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    Clinical Trial Results:
    Phase 2, Randomized, Double Blinded, Study of Nivolumab (BMS-936558) in Combination with Ipilimumab vs Ipilimumab alone in Subjects with Previously Untreated, Unresectable or Metastatic Melanoma (CheckMate 069: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 069)

    Summary
    EudraCT number
    		 2013-002018-11
    Trial protocol
    		 FR  
    Global end of trial date
    26 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Mar 2022
    First version publication date
    08 Mar 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-069
    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)
    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 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the ORR, as determined by investigators, of nivolumab combined with ipilimumab to ipilimumab monotherapy in subjects with BRAF wild type (WT) 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
    23 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    United States: 126
    Worldwide total number of subjects
    142
    EEA total number of subjects
    16
    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)
    68
    From 65 to 84 years
    71
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 142 participants were randomized, and 140 participants received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab + Ipilimumab
    Arm description
    		 Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-986165
    Investigational medicinal product code
    Other name
    Nivolumab
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q3W for 4 cycles, then 3 mg/kg Q2W

    Investigational medicinal product name
    Placebo matching BMS-986165
    Investigational medicinal product code
    Other name
    0.9% Sodium Chloride
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    matching nivolumab (BMS-986165)

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q3W for 4 cycles

    Arm title
    		 Ipilimumab
    Arm description
    		 Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q3W for 4 cycles

    Number of subjects in period 1
    		Nivolumab + Ipilimumab Ipilimumab
    Started
    95
    47
    Completed
    94
    46
    Not completed
    1
    1
         Adverse event unrelated to study drug
    -
    1
         Participants no longer meeting study criteria
    1
    -
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab + Ipilimumab
    Arm description
    		 Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q3W for 4 cycles

    Investigational medicinal product name
    BMS-936558
    Investigational medicinal product code
    Other name
    Nivolumab
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q3W for 4 cycles, then 3 mg/kg Q2W

    Arm title
    		 Ipilimumab
    Arm description
    		 Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo matching BMS-986165
    Investigational medicinal product code
    Other name
    0.9% Sodium Chloride
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    matching nivolumab (BMS-986165)

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q3W for 4 cycles

    Number of subjects in period 2
    		Nivolumab + Ipilimumab Ipilimumab
    Started
    94
    46
    Completed
    0
    0
    Not completed
    94
    46
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    1
         Disease progression
    17
    20
         Not Reported
    1
    1
         Study drug toxicity
    48
    10
         Participant request to discontinue
    12
    4
         Maximum Clinical Benefit
    6
    2
         Adverse event unrelated to study drug
    6
    3
         Other reasons
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.

    Reporting group title
    Ipilimumab
    Reporting group description
    		 Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.

    Reporting group values
    		 Nivolumab + Ipilimumab Ipilimumab Total
    Number of subjects
    		 95 47 142
    Age Categorical
    Units: Participants
        Younger than 65 years
    		 48 20 68
        65 years and older to younger than 75 years
    		 35 22 57
        75 years and older
    		 12 5 17
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.3 ( 11.0 ) 64.5 ( 10.2 ) -
    Sex: Female, Male
    Units:
        Female
    		 32 15 47
        Male
    		 63 32 95
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 92 47 139
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 2 0 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 82 43 125
        Unknown or Not Reported
    		 12 4 16

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.

    Reporting group title
    Ipilimumab
    Reporting group description
    		 Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.
    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.

    Reporting group title
    Ipilimumab
    Reporting group description
    		 Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.

    Primary: Objective Response Rate (ORR) - BRAF wild-type (WT) participants

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    End point title
    		 Objective Response Rate (ORR) - BRAF wild-type (WT) participants
    End point description
    Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
    End point type
    Primary
    End point timeframe
    From 12 weeks after Randomization, assessed every 6 weeks up to Week 49 of study treatment and then every 12 weeks until disease progression (up to approximately 76 months)
    End point values
    		 Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    73
    37
    Units: Percentage of participants
        number (confidence interval 95%)
    60.3 (48.1 to 71.5)
    10.8 (3.0 to 25.4)
    Statistical analysis title
    		 ORR - BRAF WT 1
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Newcombe's method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    49.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 31.4
         upper limit
    		 61.8
    Statistical analysis title
    		 ORR - BRAF WT 2
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    12.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.79
         upper limit
    		 52.55

