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    Clinical Trial Results:
    Phase IIIb/IV, Randomized, Double Blinded, Study of Nivolumab 3 mg/kg in Combination with Ipilimumab 1 mg/kg vs Nivolumab 1 mg/kg in Combination with Ipilimumab 3 mg/kg in Subjects with Previously Untreated, Unresectable or Metastatic Melanoma

    Summary
    EudraCT number
    		 2015-004920-67
    Trial protocol
    		 DE   ES   DK   GB   NL   PL   IT  
    Global end of trial date
    28 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jun 2022
    First version publication date
    06 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-511
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    23 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the incidence of drug-related Grade 3 - 5 AEs of nivolumab 3 mg/kg combined with ipilimumab 1 mg/kg to nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg in treatment-naive subjects with unresectable or metastatic melanoma.
    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
    04 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    France: 110
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 51
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Spain: 51
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    385
    EEA total number of subjects
    284
    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)
    252
    From 65 to 84 years
    131
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 387 participants were randomized, 385 were treated. Cohort C/N6I1 assessed for exploratory outcome measures not being reported in the Outcome Measures module. Safety data included with AE data.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV
    Arm description
    		 nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks.
    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 as a 30 minute IV infusion

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg was administered as a 30 minute IV infusion then flat dose 480 mg nivolumab IV as a 30-minute IV infusion

    Arm title
    		 Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Arm description
    		 nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg was administered as a 30 minute IV infusion then flat dose 480 mg nivolumab IV as a 30-minute IV infusion

    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
    3 mg/kg as a 30 minute IV infusion

    Arm title
    		 Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
    Arm description
    		 nivolumab 6 mg/kg plus ipilimumab 1 mg/kg followed by nivolumab 480 mg Flat Dose 4 weeks later and repeated every 8 weeks
    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 as a 30 minute IV infusion

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg/kg was administered as a 30 minute IV infusion then flat dose 480 mg nivolumab IV as a 30-minute IV infusion

    Number of subjects in period 1
    		Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
    Started
    180
    178
    27
    Completed
    6
    2
    2
    Not completed
    174
    176
    25
         Participant withdrew consent
    2
    2
    -
         Study drug toxicity
    46
    70
    6
         Not reported
    9
    6
    -
         Maximum clinical benefit
    4
    2
    -
         Request to discontinue treatment
    1
    4
    1
         Adverse event unrelated to study drug
    13
    6
    1
         Other reasons
    6
    6
    -
         Disease Progression
    55
    52
    14
         Completed treatment as per protocol
    36
    27
    3
         Administrative reason by sponsor
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV
    Reporting group description
    		 nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks.

    Reporting group title
    Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Reporting group description
    		 nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks

    Reporting group title
    Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
    Reporting group description
    		 nivolumab 6 mg/kg plus ipilimumab 1 mg/kg followed by nivolumab 480 mg Flat Dose 4 weeks later and repeated every 8 weeks

    Reporting group values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg Total
    Number of subjects
    		 180 178 27 385
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 115 120 17 252
        From 65-84 years
    		 64 57 10 131
        85 years and over
    		 1 1 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 57.0 ± 14.1 57.2 ± 13.4 55.1 ± 15.8 -
    Sex: Female, Male
    Units:
        Female
    		 75 77 11 163
        Male
    		 105 101 16 222
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 1 0 1 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 2 1 3
        White
    		 174 168 23 365
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 5 8 2 15

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV
    Reporting group description
    		 nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks.

    Reporting group title
    Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Reporting group description
    		 nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks

    Reporting group title
    Cohort C, Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
    Reporting group description
    		 nivolumab 6 mg/kg plus ipilimumab 1 mg/kg followed by nivolumab 480 mg Flat Dose 4 weeks later and repeated every 8 weeks

    Primary: The Percentage of Participants with Drug-Related Grade 3 - 5 Adverse Events (AEs)

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    End point title
    		 The Percentage of Participants with Drug-Related Grade 3 - 5 Adverse Events (AEs) [1]
    End point description
    The percentage of participants who experienced at least 1 AE of Grade 3 or higher, judged to be related to study drug by the investigator, and with onset on or after the first dose of study treatment and within 30 days of the last dose of study treatment. AE grade was defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria.
    End point type
    Primary
    End point timeframe
    From first dose of study treatment up to primary completion date 20-Apr-2017 (up to approximately 12 months)
    Notes
    [1] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    180
    178
    Units: Percentage of participants
        number (confidence interval 95%)
    32.8 (26.0 to 40.2)
    45.5 (38.0 to 53.1)
    Statistical analysis title
    		 CMH ESTIMATE OF COMMON ODDS RATIO
    Comparison groups
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV v Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0144
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.9
    Statistical analysis title
    		 DIFFERENCE OF DRUG-RELATED GRADE 3-5 AE RATES
    Comparison groups
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV v Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Estimated Difference of rates
    Point estimate
    -12.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.7
         upper limit
    		 -2.6

