions at the same frequency of nivolumab and ipilimumab infusions.

    Reporting group title
    Arm C: Nivo
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab Placebo every 6 weeks (or every third nivolumab dose if dosing is delayed).

    Primary: Disease-Free Survival (DFS) by BICR - Part A and B

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    End point title
    		 Disease-Free Survival (DFS) by BICR - Part A and B
    End point description
    Disease-Free Survival (DFS) is defined as the time from randomization to development of local disease recurrence (ie, recurrence of primary tumor in situ or occurrence of a secondary renal cell carcinoma (RCC) primary cancer), distance metastasis, or death, whichever came first per Blinded Independent Central Review (BICR) based on Kaplan-Meier estimates. Analyzed in all randomized participants in Part A (Arm A and B) and Part B (Arm B and C). Note: 99999 - N/A (Insufficient number of participants with events) Note: 00000 - 0 Participants analyzed. Arm A was prespecified to be excluded from the endpoint objective for Part B.
    End point type
    Primary
    End point timeframe
    From randomization to development of local disease recurrence, distance metastasis, or death, whichever came first (up to an average of 72 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Number of subjects analysed
    611
    619
    411
    Units: Months
    median (confidence interval 95%)
        Part A
    99999 (99999 to 99999)
    99999 (65.58 to 99999)
    00000 (00000 to 00000)
        Part B
    00000 (00000 to 00000)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Arm A vs Arm B in Part B
    Comparison groups
    Arm B: Placebo v Arm C: Nivo
    Number of subjects included in analysis
    1030
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6556
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.28
    Statistical analysis title
    		 Arm A vs Arm B in Part A
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Placebo
    Number of subjects included in analysis
    1230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6676
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.2

    Secondary: Overall Survival (OS) - Part A and B

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    End point title
    		 Overall Survival (OS) - Part A and B
    End point description
    Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the participants was known to be alive. Based on Kaplan-Meier estimates. Analyzed in all randomized participants in Part A (Arm A and B) and Part B (Arm B and C). Note: 99999 - N/A (Insufficient number of participants with events) Note: 00000 - 0 Participants analyzed. Arm A was prespecified to be excluded from the endpoint objective for Part B.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death (up to an average of 72 months)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Number of subjects analysed
    611
    619
    411
    Units: Months
    median (confidence interval 95%)
        Part A
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    00000 (00000 to 00000)
        Part B
    00000 (00000 to 00000)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Arm B vs Arm C in Part B
    Statistical analysis description
    Part B
    Comparison groups
    Arm B: Placebo v Arm C: Nivo
    Number of subjects included in analysis
    1030
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 3.07
    Statistical analysis title
    		 Arm A vs Arm B in Part A
    Statistical analysis description
    Part A
    Comparison groups
    Arm A: Nivo + Ipi v Arm B: Placebo
    Number of subjects included in analysis
    1230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2436
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.85

    Secondary: Overall Survival (OS) Rate (5 years) - Part A and B

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    End point title
    		 Overall Survival (OS) Rate (5 years) - Part A and B
    End point description
    Overall survival rate at 5 years is defined as the percentage of participants who are alive at 5 years. Analyzed in all randomized participants in Part A (Arm A and B) and Part B (Arm B and C).
    End point type
    Secondary
    End point timeframe
    At 5 years
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Number of subjects analysed
    611 [1]
    619 [2]
    0 [3]
    Units: Months
    median (confidence interval 95%)
        Part A
    85.0 (80.8 to 88.3)
    87.2 (82.8 to 90.5)
    ( to )
        Part B
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    ( to )
    Notes
    [1] - The minimum follow-up of 5-years was not achieved for Part B.
    [2] - The minimum follow-up of 5-years was not achieved for Part B.
    [3] - The minimum follow-up of 5-years was not achieved.
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS) per BICR in Contemporaneously Randomized Combination and Monotherapy Participants - Part B