    Secondary: Progression-Free Survival (PFS) - BRAF wild-type (WT) participants

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    End point title
    		 Progression-Free Survival (PFS) - BRAF wild-type (WT) participants
    End point description
    PFS is defined as the time between the date of randomization and the first date of documented progression, as assessed by the investigator, or death due to any cause, whichever occurs first. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or died were censored on the date of their last evaluable tumor assessment. PFS values are based on Kaplan-Meier Estimates.
    End point type
    Secondary
    End point timeframe
    From randomization to progression or death (up to approximately 88 months)
    End point values
    		 Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    73
    37
    Units: Months
        median (confidence interval 95%)
    58.41 (7.23 to 99999)
    4.30 (2.76 to 5.32)
    Statistical analysis title
    		 PFS - BRAF WT
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Unstratified Cox proportional hazard
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 0.59

    Secondary: Objective Response Rate (ORR) - BRAF mutant participants

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    End point title
    		 Objective Response Rate (ORR) - BRAF mutant participants
    End point description
    Objective Response Rate is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR), assessed by the investigator by using RECIST 1.1 criteria. CR=all target and nontarget lesions have disappeared. Lymph nodes selected must have returned to normal size (<10 mm). PR=at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.
    End point type
    Secondary
    End point timeframe
    From 12 weeks after Randomization, assessed every 6 weeks up to Week 49 of study treatment and then every 12 weeks until disease progression (up to approximately 76 months)
    End point values
    		 Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    22
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    54.5 (32.2 to 75.6)
    10.0 (0.3 to 44.5)
    Statistical analysis title
    		 ORR - BRAF Mutant 1
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Newcombe's method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    44.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.2
         upper limit
    		 64.8
    Statistical analysis title
    		 ORR - BRAF Mutant 2
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    10.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 511.89

    Secondary: Progression-Free Survival (PFS) - BRAF mutant participants

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    End point title
    		 Progression-Free Survival (PFS) - BRAF mutant participants
    End point description
    PFS is defined as the time between the date of randomization and the first date of documented progression, as assessed by the investigator, or death due to any cause, whichever occurs first. Participants who died without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or died were censored on the date of their last evaluable tumor assessment. PFS values are based on Kaplan-Meier Estimates.
    End point type
    Secondary
    End point timeframe
    From randomization to progression or death (up to approximately 88 months)
    End point values
    		 Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    22
    10
    Units: Months
        median (confidence interval 95%)
    8.61 (2.79 to 99999)
    2.73 (0.99 to 5.42)
    Statistical analysis title
    		 PFS - BRAF Mutant
    Comparison groups
    Nivolumab + Ipilimumab v Ipilimumab
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Unstratified Cox proportional hazard
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.97

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Overall Quality of Life (QOL) C30 Score