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [2]
    End point description
    The percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). BOR is defined as the best response, as determined by the investigator, recorded between the date of randomization and the date of progression per RECIST 1.1 or the date of subsequent anticancer therapy, whichever occurred first. For subjects without documented progression or subsequent therapy, all available response designations will contribute to the BOR assessment. Tumor assessments are scheduled at Week 12 following randomization, every 8 weeks for the first 12 months and then every 12 weeks until disease progression. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (up to approximately 5 years)
    Notes
    [2] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    180
    178
    Units: Percentage of participants
        number (confidence interval 95%)
    47.8 (40.3 to 55.3)
    53.4 (45.8 to 60.9)
    Statistical analysis title
    		 CMH ESTIMATE OF COMMON ODDS RATIO
    Statistical analysis description
    Estimate of NIVO 3 + IPI 1- NIVO 1 + IPI 3 is based on Cochran-Mantel-Haenszel (CMH) method of weighting, adjusting for PD-L1 expression and M stage at screening as entered into the IVRS.
    Comparison groups
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV v Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2923
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.21

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [3]
    End point description
    The time between the date of randomization and the date of death due to any cause. A participant who has not died will be censored at the last known alive date. OS will be followed continuously while participants are on the study drug and every 3 months via in-person or phone contact after participants discontinue the study drug. Based on Kaplan-Meier Estimates. Note: 99999 = N/A due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the date of first documented progression or date of death from any cause, whichever came first (up tp approximately 5 years)
    Notes
    [3] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    180
    178
    Units: Months
        median (confidence interval 95%)
    99999 (43.73 to 99999)
    99999 (40.84 to 99999)
    Statistical analysis title
    		 Hazard Ratio of NIVO 3 + IPI 1 over NIVO 1 + IPI 3
    Statistical analysis description
    Stratified Cox proportional hazard model. Hazard Ratio is NIVO 3 + IPI 1 over NIVO 1 + IPI 3.
    Comparison groups
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV v Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.47

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS) [4]
    End point description
    The time between the date of randomization and the first date of documented progression, determined by the investigator, or death due to any cause, whichever occurs first. Participants who die without a reported progression will be considered to have progressed on the date of their death. Those who did not progress or die will be censored on the date of their last evaluable tumor assessment. Participants without on study tumor assessments and who did not die will be censored on their date of randomization. Participants who started anti-cancer therapy without a prior reported progression will be censored on the date of their last evaluable tumor assessment prior to the initiation of subsequent anti-cancer therapy. Progression is defined as at least a 20% increase in the sum of diameters of target lesions or the appearance of one or more new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. (Based on Kaplan-Meier Estimates)
    End point type
    Secondary
    End point timeframe
    From randomization to the first date of documented progression or death due to any cause, whichever occurs first (up to approximately 5 years)
    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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    180
    178
    Units: Months
        median (confidence interval 95%)
    10.18 (6.24 to 21.91)
    9.99 (6.28 to 28.88)
    Statistical analysis title
    		 Hazard Ratio NIVO 3 + IPI 1 over NIVO 1 + IPI 3
    Comparison groups
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV v Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4512
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.48

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Physical Functioning Scale

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Physical Functioning Scale [5]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Physical Functioning sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [5] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    -2.1 ± 16.2
    -4.9 ± 16.5
        Week 16
    -1.9 ± 15.3
    -2.7 ± 15.8
        Week 20
    -1.4 ± 10.7
    -2.7 ± 13.7
        Week 24
    -5.1 ± 15.6
    -5.7 ± 13.6
        Week 28
    -2.5 ± 15.0
    -0.7 ± 14.8
        Week 32
    -3.3 ± 16.5
    -3.5 ± 15.4
        Week 36
    -4.0 ± 19.1
    -2.9 ± 14.8
        Week 40
    -3.3 ± 17.3
    -3.4 ± 16.7
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Role Functioning Scale

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Role Functioning Scale [6]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Role Functioning sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [6] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    -2.5 ± 28.3
    -8.8 ± 25.6
        Week 16
    -6.6 ± 30.3
    2.1 ± 25.6
        Week 20
    -1.8 ± 19.9
    -5.2 ± 25.2
        Week 24
    -3.9 ± 19.9
    -9.8 ± 29.3
        Week 28
    -0.9 ± 23.4
    -1.3 ± 26.0
        Week 32
    -3.6 ± 25.1
    -2.2 ± 29.3
        Week 36
    -3.9 ± 26.4
    -2.9 ± 30.5
        Week 40
    -4.0 ± 26.7
    -5.2 ± 34.2
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Emotional Functioning Scale

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Emotional Functioning Scale [7]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Emotional Functioning sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    4.5 ± 17.9
    4.4 ± 16.8
        Week 16
    0.0 ± 21.7
    6.6 ± 20.1
        Week 20
    3.9 ± 18.0
    4.5 ± 18.0
        Week 24
    3.4 ± 18.4
    2.6 ± 23.3
        Week 28
    5.9 ± 19.5
    5.6 ± 22.5
        Week 32
    5.5 ± 17.3
    5.1 ± 21.6
        Week 36
    3.0 ± 17.0
    4.7 ± 22.0
        Week 40
    4.5 ± 21.4
    5.4 ± 19.9
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Cognitive Functioning Scale