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    End point title
    		 Disease-Free Survival (DFS) per BICR in Contemporaneously Randomized Combination and Monotherapy Participants - Part B [4]
    End point description
    Disease-Free Survival (DFS) is defined as the time from randomization to development of local disease recurrence (ie, recurrence of primary tumor in situ or occurrence of a secondary renal cell carcinoma (RCC) primary cancer), distance metastasis, or death, whichever came first per Blinded Independent Central Review (BICR) based on Kaplan-Meier estimates. Analyzed for all randomized combination and monotherapy participants in Part B. Prespecified to be collected for Part B only. Arm B was prespecified to be excluded from the endpoint objective. Note: 99999 - N/A (Insufficient number of participants with events)
    End point type
    Secondary
    End point timeframe
    From randomization to development of local disease recurrence, distance metastasis, or death, whichever came first (up to an average of 72 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Part B only.
    End point values
    		 Arm A: Nivo + Ipi Arm C: Nivo
    Number of subjects analysed
    206 [5]
    411 [6]
    Units: Months
        median (confidence interval 95%)
    99999 (36.17 to 99999)
    99999 (99999 to 99999)
    Notes
    [5] - Part B
    [6] - Part B
    Statistical analysis title
    		 Arm A vs Arm C
    Comparison groups
    Arm A: Nivo + Ipi v Arm C: Nivo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.67

    Secondary: Overall Survival (OS) in the Contemporaneously Randomized Combination and Monotherapy Participants - Part B

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    End point title
    		 Overall Survival (OS) in the Contemporaneously Randomized Combination and Monotherapy Participants - Part B [7]
    End point description
    Overall Survival (OS) is defined as the time between the date of randomization and the date of death. For participants without documentation of death, OS will be censored on the last date the participants was known to be alive. Based on Kaplan-Meier estimates. Analyzed for all randomized combination and monotherapy participants in Part B. Prespecified to be collected for Part B only. Arm B was prespecified to be excluded from the endpoint objective. Note: 99999 - N/A (Insufficient number of participants with events)
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death (up to an average of 72 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Part B only.
    End point values
    		 Arm A: Nivo + Ipi Arm C: Nivo
    Number of subjects analysed
    206 [8]
    411 [9]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [8] - Part B
    [9] - Part B
    Statistical analysis title
    		 Arm A vs Arm C
    Comparison groups
    Arm A: Nivo + Ipi v Arm C: Nivo
    Number of subjects included in analysis
    617
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.68

    Secondary: The Number of Participants with Adverse Events up to 30 Days After Last Dose of Study Therapy - Part A

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    End point title
    		 The Number of Participants with Adverse Events up to 30 Days After Last Dose of Study Therapy - Part A [10]
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Graded according to NCI CTCAE (Version 4) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death. Analyzed in all treated participants in Part A.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post last dose (up to approximately 40 weeks)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Part A only.
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo
    Number of subjects analysed
    404
    407
    Units: Participants
        Any Grade AE
    392
    362
        Grade 3-4 AE
    154
    44
        Grade 5 AE
    1
    0
        Any Grade Drug-Related AE
    359
    230
        Grade 3-4 Drug-Related AE
    114
    8
        Grade 5 Drug-Related AE
    0
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants with Adverse Events up to 30 Days After Last Dose of Study Therapy - Part B

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    End point title
    		 The Number of Participants with Adverse Events up to 30 Days After Last Dose of Study Therapy - Part B
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Graded according to NCI CTCAE (Version 4) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death. Analyzed in all treated participants in Part B.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post last dose (up to approximately 40 weeks)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Number of subjects analysed
    204 [11]
    207 [12]
    408 [13]
    Units: Participants
        Any Grade AE
    193
    182
    362
        Grade 3-4 AE
    59
    31
    70
        Grade 5 AE
    1
    1
    0
        Any Grade Drug-Related AE
    173
    107
    297
        Grade 3-4 Drug-Related AE
    41
    4
    36
        Grade 5 Drug-Related AE
    0
    0
    0
    Notes
    [11] - Part B
    [12] - Part B
    [13] - Part B
    No statistical analyses for this end point

    Secondary: The Number of Participants with Adverse Events up to 100 Days After Last Dose of Study Therapy - Part A

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    End point title
    		 The Number of Participants with Adverse Events up to 100 Days After Last Dose of Study Therapy - Part A [14]
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Graded according to NCI CTCAE (Version 4) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death. Analyzed in all treated participants in Part A.
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days post last dose (up to approximately 50 weeks)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Part A only.
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo
    Number of subjects analysed
    404
    407
    Units: Participants
        Any Grade AE
    393
    365
        Grade 3-4 AE
    167
    52
        Grade 5 AE
    4
    1
        Any Grade Drug-Related AE
    361
    230
        Grade 3-4 Drug-Related AE
    128
    9
        Grade 5 Drug-Related AE
    2
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants with Adverse Events up to 100 Days After Last Dose of Study Therapy - Part B