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Overall Quality of Life (QOL) C30 Score
    End point description
    The EORTC QLQ-C30 version 3 is a questionnaire developed to assess the QOL of cancer patients. The questionnaire is a 30-item tool, and it comprises 6 functional subscales (physical functioning, role functioning, cognitive functioning, emotional functioning, social functioning and global quality of life) as well as 9 symptom subscales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Scores for each subscale range from 0 to 100. For the 6 functional subscales, a higher score represents a better level of functioning/health status. For the 9 symptom subscales, a lower score represents a better outcome (low level of symptomatology). Scores for the 15 subscales are presented individually.
    End point type
    Secondary
    End point timeframe
    From Baseline (prior to start of study treatment) to Week 25 after first dose
    End point values
    		 Nivolumab + Ipilimumab Ipilimumab
    Number of subjects analysed
    22
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Physical Functioning
    2.12 ( 17.625 )
    1.03 ( 9.367 )
        Role Functioning
    -1.52 ( 22.950 )
    5.13 ( 21.926 )
        Emotional Functioning
    8.33 ( 10.603 )
    10.26 ( 17.063 )
        Cognitive Functioning
    -1.52 ( 15.352 )
    -2.56 ( 11.479 )
        Social Functioning
    2.27 ( 22.593 )
    0.00 ( 16.667 )
        Global Health Status
    3.79 ( 11.422 )
    -0.64 ( 29.357 )
        Fatigue
    -3.54 ( 21.520 )
    -0.85 ( 17.836 )
        Nausea and Vomiting
    -3.03 ( 12.211 )
    -2.56 ( 6.259 )
        Pain
    -2.27 ( 12.905 )
    -8.97 ( 21.099 )
        Dyspnea
    -9.09 ( 23.417 )
    -7.69 ( 27.735 )
        Insomnia
    -12.12 ( 31.782 )
    -12.82 ( 16.879 )
        Appetite Loss
    -13.64 ( 30.271 )
    -2.56 ( 16.452 )
        Constipation
    -3.03 ( 20.339 )
    0.00 ( 13.608 )
        Diarrhea
    -3.03 ( 14.213 )
    5.13 ( 12.518 )
        Financial Difficulties
    -3.03 ( 22.792 )
    -2.78 ( 22.285 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was assessed from date of first dose to study completion. Serious Adverse events and other adverse events were assessed from date of first dose to 100 days following date of last dose.
    Adverse event reporting additional description
    All treated participants
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Ipilimumab
    Reporting group description
    		 Participants received placebo-matching nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then placebo-matching nivolumab solution intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.

    Reporting group title
    Nivolumab + Ipilimumab
    Reporting group description
    		 Participants received 1 mg/kg of nivolumab + 3 mg/kg of ipilimumab solution intravenously every 3 weeks for 4 doses (4 cycles), then 3 mg/kg of nivolumab intravenously every 2 weeks until documented disease progression, toxicity, withdrawal of consent, or study completion.