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Cognitive Functioning Scale [8]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Cognitive Functioning sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [8] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    -3.4 ± 15.0
    -1.9 ± 16.7
        Week 16
    -2.6 ± 14.4
    -5.9 ± 22.4
        Week 20
    -1.9 ± 16.9
    -6.0 ± 17.6
        Week 24
    -2.7 ± 15.0
    -3.4 ± 14.9
        Week 28
    -3.7 ± 17.7
    -3.7 ± 16.8
        Week 32
    -1.5 ± 16.6
    -4.8 ± 16.9
        Week 36
    -3.1 ± 18.5
    -8.8 ± 20.6
        Week 40
    -2.6 ± 20.3
    -4.4 ± 15.2
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Social Functioning Scale

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Social Functioning Scale [9]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Social Functioning sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [9] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    120
    110
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    -3.1 ± 22.8
    -6.1 ± 25.0
        Week 16
    -6.3 ± 23.5
    -2.8 ± 26.7
        Week 20
    -4.6 ± 21.0
    -3.2 ± 20.5
        Week 24
    -1.6 ± 17.2
    -3.7 ± 20.0
        Week 28
    1.4 ± 18.1
    -1.0 ± 22.2
        Week 32
    0.3 ± 17.6
    -1.0 ± 19.6
        Week 36
    0.5 ± 20.4
    0.3 ± 22.7
        Week 40
    1.1 ± 22.0
    -4.1 ± 23.3
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Global Health Status

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Global Health Status [10]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The EORTC QLQ-C30 comprises 6 functional scales (role function, physical functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). With the exception of 2 items included in the global health/quality of life scale, for which responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores for all functional scales and Global Health Status indicate better HRQoL; an increase from baseline indicates improvement in HRQoL compared to baseline.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    120
    111
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    0.5 ± 22.9
    -0.5 ± 19.0
        Week 16
    0.0 ± 18.5
    5.0 ± 24.5
        Week 20
    -1.5 ± 19.9
    0.0 ± 19.1
        Week 24
    -0.5 ± 16.1
    -1.6 ± 24.9
        Week 28
    0.7 ± 21.1
    6.3 ± 23.4
        Week 32
    -0.5 ± 23.2
    5.4 ± 23.9
        Week 36
    -2.9 ± 21.8
    2.6 ± 25.6
        Week 40
    -0.8 ± 22.2
    3.7 ± 21.1
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Dyspnea

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Dyspnea [11]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Dyspnea sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [11] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    4.4 ± 21.5
    6.3 ± 23.0
        Week 16
    5.8 ± 22.0
    2.1 ± 21.1
        Week 20
    2.7 ± 22.7
    2.3 ± 22.4
        Week 24
    2.3 ± 19.5
    2.3 ± 22.4
        Week 28
    3.2 ± 25.7
    0.0 ± 23.3
        Week 32
    2.6 ± 23.1
    2.6 ± 22.7
        Week 36
    4.2 ± 21.8
    0.0 ± 21.1
        Week 40
    3.7 ± 22.5
    2.2 ± 21.8
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Insomnia

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Insomnia [12]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Insomnia sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [12] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    120
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    0.6 ± 28.7
    -1.5 ± 30.5
        Week 16
    -0.5 ± 28.0
    -2.8 ± 29.0
        Week 20
    -0.9 ± 28.5
    -6.3 ± 28.9
        Week 24
    2.3 ± 28.0
    -7.5 ± 26.5
        Week 28
    0.9 ± 25.6
    -7.3 ± 28.0
        Week 32
    -3.1 ± 24.1
    -10.5 ± 29.4
        Week 36
    0.5 ± 24.8
    -8.5 ± 30.4
        Week 40
    -1.1 ± 18.9
    -14.1 ± 31.4
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Appetite Loss

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Appetite Loss [13]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Appetite loss sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [13] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    3.0 ± 24.7
    4.8 ± 28.6
        Week 16
    2.1 ± 28.6
    -1.4 ± 31.5
        Week 20
    1.4 ± 21.8
    -3.5 ± 25.7
        Week 24
    -0.9 ± 22.9
    -2.9 ± 32.0
        Week 28
    -0.9 ± 23.0
    -7.3 ± 26.3
        Week 32
    1.0 ± 27.6
    -7.7 ± 23.4
        Week 36
    -2.6 ± 24.7
    -9.2 ± 26.7
        Week 40
    -2.6 ± 22.6
    -6.7 ± 31.5
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Constipation