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    End point title
    		 The Number of Participants with Adverse Events up to 100 Days After Last Dose of Study Therapy - Part B
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Graded according to NCI CTCAE (Version 4) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death. Analyzed in all treated participants in Part B.
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days post last dose (up to approximately 50 weeks)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Number of subjects analysed
    204
    207
    408
    Units: Participants
        Any Grade AE
    196
    182
    367
        Grade 3-4 AE
    68
    32
    85
        Grade 5 AE
    5
    2
    2
        Any Grade Drug-Related AE
    175
    108
    300
        Grade 3-4 Drug-Related AE
    46
    5
    46
        Grade 5 Drug-Related AE
    0
    0
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants Experiencing Laboratory Parameters by Worst CTC (Grade 3-4) that Worsened Relative to Baseline up to 30 days - Part A

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    End point title
    		 The Number of Participants Experiencing Laboratory Parameters by Worst CTC (Grade 3-4) that Worsened Relative to Baseline up to 30 days - Part A [15]
    End point description
    Graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE, Version 4.0] where grade 3 = severe, and grade 4 = life-threatening. Baseline evaluations are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Analyzed in all treated participants in Part A with a CTC graded laboratory result for the given parameter from both baseline and on-treatment. Note: n = number of participants analyzed for each arm, LL = Local Lab, AT = Aminotransferase, ABS = Absolute.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post last dose (up to approximately 40 weeks)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Part A only.
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo
    Number of subjects analysed
    398
    404
    Units: Participants
        HEMOGLOBIN (n = 398, n = 404)
    1
    1
        PLATELET COUNT (n = 398, n = 404)
    1
    0
        LEUKOCYTES, LL (n = 398, n = 404)
    0
    0
        LYMPHOCYTES (ABS), TOTAL (n = 398, n = 404)
    6
    3
        ABS NEUTROPHIL COUNT (n = 398, n = 404)
    2
    0
        ALKALINE PHOSPHATASE, LL (n = 397, n = 404)
    3
    0
        ASPARTATE AT, LL (n = 398, n = 404)
    14
    3
        ALANINE AT, LL (n = 398, n = 404)
    16
    5
        BILIRUBIN, TOTAL, LL (n = 395, n = 404)
    1
    0
        CREATININE, LL (n = 398, n = 404)
    1
    1
        HYPERNATREMIA (n = 398, n = 404)
    0
    0
        HYPONATREMIA (n = 398, n = 404)
    28
    7
        HYPERKALEMIA (n = 398, n = 404)
    6
    5
        HYPOKALEMIA (n = 398, n = 404)
    3
    1
        HYPERCALCEMIA (n = 381, n = 389)
    3
    0
        HYPOCALCEMIA (n = 381, n = 389)
    1
    0
        HYPERMAGNESEMIA (n = 392, n = 401)
    1
    1
        HYPOMAGNESEMIA (n = 392, n = 401)
    1
    0
        HYPERGLYCEMIA (n = 180, n = 179)
    6
    1
        HYPOGLYCEMIA (n = 391, n = 397)
    1
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants Experiencing Laboratory Parameters by Worst CTC (Grade 3-4) that Worsened Relative to Baseline up to 30 days - Part B