    Serious adverse events
    		 Ipilimumab Nivolumab + Ipilimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 46 (58.70%)
    69 / 94 (73.40%)
         number of deaths (all causes)
    29
    44
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    8 / 46 (17.39%)
    10 / 94 (10.64%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 10
         deaths causally related to treatment / all
    0 / 8
    0 / 9
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 46 (8.70%)
    6 / 94 (6.38%)
         occurrences causally related to treatment / all
    2 / 4
    4 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 46 (2.17%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 46 (4.35%)
    7 / 94 (7.45%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory failure
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoradiculitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    2 / 46 (4.35%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 46 (4.35%)
    13 / 94 (13.83%)
         occurrences causally related to treatment / all
    3 / 3
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 46 (10.87%)
    10 / 94 (10.64%)
         occurrences causally related to treatment / all
    5 / 6
    10 / 11
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal pain
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorder
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 46 (0.00%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 94 (4.26%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ipilimumab Nivolumab + Ipilimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 46 (97.83%)
    90 / 94 (95.74%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 46 (8.70%)
    12 / 94 (12.77%)
         occurrences all number
    4
    16
    Hot flush
         subjects affected / exposed
    3 / 46 (6.52%)
    1 / 94 (1.06%)
         occurrences all number
    3
    1
    Flushing
         subjects affected / exposed
    1 / 46 (2.17%)
    5 / 94 (5.32%)
         occurrences all number
    1
    5
    Hypotension
         subjects affected / exposed
    5 / 46 (10.87%)
    11 / 94 (11.70%)
         occurrences all number
    5
    13
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 46 (23.91%)
    17 / 94 (18.09%)
         occurrences all number
    15
    31
    Chills
         subjects affected / exposed
    8 / 46 (17.39%)
    21 / 94 (22.34%)
         occurrences all number
    11
    25
    Fatigue
         subjects affected / exposed
    34 / 46 (73.91%)
    57 / 94 (60.64%)
         occurrences all number
    47
    86
    Influenza like illness
         subjects affected / exposed
    6 / 46 (13.04%)
    5 / 94 (5.32%)
         occurrences all number
    7
    5
    Malaise
         subjects affected / exposed
    3 / 46 (6.52%)
    2 / 94 (2.13%)
         occurrences all number
    3
    2
    Mucosal inflammation
         subjects affected / exposed
    5 / 46 (10.87%)
    3 / 94 (3.19%)
         occurrences all number
    5
    3
    Non-cardiac chest pain
         subjects affected / exposed
    4 / 46 (8.70%)
    5 / 94 (5.32%)
         occurrences all number
    4
    9
    Oedema peripheral
         subjects affected / exposed
    10 / 46 (21.74%)
    26 / 94 (27.66%)
         occurrences all number
    11
    37
    Pain
         subjects affected / exposed
    10 / 46 (21.74%)
    14 / 94 (14.89%)
         occurrences all number
    11
    20
    Peripheral swelling
         subjects affected / exposed
    3 / 46 (6.52%)
    3 / 94 (3.19%)
         occurrences all number
    3
    4
    Pyrexia
         subjects affected / exposed
    17 / 46 (36.96%)
    32 / 94 (34.04%)
         occurrences all number
    21
    51
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    3 / 46 (6.52%)
    0 / 94 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 46 (43.48%)
    30 / 94 (31.91%)
         occurrences all number
    25
    43
    Dysphonia
         subjects affected / exposed
    3 / 46 (6.52%)
    7 / 94 (7.45%)
         occurrences all number
    3
    7
    Dyspnoea
         subjects affected / exposed
    14 / 46 (30.43%)
    28 / 94 (29.79%)
         occurrences all number
    14
    32
    Epistaxis
         subjects affected / exposed
    1 / 46 (2.17%)
    5 / 94 (5.32%)
         occurrences all number
    3
    5
    Nasal congestion
         subjects affected / exposed
    5 / 46 (10.87%)
    9 / 94 (9.57%)
         occurrences all number
    8
    10
    Oropharyngeal pain
         subjects affected / exposed
    5 / 46 (10.87%)
    9 / 94 (9.57%)
         occurrences all number
    5
    9
    Pleural effusion
         subjects affected / exposed
    4 / 46 (8.70%)
    5 / 94 (5.32%)
         occurrences all number
    4
    6
    Productive cough
         subjects affected / exposed
    4 / 46 (8.70%)
    3 / 94 (3.19%)
         occurrences all number
    4
    4
    Pneumonitis
         subjects affected / exposed
    2 / 46 (4.35%)
    5 / 94 (5.32%)
         occurrences all number
    2
    6
    Rhinorrhoea
         subjects affected / exposed
    3 / 46 (6.52%)
    2 / 94 (2.13%)
         occurrences all number