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Constipation [14]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Constipation sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    0.3 ± 26.4
    2.4 ± 26.7
        Week 16
    5.3 ± 22.6
    -2.8 ± 32.1
        Week 20
    3.7 ± 26.4
    1.1 ± 25.7
        Week 24
    -0.5 ± 23.2
    -1.7 ± 26.8
        Week 28
    3.2 ± 27.5
    1.4 ± 28.8
        Week 32
    2.6 ± 23.1
    -5.1 ± 27.5
        Week 36
    3.7 ± 23.3
    -0.7 ± 29.4
        Week 40
    1.1 ± 21.6
    0.7 ± 29.7
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Diarrhea

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Diarrhea [15]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Diarrhea sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    1.4 ± 18.5
    1.2 ± 23.6
        Week 16
    8.5 ± 22.4
    2.8 ± 30.6
        Week 20
    2.3 ± 19.6
    -1.7 ± 22.0
        Week 24
    1.8 ± 17.5
    1.1 ± 25.7
        Week 28
    2.8 ± 19.2
    0.0 ± 19.4
        Week 32
    0.5 ± 19.1
    -2.6 ± 21.7
        Week 36
    3.6 ± 16.9
    -2.0 ± 20.5
        Week 40
    -0.5 ± 18.4
    -3.7 ± 16.2
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Financial Difficulties

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Financial Difficulties [16]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Financial difficulties sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    118
    109
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    2.0 ± 24.4
    2.4 ± 22.5
        Week 16
    1.1 ± 19.8
    4.9 ± 21.7
        Week 20
    2.8 ± 20.7
    5.3 ± 19.7
        Week 24
    1.8 ± 22.8
    5.7 ± 17.8
        Week 28
    2.8 ± 23.6
    6.8 ± 22.5
        Week 32
    2.1 ± 22.7
    5.8 ± 22.6
        Week 36
    3.6 ± 22.3
    8.5 ± 18.7
        Week 40
    1.1 ± 23.9
    8.1 ± 19.0
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Fatigue

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Fatigue [17]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Fatigue sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [17] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    5.1 ± 23.3
    11.5 ± 23.2
        Week 16
    9.2 ± 25.8
    5.1 ± 24.4
        Week 20
    4.4 ± 20.6
    7.9 ± 20.5
        Week 24
    5.4 ± 20.5
    6.9 ± 24.3
        Week 28
    4.8 ± 22.9
    2.1 ± 19.5
        Week 32
    5.5 ± 23.7
    3.2 ± 22.9
        Week 36
    5.4 ± 27.1
    1.7 ± 21.2
        Week 40
    5.8 ± 24.3
    0.7 ± 24.7
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Nausea and Vomiting

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Nausea and Vomiting [18]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Nausea and Vomiting sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [18] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    112
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    1.5 ± 16.4
    4.9 ± 18.3
        Week 16
    -0.3 ± 20.4
    3.1 ± 11.7
        Week 20
    -2.3 ± 10.1
    1.1 ± 13.9
        Week 24
    -0.5 ± 16.2
    4.0 ± 18.0
        Week 28
    0.7 ± 13.5
    0.7 ± 14.3
        Week 32
    -1.3 ± 14.2
    0.3 ± 15.7
        Week 36
    0.0 ± 18.5
    1.6 ± 16.1
        Week 40
    -1.3 ± 12.1
    0.7 ± 12.3
    No statistical analyses for this end point

    Secondary: Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Pain

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    End point title
    		 Mean Changes from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30) Pain [19]
    End point description
    Health Related Quality of Life (HRQoL) was assessed using the EORTC QLQ-C30 questionnaire. The Pain sub-scale item responses range from 1 (Not at all) to 4 (Very much). Raw scores for the EORTC QLQ-C30 are transformed to a 0-100 metric such that higher scores indicate a higher level of symptoms; lower scores indicating lesser burden and improved symptoms or quality of life. A clinically meaningful change in score may be regarded as 10 points.
    End point type
    Secondary
    End point timeframe
    Weeks 7, 16, 20, 24, 28, 32, 36, 40
    Notes
    [19] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    121
    111
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 7
    -1.7 ± 28.0
    1.5 ± 25.6
        Week 16
    -2.9 ± 22.9
    -2.8 ± 23.4
        Week 20
    -5.7 ± 20.1
    1.7 ± 28.0
        Week 24
    -2.9 ± 20.9
    0.9 ± 31.9
        Week 28
    -3.0 ± 25.5
    -3.7 ± 30.9
        Week 32
    -2.8 ± 27.1
    -4.5 ± 26.0
        Week 36
    -2.6 ± 21.3
    -2.6 ± 29.9
        Week 40
    0.3 ± 25.3
    -3.3 ± 27.2
    No statistical analyses for this end point

    Post-hoc: The Percentage of Participants with Drug-Related Grade 3 - 5 Adverse Events (AEs) - Extended Collection