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    End point title
    		 The Number of Participants Experiencing Laboratory Parameters by Worst CTC (Grade 3-4) that Worsened Relative to Baseline up to 30 days - Part B
    End point description
    Graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE, Version 4.0] where grade 3 = severe, and grade 4 = life-threatening. Baseline evaluations are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Analyzed in all treated participants in Part B with a CTC graded laboratory result for the given parameter from both baseline and on-treatment. Note: n = number of participants analyzed for each arm, LL = Local Lab, AT = Aminotransferase, ABS = Absolute.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post last dose (up to approximately 40 weeks)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Number of subjects analysed
    201
    205
    406
    Units: Participants
        HEMOGLOBIN (n = 201, n =205, n = 406)
    0
    3
    0
        PLATELET COUNT (n = 201, n =204, n = 406)
    0
    1
    0
        LEUKOCYTES, LL (n = 201, n =205, n = 406)
    0
    0
    1
        LYMPHOCYTES (ABS), TOTAL (n=201, n=205, n=406)
    3
    1
    4
        ABS NEUTROPHIL COUNT (n = 201, n =205, n = 406)
    0
    0
    1
        ALKALINE PHOSPHATASE, LL (n=201, n=205, n=404)
    1
    1
    0
        ASPARTATE AT, LL (n = 201, n =205, n = 405)
    4
    4
    5
        ALANINE AT, LL (n = 201, n =205, n = 405)
    7
    3
    8
        BILIRUBIN, TOTAL, LL (n = 200, n =205, n = 405)
    0
    1
    0
        CREATININE, LL (n = 201, n =205, n = 406)
    3
    0
    0
        HYPERNATREMIA (n = 201, n =204, n = 405)
    0
    0
    0
        HYPONATREMIA (n = 201, n =204, n = 405)
    11
    1
    9
        HYPERKALEMIA (n = 201, n =205, n = 406)
    1
    2
    2
        HYPOKALEMIA (n = 201, n =205, n = 406)
    1
    1
    0
        HYPERCALCEMIA (n = 197, n =199, n = 396)
    1
    0
    1
        HYPOCALCEMIA (n = 197, n =199, n = 396)
    0
    1
    0
        HYPERMAGNESEMIA (n = 196, n =203, n = 404)
    2
    2
    3
        HYPOMAGNESEMIA (n = 196, n =203, n = 404)
    0
    1
    1
        HYPERGLYCEMIA (n = 99, n =109, n = 208)
    3
    1
    3
        HYPOGLYCEMIA (n = 196, n =195, n = 401)
    0
    0
    1
    No statistical analyses for this end point

    Secondary: The Number of Participants Experiencing Laboratory Parameters by Worst CTC (Grade 3-4) that Worsened Relative to Baseline up to 100 days - Part A

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    End point title
    		 The Number of Participants Experiencing Laboratory Parameters by Worst CTC (Grade 3-4) that Worsened Relative to Baseline up to 100 days - Part A [16]
    End point description
    Graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE, Version 4.0] where grade 3 = severe, and grade 4 = life-threatening. Baseline evaluations are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Analyzed in all treated participants in Part A with a CTC graded laboratory result for the given parameter from both baseline and on-treatment. Note: n = number of participants analyzed for each arm, LL = Local Lab, AT = Aminotransferase, ABS = Absolute.
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days post last dose (up to approximately 50 weeks)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Prespecified to be collected for Part A only.
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo
    Number of subjects analysed
    401
    406
    Units: Participants
        HEMOGLOBIN (n = 401, n = 406)
    1
    1
        PLATELET COUNT (n = 401, n = 406)
    1
    0
        LEUKOCYTES, LL (n = 401, n = 406)
    0
    0
        LYMPHOCYTES (ABS), TOTAL (n = 401, n = 406)
    11
    3
        ABS NEUTROPHIL COUNT (n = 401, n = 406)
    2
    0
        ALKALINE PHOSPHATASE, LL (n = 400, n = 406)
    5
    0
        ASPARTATE AT, LL (n = 401, n = 406)
    17
    3
        ALANINE AT, LL (n = 401, n = 406)
    20
    6
        BILIRUBIN, TOTAL, LL (n = 399, n = 406)
    3
    0
        CREATININE, LL (n = 401, n = 406)
    4
    1
        HYPERNATREMIA (n = 401, n = 406)
    0
    0
        HYPONATREMIA (n = 401, n = 406)
    30
    7
        HYPERKALEMIA (n = 401, n = 406)
    6
    5
        HYPOKALEMIA (n = 401, n = 406)
    5
    1
        HYPERCALCEMIA (n = 384, n = 391)
    3
    0
        HYPOCALCEMIA (n = 384, n = 391)
    1
    0
        HYPERMAGNESEMIA (n = 395, n = 403)
    1
    1
        HYPOMAGNESEMIA (n = 395, n = 403)
    1
    0
        HYPERGLYCEMIA (n = 183, n = 179)
    7
    1
        HYPOGLYCEMIA (n = 394, n = 398)
    1
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants Experiencing Laboratory Parameters by Worst CTC (Grade 3-4) that Worsened Relative to Baseline up to 100 days - Part B

