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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind Study of Adjuvant Immunotherapy with Nivolumab versus Ipilimumab after Complete Resection of Stage IIIb/c or Stage IV Melanoma in Subjects who are at High Risk for Recurrence (CheckMate 238: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 2238)

    Summary
    EudraCT number
    		 2014-002351-26
    Trial protocol
    		 BE   IE   GB   NO   FI   SE   CZ   ES   AT   NL   FR   HU   GR   PL   RO   Outside EU/EEA   IT  
    Global end of trial date
    16 Oct 2024

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-238
    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
    Global Submission Management, Clinical Trials, Bristol-Myers Squibb International Corporation, mg-gsm-ct@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, mg-gsm-ct@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Nov 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy, as measured by RFS, provided by nivolumab versus ipilimumab in subjects with completely resected Stage IIIb/c or Stage IV NED melanoma who are at high risk for recurrence.
    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 subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Mar 2015
    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
    Canada: 46
    Country: Number of subjects enrolled
    United States: 211
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 68
    Country: Number of subjects enrolled
    Greece: 26
    Country: Number of subjects enrolled
    Ireland: 9
    Country: Number of subjects enrolled
    Italy: 137
    Country: Number of subjects enrolled
    Netherlands: 21
    Country: Number of subjects enrolled
    Norway: 9
    Country: Number of subjects enrolled
    Spain: 57
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    United Kingdom: 68
    Country: Number of subjects enrolled
    Czechia: 28
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Romania: 25
    Country: Number of subjects enrolled
    Japan: 28
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Australia: 78
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    South Africa: 4
    Worldwide total number of subjects
    906
    EEA total number of subjects
    447
    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)
    672
    From 65 to 84 years
    233
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 906 participants randomized and 905 treated.

    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 3 mg/kg
    Arm description
    		 Nivolumab 3 mg/kg IV q2 wks and Ipilimumab placebo IV q3 wks for 4 doses then q12 wks starting at Wk 24
    Arm type
    		 Experimental

    Investigational medicinal product name
    ipilimumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    placebo

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3mg/kg

    Arm title
    		 Ipilimumab 10 mg/kg
    Arm description
    		 Ipilimumab 10 mg/kg IV q3 wks for 4 doses then q12 wks starting at Wk 24 and Nivolumab placebo IV q2 wks
    Arm type
    		 Experimental

    Investigational medicinal product name
    ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    10mg/kg

    Investigational medicinal product name
    nivolumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    placebo

    Number of subjects in period 1
    		Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Started
    453
    453
    Completed
    452
    453
    Not completed
    1
    0
         Participant withdrew consent
    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 3 mg/kg
    Arm description
    		 Nivolumab 3 mg/kg IV q2 wks and Ipilimumab placebo IV q3 wks for 4 doses then q12 wks starting at Wk 24
    Arm type
    		 Experimental

    Investigational medicinal product name
    ipilimumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    placebo

    Investigational medicinal product name
    nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    3mg/kg

    Arm title
    		 Ipilimumab 10 mg/kg
    Arm description
    		 Ipilimumab 10 mg/kg IV q3 wks for 4 doses then q12 wks starting at Wk 24 and Nivolumab placebo IV q2 wks
    Arm type
    		 Experimental

    Investigational medicinal product name
    nivolumab placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    placebo

    Investigational medicinal product name
    ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    10mg/kg

    Number of subjects in period 2
    		Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Started
    452
    453
    Completed
    275
    123
    Not completed
    177
    330
         Disease progression
    121
    100
         Adverse Event (AE) unrelated to study drug
    5
    5
         Participant request to stop treatment
    5
    9
         Participant withdrew consent
    2
    3
         Study drug toxicity
    41
    208
         Participant no longer meets study criteria
    -
    1
         Other reasons
    3
    3
         Poor/non-compliance
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab 3 mg/kg
    Reporting group description
    		 Nivolumab 3 mg/kg IV q2 wks and Ipilimumab placebo IV q3 wks for 4 doses then q12 wks starting at Wk 24

    Reporting group title
    Ipilimumab 10 mg/kg
    Reporting group description
    		 Ipilimumab 10 mg/kg IV q3 wks for 4 doses then q12 wks starting at Wk 24 and Nivolumab placebo IV q2 wks

    Reporting group values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg Total
    Number of subjects
    		 453 453 906
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 333 339 672
        From 65-84 years
    		 120 113 233
        85 years and over
    		 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.4 ( 13.34 ) 53.6 ( 13.50 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 195 184 379
        Male
    		 258 269 527
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 25 18 43
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 0 0 0
        White
    		 425 434 859
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 2 1 3
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 6 8 14
        Not Hispanic or Latino
    		 215 208 423
        Unknown or Not Reported
    		 232 237 469