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    End point title
    		 The Percentage of Participants with Drug-Related Grade 3 - 5 Adverse Events (AEs) - Extended Collection [20]
    End point description
    The percentage of participants who experienced at least 1 AE of Grade 3 or higher, judged to be related to study drug by the investigator, and with onset on or after the first dose of study treatment and within 30 days of the last dose of study treatment. AE grade was defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until study completion date: 28-May-2021)
    End point type
    Post-hoc
    End point timeframe
    From first dose of study treatment to 30 days after the last dose of study treatment (up to approximately 30 months)
    Notes
    [20] - 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: Cohort C/N6I1 assessed for exploratory outcome measures only and not reported in the Outcome Measures module
    End point values
    		 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects analysed
    180
    178
    Units: Percentage of participants
        number (confidence interval 95%)
    33.9 (27.0 to 41.3)
    48.3 (40.8 to 55.9)
    Statistical analysis title
    		 DIFFERENCE OF DRUG-RELATED GRADE 3-5 AE RATES
    Comparison groups
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV v Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Estimated Difference of rates
    Point estimate
    -14.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.5
         upper limit
    		 -4.3
    Statistical analysis title
    		 CMH ESTIMATE OF COMMON ODDS RATIO
    Statistical analysis description
    Estimate of NIVO 3 + IPI 1- NIVO 1 + IPI 3 is based on Cochran-Mantel-Haenszel (CMH) method of weighting, adjusting for PD-L1 expression and M stage at screening as entered into the IVRS.
    Comparison groups
    Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV v Ipilimumab 3 mg/kg IV + Nivolumab 1 mg/kg IV
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0059
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.84

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs/SAEs are collected from the first dose date until the last dose date + 30 days (Up to approximately 30 months) Participants were assessed for All Cause Mortality from their first dose until the study was completed (up to approximately 5 years)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks

    Reporting group title
    Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg
    Reporting group description
    		 nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses then nivolumab (flat dose 480 mg) every 4 weeks.

    Reporting group title
    Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
    Reporting group description
    		 nivolumab 6 mg/kg plus ipilimumab 1 mg/kg followed by nivolumab 480 mg Flat Dose 4 weeks later and repeated every 8 weeks