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    End point title
    		 The Number of Participants Experiencing Laboratory Parameters by Worst CTC (Grade 3-4) that Worsened Relative to Baseline up to 100 days - Part B
    End point description
    Graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE, Version 4.0] where grade 3 = severe, and grade 4 = life-threatening. Baseline evaluations are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Analyzed in all treated participants in Part A with a CTC graded laboratory result for the given parameter from both baseline and on-treatment. Note: n = number of participants analyzed for each arm, LL = Local Lab, AT = Aminotransferase, ABS = Absolute.
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days post last dose (up to approximately 50 weeks)
    End point values
    		 Arm A: Nivo + Ipi Arm B: Placebo Arm C: Nivo
    Number of subjects analysed
    203
    205
    407
    Units: Participants
        HEMOGLOBIN (n = 203, n =205, n = 407)
    2
    3
    1
        PLATELET COUNT (n = 203, n =204, n = 407)
    0
    1
    0
        LEUKOCYTES, LL (n = 203, n =205, n = 407)
    0
    0
    2
        LYMPHOCYTES (ABS), TOTAL (n=203, n=205, n= 407)
    3
    2
    7
        ABS NEUTROPHIL COUNT (n = 203, n =205, n = 407)
    0
    0
    2
        ALKALINE PHOSPHATASE, LL (n=203, n=205, n=405)
    2
    1
    0
        ASPARTATE AT, LL (n = 203, n =205, n = 406)
    6
    4
    6
        ALANINE AT, LL (n = 203, n =205, n = 406)
    9
    3
    10
        BILIRUBIN, TOTAL, LL (n = 202, n =205, n = 406)
    0
    1
    0
        CREATININE, LL (n = 203, n =205, n = 407)
    4
    0
    3
        HYPERNATREMIA (n = 203, n =204, n = 406)
    0
    0
    0
        HYPONATREMIA (n = 203, n =204, n = 407)
    12
    1
    13
        HYPERKALEMIA (n = 203, n =205, n = 407)
    1
    2
    4
        HYPOKALEMIA (n = 203, n =205, n = 407)
    1
    2
    2
        HYPERCALCEMIA (n = 199, n =199, n = 397)
    1
    0
    1
        HYPOCALCEMIA (n = 199, n =199, n = 397)
    0
    1
    1
        HYPERMAGNESEMIA (n = 198, n = 203, n = 405)
    3
    2
    3
        HYPOMAGNESEMIA (n = 198, n = 203, n = 405)
    0
    1
    1
        HYPERGLYCEMIA (n = 99, n = 109, n = 211)
    3
    1
    4
        HYPOGLYCEMIA (n = 99, n = 195, n = 402)
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was assessed from a participants first dose to their study completion (up to an average of 72 months) SAEs and Other AEs were assessed from first dose to 100 days following last dose (up to approximately 50 weeks).
    Adverse event reporting additional description
    The number at Risk for All-Cause Mortality and Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is delayed).

    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 240 mg every 2 weeks and ipilimumab Placebo every 6 weeks (or every third nivolumab dose if dosing is delayed).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo infusions at the same frequency of nivolumab and ipilimumab infusions.