    3
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 46 (8.70%)
    7 / 94 (7.45%)
         occurrences all number
    4
    7
    Insomnia
         subjects affected / exposed
    11 / 46 (23.91%)
    20 / 94 (21.28%)
         occurrences all number
    11
    20
    Depression
         subjects affected / exposed
    4 / 46 (8.70%)
    4 / 94 (4.26%)
         occurrences all number
    4
    4
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 46 (15.22%)
    31 / 94 (32.98%)
         occurrences all number
    7
    48
    Amylase increased
         subjects affected / exposed
    3 / 46 (6.52%)
    14 / 94 (14.89%)
         occurrences all number
    3
    20
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 46 (15.22%)
    30 / 94 (31.91%)
         occurrences all number
    8
    40
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 46 (15.22%)
    13 / 94 (13.83%)
         occurrences all number
    7
    16
    Blood bilirubin increased
         subjects affected / exposed
    1 / 46 (2.17%)
    12 / 94 (12.77%)
         occurrences all number
    1
    16
    Blood creatinine increased
         subjects affected / exposed
    4 / 46 (8.70%)
    10 / 94 (10.64%)
         occurrences all number
    4
    18
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 46 (2.17%)
    7 / 94 (7.45%)
         occurrences all number
    1
    7
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 46 (0.00%)
    8 / 94 (8.51%)
         occurrences all number
    0
    9
    Lipase increased
         subjects affected / exposed
    6 / 46 (13.04%)
    22 / 94 (23.40%)
         occurrences all number
    8
    37
    Platelet count decreased
         subjects affected / exposed
    0 / 46 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    8
    Weight decreased
         subjects affected / exposed
    2 / 46 (4.35%)
    16 / 94 (17.02%)
         occurrences all number
    2
    17
    Weight increased
         subjects affected / exposed
    3 / 46 (6.52%)
    5 / 94 (5.32%)
         occurrences all number
    3
    8
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 94 (4.26%)
         occurrences all number
    3
    4
    Atrial fibrillation
         subjects affected / exposed
    3 / 46 (6.52%)
    6 / 94 (6.38%)
         occurrences all number
    3
    9
    Tachycardia
         subjects affected / exposed
    5 / 46 (10.87%)
    5 / 94 (5.32%)
         occurrences all number
    5
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 46 (23.91%)
    35 / 94 (37.23%)
         occurrences all number
    14
    49
    Dysgeusia
         subjects affected / exposed
    1 / 46 (2.17%)
    6 / 94 (6.38%)
         occurrences all number
    1
    6
    Dizziness
         subjects affected / exposed
    5 / 46 (10.87%)
    17 / 94 (18.09%)
         occurrences all number
    7
    31
    Paraesthesia
         subjects affected / exposed
    0 / 46 (0.00%)
    9 / 94 (9.57%)
         occurrences all number
    0
    9
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 46 (8.70%)
    4 / 94 (4.26%)
         occurrences all number
    6
    4
    Taste disorder
         subjects affected / exposed
    0 / 46 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 46 (32.61%)
    24 / 94 (25.53%)
         occurrences all number
    17
    35
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 46 (2.17%)
    5 / 94 (5.32%)
         occurrences all number
    1
    7
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 46 (0.00%)
    15 / 94 (15.96%)
         occurrences all number
    0
    17
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    3 / 46 (6.52%)
    4 / 94 (4.26%)
         occurrences all number
    4
    4
    Abdominal distension
         subjects affected / exposed
    3 / 46 (6.52%)
    9 / 94 (9.57%)
         occurrences all number
    4
    12
    Abdominal pain upper
         subjects affected / exposed
    3 / 46 (6.52%)
    9 / 94 (9.57%)
         occurrences all number
    4
    11
    Abdominal pain
         subjects affected / exposed
    12 / 46 (26.09%)
    20 / 94 (21.28%)
         occurrences all number
    20
    25
    Colitis
         subjects affected / exposed
    4 / 46 (8.70%)
    9 / 94 (9.57%)
         occurrences all number
    4
    9
    Constipation
         subjects affected / exposed
    14 / 46 (30.43%)
    32 / 94 (34.04%)
         occurrences all number
    15
    42
    Diarrhoea
         subjects affected / exposed
    24 / 46 (52.17%)
    54 / 94 (57.45%)
         occurrences all number
    46
    112
    Dry mouth
         subjects affected / exposed
    6 / 46 (13.04%)
    9 / 94 (9.57%)
         occurrences all number
    6
    9
    Dyspepsia
         subjects affected / exposed
    3 / 46 (6.52%)
    7 / 94 (7.45%)
         occurrences all number
    3
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 46 (4.35%)
    5 / 94 (5.32%)
         occurrences all number
    2
    5
    Flatulence
         subjects affected / exposed
    4 / 46 (8.70%)
    4 / 94 (4.26%)
         occurrences all number
    4
    4
    Nausea
         subjects affected / exposed
    25 / 46 (54.35%)