    Serious adverse events
    		 Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    127 / 178 (71.35%)
    109 / 180 (60.56%)
    14 / 27 (51.85%)
         number of deaths (all causes)
    78
    85
    15
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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 neoplasm progression
         subjects affected / exposed
    26 / 178 (14.61%)
    23 / 180 (12.78%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    3 / 28
    1 / 25
    0 / 3
         deaths causally related to treatment / all
    1 / 14
    0 / 13
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Vasculitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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 artery stenosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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 embolism
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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 ischaemia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Shock haemorrhagic
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Chest pain
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 180 (0.56%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 178 (6.18%)
    5 / 180 (2.78%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    7 / 13
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Hyperthermia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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 system disorders
    Cytokine release syndrome
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Sarcoidosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Hypersensitivity
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Cough
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Dyspnoea
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Interstitial lung disease
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Lung disorder
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Organising pneumonia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Pleural effusion
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Pleurisy
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Pneumonitis
         subjects affected / exposed
    1 / 178 (0.56%)
    7 / 180 (3.89%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sarcoidosis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Respiratory distress
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Bronchial obstruction
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Mania
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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 A virus test positive
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Lipase increased
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 180 (1.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 180 (0.00%)
    0 / 27 (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
    Antibiotic level below therapeutic
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Rib fracture
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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 coronary syndrome
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Angina pectoris
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Myocarditis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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-mediated myocarditis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Dystonia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Headache
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Hyperaesthesia
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Loss of consciousness
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Meningism
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningoradiculitis
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Motor dysfunction
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Paraesthesia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Partial seizures
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Seizure
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (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
    Spinal cord compression
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Status epilepticus
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Febrile neutropenia
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Lymph node pain
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Dry eye
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Keratitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Orbital myositis
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 180 (1.11%)
    0 / 27 (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
    Autoimmune colitis
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 27 (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
    Colitis
         subjects affected / exposed
    10 / 178 (5.62%)
    6 / 180 (3.33%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    11 / 11
    5 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    12 / 178 (6.74%)
    5 / 180 (2.78%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    13 / 14
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dry mouth
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Dysphagia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Gastric haemorrhage
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Gastritis
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 180 (1.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 178 (1.69%)
    3 / 180 (1.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 178 (0.56%)
    3 / 180 (1.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 178 (2.25%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Colitis ulcerative
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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 enterocolitis
         subjects affected / exposed
    2 / 178 (1.12%)
    2 / 180 (1.11%)
    0 / 27 (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
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    5 / 178 (2.81%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    8 / 178 (4.49%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 178 (0.56%)
    3 / 180 (1.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (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
    Hepatic cytolysis
         subjects affected / exposed
    4 / 178 (2.25%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Skin and subcutaneous tissue disorders
    Pemphigoid
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (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
    Rash
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Toxic skin eruption
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (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
    Renal failure
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (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
    Chronic kidney disease
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Nephritis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    3 / 178 (1.69%)
    1 / 180 (0.56%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Hyperthyroidism
         subjects affected / exposed
    3 / 178 (1.69%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    6 / 178 (3.37%)
    2 / 180 (1.11%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    6 / 6
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 27 (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
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Glucocorticoid deficiency
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Arthralgia
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Fasciitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Myalgia