    Serious adverse events
    		 Nivolumab + Ipilimumab Nivolumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    196 / 608 (32.24%)
    56 / 408 (13.73%)
    49 / 614 (7.98%)
         number of deaths (all causes)
    65
    22
    55
         number of deaths resulting from adverse events
    12
    5
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma stage 0
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Recurrent cancer
         subjects affected / exposed
    2 / 608 (0.33%)
    2 / 408 (0.49%)
    3 / 614 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Renal cell carcinoma recurrent
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Assisted suicide
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Disease recurrence
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 608 (0.66%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    7 / 608 (1.15%)
    4 / 408 (0.98%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    6 / 7
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 608 (0.49%)
    1 / 408 (0.25%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    2 / 608 (0.33%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subacute hepatic failure
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 608 (0.49%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arterial injury
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heat stroke
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Open fracture
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative thoracic procedure complication
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic injury
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Paraduodenal hernia
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    3 / 608 (0.49%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Myocardial injury
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 608 (0.16%)
    2 / 408 (0.49%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalitis autoimmune
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 608 (0.49%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated encephalitis
         subjects affected / exposed
    2 / 608 (0.33%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osmotic demyelination syndrome
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Serous retinal detachment
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orbital myositis
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 608 (2.63%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    15 / 16
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    12 / 608 (1.97%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    12 / 12
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 608 (0.66%)
    1 / 408 (0.25%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    3 / 608 (0.49%)
    2 / 408 (0.49%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesenteric panniculitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Immune-mediated enterocolitis
         subjects affected / exposed
    6 / 608 (0.99%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 608 (0.33%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 608 (0.82%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    13 / 608 (2.14%)
    2 / 408 (0.49%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    8 / 13
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder hypertrophy
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated nephritis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    4 / 608 (0.66%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocytic hypophysitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    12 / 608 (1.97%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    11 / 12
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    21 / 608 (3.45%)
    3 / 408 (0.74%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    24 / 24
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated myositis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    2 / 608 (0.33%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Appendicitis
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal fungal infection
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster meningitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 608 (0.99%)
    1 / 408 (0.25%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    2 / 614 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 608 (0.00%)
    0 / 408 (0.00%)
    1 / 614 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spontaneous bacterial peritonitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 608 (0.66%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    4 / 608 (0.66%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    3 / 608 (0.49%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    3 / 608 (0.49%)
    3 / 408 (0.74%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 608 (0.33%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    5 / 608 (0.82%)
    3 / 408 (0.74%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 608 (0.16%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 608 (0.16%)
    0 / 408 (0.00%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    6 / 608 (0.99%)
    2 / 408 (0.49%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 608 (0.00%)
    1 / 408 (0.25%)
    0 / 614 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nivolumab + Ipilimumab Nivolumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    544 / 608 (89.47%)
    325 / 408 (79.66%)
    469 / 614 (76.38%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    31 / 608 (5.10%)
    21 / 408 (5.15%)
    45 / 614 (7.33%)
         occurrences all number
    36
    24
    58
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    61 / 608 (10.03%)
    13 / 408 (3.19%)
    25 / 614 (4.07%)
         occurrences all number
    77
    15
    29
    Fatigue
         subjects affected / exposed
    189 / 608 (31.09%)
    99 / 408 (24.26%)
    158 / 614 (25.73%)
         occurrences all number
    228
    145
    190
    Asthenia
         subjects affected / exposed
    72 / 608 (11.84%)
    46 / 408 (11.27%)
    55 / 614 (8.96%)
         occurrences all number
    110
    58
    96
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    36 / 608 (5.92%)
    21 / 408 (5.15%)
    38 / 614 (6.19%)
         occurrences all number
    41
    24
    41
    Cough
         subjects affected / exposed
    66 / 608 (10.86%)
    25 / 408 (6.13%)
    67 / 614 (10.91%)
         occurrences all number
    70
    27
    80
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    51 / 608 (8.39%)
    25 / 408 (6.13%)
    37 / 614 (6.03%)
         occurrences all number
    54
    25
    39
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    74 / 608 (12.17%)
    34 / 408 (8.33%)
    24 / 614 (3.91%)
         occurrences all number
    88
    38
    32
    Aspartate aminotransferase increased
         subjects affected / exposed
    60 / 608 (9.87%)
    22 / 408 (5.39%)
    15 / 614 (2.44%)
         occurrences all number
    67
    31
    17
    Blood creatinine increased
         subjects affected / exposed
    82 / 608 (13.49%)
    40 / 408 (9.80%)
    59 / 614 (9.61%)
         occurrences all number
    101
    55
    80
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    37 / 608 (6.09%)
    17 / 408 (4.17%)
    38 / 614 (6.19%)
         occurrences all number
    42
    21
    43
    Headache
         subjects affected / exposed
    102 / 608 (16.78%)
    53 / 408 (12.99%)
    89 / 614 (14.50%)
         occurrences all number
    122
    76
    131
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    42 / 608 (6.91%)
    21 / 408 (5.15%)
    24 / 614 (3.91%)
         occurrences all number
    54
    30
    34
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    180 / 608 (29.61%)
    77 / 408 (18.87%)
    120 / 614 (19.54%)
         occurrences all number
    272
    114
    187
    Constipation
         subjects affected / exposed
    57 / 608 (9.38%)
    29 / 408 (7.11%)
    49 / 614 (7.98%)
         occurrences all number
    68
    34
    52
    Abdominal pain
         subjects affected / exposed
    40 / 608 (6.58%)
    21 / 408 (5.15%)
    44 / 614 (7.17%)
         occurrences all number
    46
    28
    51
    Vomiting
         subjects affected / exposed
    52 / 608 (8.55%)
    27 / 408 (6.62%)
    30 / 614 (4.89%)
         occurrences all number
    66
    37
    43
    Nausea
         subjects affected / exposed
    102 / 608 (16.78%)
    53 / 408 (12.99%)
    73 / 614 (11.89%)
         occurrences all number
    128
    74
    91
    Dry mouth
         subjects affected / exposed
    49 / 608 (8.06%)
    20 / 408 (4.90%)
    15 / 614 (2.44%)
         occurrences all number
    51
    20
    17
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    47 / 608 (7.73%)
    19 / 408 (4.66%)
    30 / 614 (4.89%)
         occurrences all number
    50
    20
    32
    Rash maculo-papular
         subjects affected / exposed
    51 / 608 (8.39%)
    23 / 408 (5.64%)
    6 / 614 (0.98%)
         occurrences all number
    62
    28
    6
    Rash
         subjects affected / exposed
    131 / 608 (21.55%)
    50 / 408 (12.25%)
    57 / 614 (9.28%)
         occurrences all number
    163
    63
    84
    Pruritus
         subjects affected / exposed
    213 / 608 (35.03%)
    103 / 408 (25.25%)
    103 / 614 (16.78%)
         occurrences all number
    274
    125
    118
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    52 / 608 (8.55%)
    13 / 408 (3.19%)
    4 / 614 (0.65%)
         occurrences all number
    59
    13
    4
    Hypothyroidism
         subjects affected / exposed
    131 / 608 (21.55%)
    54 / 408 (13.24%)
    28 / 614 (4.56%)
         occurrences all number
    133
    54
    37
    Hyperthyroidism
         subjects affected / exposed
    98 / 608 (16.12%)
    47 / 408 (11.52%)
    8 / 614 (1.30%)
         occurrences all number
    104
    47
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    111 / 608 (18.26%)
    58 / 408 (14.22%)
    97 / 614 (15.80%)
         occurrences all number
    141
    72
    107
    Back pain
         subjects affected / exposed
    45 / 608 (7.40%)
    48 / 408 (11.76%)
    66 / 614 (10.75%)
         occurrences all number
    52
    57
    77
    Myalgia
         subjects affected / exposed
    57 / 608 (9.38%)
    39 / 408 (9.56%)
    47 / 614 (7.65%)
         occurrences all number
    66
    49
    52
    Pain in extremity
         subjects affected / exposed
    27 / 608 (4.44%)
    22 / 408 (5.39%)
    29 / 614 (4.72%)
         occurrences all number
    29
    22
    34
    Infections and infestations
    COVID-19
         subjects affected / exposed
    15 / 608 (2.47%)
    29 / 408 (7.11%)
    19 / 614 (3.09%)
         occurrences all number
    16
    31
    19
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    71 / 608 (11.68%)
    15 / 408 (3.68%)
    19 / 614 (3.09%)
         occurrences all number
    80
    15
    20
    Hyperglycaemia
         subjects affected / exposed
    35 / 608 (5.76%)
    27 / 408 (6.62%)
    25 / 614 (4.07%)
         occurrences all number
    51
    38
    33