    40 / 94 (42.55%)
         occurrences all number
    29
    64
    Vomiting
         subjects affected / exposed
    11 / 46 (23.91%)
    29 / 94 (30.85%)
         occurrences all number
    13
    44
    Rectal haemorrhage
         subjects affected / exposed
    4 / 46 (8.70%)
    1 / 94 (1.06%)
         occurrences all number
    4
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    5 / 46 (10.87%)
    9 / 94 (9.57%)
         occurrences all number
    5
    10
    Erythema
         subjects affected / exposed
    1 / 46 (2.17%)
    10 / 94 (10.64%)
         occurrences all number
    1
    10
    Night sweats
         subjects affected / exposed
    1 / 46 (2.17%)
    8 / 94 (8.51%)
         occurrences all number
    1
    8
    Rash erythematous
         subjects affected / exposed
    4 / 46 (8.70%)
    2 / 94 (2.13%)
         occurrences all number
    5
    2
    Rash
         subjects affected / exposed
    17 / 46 (36.96%)
    45 / 94 (47.87%)
         occurrences all number
    24
    73
    Pruritus
         subjects affected / exposed
    17 / 46 (36.96%)
    47 / 94 (50.00%)
         occurrences all number
    25
    65
    Rash maculo-papular
         subjects affected / exposed
    8 / 46 (17.39%)
    16 / 94 (17.02%)
         occurrences all number
    10
    20
    Rash pruritic
         subjects affected / exposed
    4 / 46 (8.70%)
    3 / 94 (3.19%)
         occurrences all number
    4
    3
    Skin hypopigmentation
         subjects affected / exposed
    0 / 46 (0.00%)
    5 / 94 (5.32%)
         occurrences all number
    0
    5
    Vitiligo
         subjects affected / exposed
    4 / 46 (8.70%)
    11 / 94 (11.70%)
         occurrences all number
    4
    11
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 46 (2.17%)
    5 / 94 (5.32%)
         occurrences all number
    1
    5
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    2 / 46 (4.35%)
    10 / 94 (10.64%)
         occurrences all number
    2
    10
    Adrenal insufficiency
         subjects affected / exposed
    3 / 46 (6.52%)
    7 / 94 (7.45%)
         occurrences all number
    3
    8
    Hypothyroidism
         subjects affected / exposed
    7 / 46 (15.22%)
    18 / 94 (19.15%)
         occurrences all number
    7
    18
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 46 (15.22%)
    19 / 94 (20.21%)
         occurrences all number
    10
    25
    Arthralgia
         subjects affected / exposed
    11 / 46 (23.91%)
    26 / 94 (27.66%)
         occurrences all number
    12
    40
    Muscular weakness
         subjects affected / exposed
    2 / 46 (4.35%)
    12 / 94 (12.77%)
         occurrences all number
    2
    12
    Muscle spasms
         subjects affected / exposed
    2 / 46 (4.35%)
    6 / 94 (6.38%)
         occurrences all number
    3
    7
    Myalgia
         subjects affected / exposed
    13 / 46 (28.26%)
    14 / 94 (14.89%)
         occurrences all number
    13
    19
    Pain in extremity
         subjects affected / exposed
    9 / 46 (19.57%)
    10 / 94 (10.64%)
         occurrences all number
    9
    11
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 46 (10.87%)
    2 / 94 (2.13%)
         occurrences all number
    5
    2
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 46 (10.87%)
    7 / 94 (7.45%)
         occurrences all number
    5
    8
    Urinary tract infection
         subjects affected / exposed
    2 / 46 (4.35%)
    9 / 94 (9.57%)
         occurrences all number
    2
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 46 (36.96%)
    26 / 94 (27.66%)
         occurrences all number
    21
    28
    Dehydration
         subjects affected / exposed
    4 / 46 (8.70%)
    22 / 94 (23.40%)
         occurrences all number
    6
    28
    Hyperglycaemia
         subjects affected / exposed
    3 / 46 (6.52%)
    13 / 94 (13.83%)
         occurrences all number
    3
    16
    Hyperkalaemia
         subjects affected / exposed
    2 / 46 (4.35%)
    8 / 94 (8.51%)
         occurrences all number
    4
    12
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 46 (13.04%)
    11 / 94 (11.70%)
         occurrences all number
    6
    14
    Hypocalcaemia
         subjects affected / exposed
    2 / 46 (4.35%)
    5 / 94 (5.32%)
         occurrences all number
    2
    9
    Hypokalaemia
         subjects affected / exposed
    5 / 46 (10.87%)
    15 / 94 (15.96%)
         occurrences all number
    6
    22
    Hypomagnesaemia
         subjects affected / exposed
    3 / 46 (6.52%)
    11 / 94 (11.70%)
         occurrences all number
    3
    13
    Hyponatraemia
         subjects affected / exposed
    6 / 46 (13.04%)
    22 / 94 (23.40%)
         occurrences all number
    7
    38

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jul 2013
    Updated Study Design and Statistical Analysis Design
    07 Oct 2013
    Updated Clinical Lab evaluations section
    17 Dec 2014
    Provided instructions for unblinding participants
    30 Aug 2016
    Updated frequency of assessments

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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