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 27 (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
    Myositis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 27 (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
    Rhabdomyolysis
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Arthritis bacterial
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Bronchitis
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 180 (1.11%)
    0 / 27 (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
    Cellulitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Chorioretinitis
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Diverticulitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Endocarditis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Erysipelas
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (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
    Infected cyst
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Influenza
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Meningoencephalitis viral
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Pneumonia
         subjects affected / exposed
    4 / 178 (2.25%)
    5 / 180 (2.78%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    3 / 178 (1.69%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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 infection
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 180 (1.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Diverticulitis intestinal perforated
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Folliculitis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Pneumonia bacterial
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (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
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Decreased appetite
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    0 / 27 (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
    Hypercalcaemia
         subjects affected / exposed
    2 / 178 (1.12%)
    0 / 180 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 178 (0.00%)
    1 / 180 (0.56%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    0 / 27 (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
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 178 (0.56%)
    2 / 180 (1.11%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Nivolumab 6 mg/kg + Ipilimumab 1 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 178 (96.63%)
    169 / 180 (93.89%)
    26 / 27 (96.30%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 178 (3.37%)
    9 / 180 (5.00%)
    3 / 27 (11.11%)
         occurrences all number
    6
    9
    3
    Lymphoedema
         subjects affected / exposed
    2 / 178 (1.12%)
    5 / 180 (2.78%)
    2 / 27 (7.41%)
         occurrences all number
    2
    6
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    54 / 178 (30.34%)
    49 / 180 (27.22%)
    8 / 27 (29.63%)
         occurrences all number
    67
    66
    11
    Chills
         subjects affected / exposed
    10 / 178 (5.62%)
    12 / 180 (6.67%)
    3 / 27 (11.11%)
         occurrences all number
    12
    13
    3
    Fatigue
         subjects affected / exposed
    51 / 178 (28.65%)
    66 / 180 (36.67%)
    8 / 27 (29.63%)
         occurrences all number
    57
    76
    9
    Mucosal inflammation
         subjects affected / exposed
    6 / 178 (3.37%)
    2 / 180 (1.11%)
    2 / 27 (7.41%)
         occurrences all number
    8
    2
    3
    Influenza like illness
         subjects affected / exposed
    15 / 178 (8.43%)
    14 / 180 (7.78%)
    1 / 27 (3.70%)
         occurrences all number
    18
    19
    1
    Oedema peripheral
         subjects affected / exposed
    12 / 178 (6.74%)
    18 / 180 (10.00%)
    2 / 27 (7.41%)
         occurrences all number
    13
    19
    3
    Pyrexia
         subjects affected / exposed
    47 / 178 (26.40%)
    39 / 180 (21.67%)
    6 / 27 (22.22%)
         occurrences all number
    69
    53
    6
    Reproductive system and breast disorders
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    35 / 178 (19.66%)
    38 / 180 (21.11%)
    6 / 27 (22.22%)
         occurrences all number
    45
    45
    8
    Dyspnoea
         subjects affected / exposed
    26 / 178 (14.61%)
    33 / 180 (18.33%)
    1 / 27 (3.70%)
         occurrences all number
    29
    38
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    3 / 27 (11.11%)
         occurrences all number
    1
    1
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    18 / 178 (10.11%)
    24 / 180 (13.33%)
    0 / 27 (0.00%)
         occurrences all number
    19
    28
    0
    Anxiety
         subjects affected / exposed
    7 / 178 (3.93%)
    7 / 180 (3.89%)
    2 / 27 (7.41%)
         occurrences all number
    7
    8
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    36 / 178 (20.22%)
    22 / 180 (12.22%)
    6 / 27 (22.22%)
         occurrences all number
    47
    25
    9
    Amylase increased
         subjects affected / exposed
    14 / 178 (7.87%)
    16 / 180 (8.89%)
    4 / 27 (14.81%)
         occurrences all number
    15
    21
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    30 / 178 (16.85%)
    18 / 180 (10.00%)
    5 / 27 (18.52%)
         occurrences all number
    38
    20
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 178 (1.69%)
    10 / 180 (5.56%)
    2 / 27 (7.41%)
         occurrences all number
    3
    12
    3
    Blood cholesterol increased
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    2 / 27 (7.41%)
         occurrences all number
    1
    2
    6
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 178 (1.69%)
    7 / 180 (3.89%)
    3 / 27 (11.11%)
         occurrences all number
    5
    7
    3
    Blood creatinine increased
         subjects affected / exposed
    12 / 178 (6.74%)
    6 / 180 (3.33%)
    2 / 27 (7.41%)
         occurrences all number
    12
    7
    5
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    2 / 178 (1.12%)
    5 / 180 (2.78%)
    4 / 27 (14.81%)
         occurrences all number
    2
    6
    7
    Cortisol decreased
         subjects affected / exposed
    0 / 178 (0.00%)
    3 / 180 (1.67%)
    2 / 27 (7.41%)
         occurrences all number
    0
    3
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 178 (4.49%)
    13 / 180 (7.22%)
    1 / 27 (3.70%)
         occurrences all number
    9
    15
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 178 (0.56%)
    1 / 180 (0.56%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    5
    Lipase increased
         subjects affected / exposed
    20 / 178 (11.24%)
    17 / 180 (9.44%)
    3 / 27 (11.11%)
         occurrences all number
    25
    23
    5
    Neutrophil count decreased
         subjects affected / exposed
    2 / 178 (1.12%)
    1 / 180 (0.56%)
    2 / 27 (7.41%)
         occurrences all number
    3
    4
    5
    Weight decreased
         subjects affected / exposed
    29 / 178 (16.29%)
    25 / 180 (13.89%)
    1 / 27 (3.70%)
         occurrences all number
    31
    25
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 178 (0.56%)
    3 / 180 (1.67%)
    2 / 27 (7.41%)
         occurrences all number
    1
    4
    3
    Blood magnesium decreased
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Protein total decreased
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    5 / 178 (2.81%)
    3 / 180 (1.67%)
    2 / 27 (7.41%)
         occurrences all number
    5
    5
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 178 (5.06%)
    9 / 180 (5.00%)
    6 / 27 (22.22%)
         occurrences all number
    11
    9
    6
    Headache
         subjects affected / exposed
    51 / 178 (28.65%)
    38 / 180 (21.11%)
    4 / 27 (14.81%)
         occurrences all number
    76
    53
    4
    Paraesthesia
         subjects affected / exposed