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2017
    - Consider the placebo products as investigational products - Remove the bioequivalence language
    06 Apr 2018
    Reduce frequency of patient questionnaires, update exclusion criterion for serum creatinine, remove 42-day screening window, provide more flexibility in scheduling scans, update background data, and provide additional information and/or clarification to sections indicated.
    01 Nov 2019
    Add Part B to the study for evaluation of nivolumab monotherapy.
    27 Oct 2020
    Remove Interim Analysis 1 for disease-free survival (DFS), from both Part A and Part B, to delay Interim Analysis 2 for DFS in Part A, and for both Part A and Part B Overall Survival (OS) to be hierarchically analyzed at the same time as the interim or final analysis for DFS in the same group of subjects. This revision also incorporates several changes to provide additional information and/or clarification.
    13 Feb 2022
    Address the timing of interim and final disease-free survival (DFS) analyses in Part A, which were initially planned to occur within 6 months of each other. However, the earlier versions of the protocol did not capture the scenario to proceed directly to the final DFS analysis in Part A in the event that Part B enrollment is ongoing when the required number of events needed for interim analysis of DFS in Part A is achieved. With this amendment, the scenario with DFS final analysis only is pre-specified.
    08 Dec 2022
    Address the timing of interim and final disease-free survival (DFS) analyses in Part B, which were initially planned to occur at least 8 months of each other. However, the earlier versions of the protocol did not capture the scenario to proceed directly to the final DFS analysis in Part B in the event that the interim analysis and final analysis are projected in a shorter time interval (approximately within 6 months). With this amendment, the scenario with DFS final analysis only is explicitly stated. Also, the redundant OS interim analysis scenario in Part B is now omitted.

    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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