    16 / 178 (8.99%)
    9 / 180 (5.00%)
    1 / 27 (3.70%)
         occurrences all number
    18
    10
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 178 (9.55%)
    20 / 180 (11.11%)
    4 / 27 (14.81%)
         occurrences all number
    19
    24
    4
    Neutropenia
         subjects affected / exposed
    3 / 178 (1.69%)
    3 / 180 (1.67%)
    2 / 27 (7.41%)
         occurrences all number
    3
    3
    2
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 178 (0.56%)
    0 / 180 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    3
    Eye disorders
    Vision blurred
         subjects affected / exposed
    9 / 178 (5.06%)
    6 / 180 (3.33%)
    1 / 27 (3.70%)
         occurrences all number
    9
    9
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    25 / 178 (14.04%)
    36 / 180 (20.00%)
    6 / 27 (22.22%)
         occurrences all number
    32
    47
    7
    Abdominal pain upper
         subjects affected / exposed
    16 / 178 (8.99%)
    12 / 180 (6.67%)
    2 / 27 (7.41%)
         occurrences all number
    17
    15
    2
    Constipation
         subjects affected / exposed
    31 / 178 (17.42%)
    25 / 180 (13.89%)
    3 / 27 (11.11%)
         occurrences all number
    37
    26
    3
    Diarrhoea
         subjects affected / exposed
    73 / 178 (41.01%)
    66 / 180 (36.67%)
    11 / 27 (40.74%)
         occurrences all number
    117
    125
    16
    Dry mouth
         subjects affected / exposed
    28 / 178 (15.73%)
    16 / 180 (8.89%)
    3 / 27 (11.11%)
         occurrences all number
    30
    17
    4
    Nausea
         subjects affected / exposed
    49 / 178 (27.53%)
    41 / 180 (22.78%)
    9 / 27 (33.33%)
         occurrences all number
    77
    59
    10
    Vomiting
         subjects affected / exposed
    34 / 178 (19.10%)
    28 / 180 (15.56%)
    4 / 27 (14.81%)
         occurrences all number
    49
    40
    6
    Abdominal distension
         subjects affected / exposed
    2 / 178 (1.12%)
    4 / 180 (2.22%)
    2 / 27 (7.41%)
         occurrences all number
    2
    5
    2
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    4 / 178 (2.25%)
    1 / 180 (0.56%)
    2 / 27 (7.41%)
         occurrences all number
    4
    1
    2
    Hepatic cytolysis
         subjects affected / exposed
    6 / 178 (3.37%)
    6 / 180 (3.33%)
    3 / 27 (11.11%)
         occurrences all number
    6
    6
    3
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    11 / 178 (6.18%)
    8 / 180 (4.44%)
    0 / 27 (0.00%)
         occurrences all number
    11
    8
    0
    Eczema
         subjects affected / exposed
    3 / 178 (1.69%)
    4 / 180 (2.22%)
    4 / 27 (14.81%)
         occurrences all number
    3
    4
    5
    Intertrigo
         subjects affected / exposed
    1 / 178 (0.56%)
    3 / 180 (1.67%)
    2 / 27 (7.41%)
         occurrences all number
    1
    3
    2
    Night sweats
         subjects affected / exposed
    6 / 178 (3.37%)
    4 / 180 (2.22%)
    2 / 27 (7.41%)
         occurrences all number
    7
    5
    2
    Pruritus
         subjects affected / exposed
    60 / 178 (33.71%)
    55 / 180 (30.56%)
    13 / 27 (48.15%)
         occurrences all number
    79
    69
    18
    Rash
         subjects affected / exposed
    54 / 178 (30.34%)
    42 / 180 (23.33%)
    0 / 27 (0.00%)
         occurrences all number
    69
    51
    0
    Rash macular
         subjects affected / exposed
    8 / 178 (4.49%)
    7 / 180 (3.89%)
    2 / 27 (7.41%)
         occurrences all number
    8
    7
    2
    Rash maculo-papular
         subjects affected / exposed
    17 / 178 (9.55%)
    10 / 180 (5.56%)
    5 / 27 (18.52%)
         occurrences all number
    18
    13
    5
    Skin hypopigmentation
         subjects affected / exposed
    0 / 178 (0.00%)
    2 / 180 (1.11%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    2
    Vitiligo
         subjects affected / exposed
    16 / 178 (8.99%)
    21 / 180 (11.67%)
    3 / 27 (11.11%)
         occurrences all number
    16
    21
    3
    Rash erythematous
         subjects affected / exposed
    0 / 178 (0.00%)
    0 / 180 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Erythema
         subjects affected / exposed
    5 / 178 (2.81%)
    7 / 180 (3.89%)
    2 / 27 (7.41%)
         occurrences all number
    5
    8
    2
    Rash papular
         subjects affected / exposed
    3 / 178 (1.69%)
    2 / 180 (1.11%)
    2 / 27 (7.41%)
         occurrences all number
    3
    2
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 178 (0.56%)
    3 / 180 (1.67%)
    2 / 27 (7.41%)
         occurrences all number
    1
    3
    3
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    12 / 178 (6.74%)
    4 / 180 (2.22%)
    1 / 27 (3.70%)
         occurrences all number
    12
    4
    1
    Hyperthyroidism
         subjects affected / exposed
    31 / 178 (17.42%)
    20 / 180 (11.11%)
    3 / 27 (11.11%)
         occurrences all number
    31
    22
    3
    Hypophysitis
         subjects affected / exposed
    12 / 178 (6.74%)
    10 / 180 (5.56%)
    3 / 27 (11.11%)
         occurrences all number
    13
    10
    3
    Hypothyroidism
         subjects affected / exposed
    41 / 178 (23.03%)
    27 / 180 (15.00%)
    2 / 27 (7.41%)
         occurrences all number
    41
    27
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    36 / 178 (20.22%)
    39 / 180 (21.67%)
    6 / 27 (22.22%)
         occurrences all number
    41
    50
    7
    Myalgia
         subjects affected / exposed
    15 / 178 (8.43%)
    23 / 180 (12.78%)
    3 / 27 (11.11%)
         occurrences all number
    22
    26
    3
    Back pain
         subjects affected / exposed
    23 / 178 (12.92%)
    14 / 180 (7.78%)
    4 / 27 (14.81%)
         occurrences all number
    29
    16
    6
    Pain in extremity
         subjects affected / exposed
    16 / 178 (8.99%)
    15 / 180 (8.33%)
    5 / 27 (18.52%)
         occurrences all number
    16
    17
    8
    Muscle spasms
         subjects affected / exposed
    10 / 178 (5.62%)
    7 / 180 (3.89%)
    0 / 27 (0.00%)
         occurrences all number
    11
    7
    0
    Muscular weakness
         subjects affected / exposed
    7 / 178 (3.93%)
    4 / 180 (2.22%)
    2 / 27 (7.41%)
         occurrences all number
    7
    5
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 178 (8.99%)
    16 / 180 (8.89%)
    5 / 27 (18.52%)
         occurrences all number
    20
    23
    5
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 178 (4.49%)
    14 / 180 (7.78%)
    1 / 27 (3.70%)
         occurrences all number
    12
    19
    2
    Urinary tract infection
         subjects affected / exposed
    13 / 178 (7.30%)
    5 / 180 (2.78%)
    1 / 27 (3.70%)
         occurrences all number
    18
    5
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    31 / 178 (17.42%)
    37 / 180 (20.56%)
    4 / 27 (14.81%)
         occurrences all number
    34
    43
    4
    Dehydration
         subjects affected / exposed
    5 / 178 (2.81%)
    2 / 180 (1.11%)
    2 / 27 (7.41%)
         occurrences all number
    5
    2
    2
    Hypokalaemia
         subjects affected / exposed
    17 / 178 (9.55%)
    15 / 180 (8.33%)
    1 / 27 (3.70%)
         occurrences all number
    22
    19
    1
    Hyponatraemia
         subjects affected / exposed
    9 / 178 (5.06%)
    5 / 180 (2.78%)
    0 / 27 (0.00%)
         occurrences all number
    9
    6
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jan 2016
    The interval between the end of Part 1 and the beginning of Part 2 has been amended from 3 to 6 weeks. The simultaneous administration of the nivolumab and ipilimumab regimen planned in Part 1 of the treatment phase has been removed.

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

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