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab 3 mg/kg
    Reporting group description
    		 Nivolumab 3 mg/kg IV q2 wks and Ipilimumab placebo IV q3 wks for 4 doses then q12 wks starting at Wk 24

    Reporting group title
    Ipilimumab 10 mg/kg
    Reporting group description
    		 Ipilimumab 10 mg/kg IV q3 wks for 4 doses then q12 wks starting at Wk 24 and Nivolumab placebo IV q2 wks
    Reporting group title
    Nivolumab 3 mg/kg
    Reporting group description
    		 Nivolumab 3 mg/kg IV q2 wks and Ipilimumab placebo IV q3 wks for 4 doses then q12 wks starting at Wk 24

    Reporting group title
    Ipilimumab 10 mg/kg
    Reporting group description
    		 Ipilimumab 10 mg/kg IV q3 wks for 4 doses then q12 wks starting at Wk 24 and Nivolumab placebo IV q2 wks

    Primary: Recurrence-free survival (RFS)

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    End point title
    		 Recurrence-free survival (RFS)
    End point description
    RFS is defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma, or death (whatever the cause), whichever occurs first. Here "99999 and -99999" = NA
    End point type
    Primary
    End point timeframe
    up to 36 months
    End point values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Number of subjects analysed
    453
    453
    Units: Months
        median (confidence interval 95%)
    61.04 (42.51 to 68.63)
    24.15 (16.56 to 35.09)
    Statistical analysis title
    		 Statistical Analysis for RFS
    Comparison groups
    Nivolumab 3 mg/kg v Ipilimumab 10 mg/kg
    Number of subjects included in analysis
    906
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0003
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.87

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as as the time between the date of randomization and the date of death. Here "99999 and -99999" = NA
    End point type
    Secondary
    End point timeframe
    up to 106.6 months
    End point values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Number of subjects analysed
    453
    453
    Units: Months
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Statistical analysis title
    		 Statistical Analysis for OS
    Comparison groups
    Nivolumab 3 mg/kg v Ipilimumab 10 mg/kg
    Number of subjects included in analysis
    906
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95.03%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.11

    Secondary: The Safety and Tolerability of Nivolumab and Ipilimumab measured by the incidence of adverse events

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    End point title
    		 The Safety and Tolerability of Nivolumab and Ipilimumab measured by the incidence of adverse events
    End point description
    the safety and tolerability of Nivolumab and Ipilimumab was measured by the incidence of adverse events
    End point type
    Secondary
    End point timeframe
    reported between first dose and 30 days after last dose of study therapy
    End point values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Number of subjects analysed
    452
    453
    Units: Participants
        Grade 3-4
    116
    251
        Any grade
    440
    446
    No statistical analyses for this end point

    Secondary: The Safety and Tolerability of Nivolumab and Ipilimumab measured by the incidence of serious adverse events

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    End point title
    		 The Safety and Tolerability of Nivolumab and Ipilimumab measured by the incidence of serious adverse events
    End point description
    The Safety and Tolerability of nivolumab and ipilimumab was measured by the incidence of serious adverse events
    End point type
    Secondary
    End point timeframe
    reported between the first dose and 30 days after last dose of study therapy
    End point values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Number of subjects analysed
    452
    453
    Units: Participants
        Grade 3-4
    48
    145
        Any grade
    80
    184
    No statistical analyses for this end point

    Secondary: the safety and tolerability of Nivolumab and Ipilimumab measured by the incidence of Deaths

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    End point title
    		 the safety and tolerability of Nivolumab and Ipilimumab measured by the incidence of Deaths
    End point description
    the safety and tolerability of Nivolumab and Ipilimumab wasmeasured by the incidence of Deaths
    End point type
    Secondary
    End point timeframe
    reported between first dose and 30 to 100 days after last dose of study therapy
    End point values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Number of subjects analysed
    452
    453
    Units: Participants
    128
    142
    No statistical analyses for this end point

    Secondary: The Safety and Tolerability of Nivolumab and Ipilimumab measured by the incidence of Laboratory abnormalities

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    End point title
    		 The Safety and Tolerability of Nivolumab and Ipilimumab measured by the incidence of Laboratory abnormalities
    End point description
    The Safety and Tolerability of Nivolumab and Ipilimumab measured by the incidence of Laboratory abnormalities.
    End point type
    Secondary
    End point timeframe
    reported after first dose and within 30 days of last dose of the study therapy
    End point values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Number of subjects analysed
    452
    453
    Units: Participants
        Heamoglobin (grade1-4)
    114
    148
        Heamoglobin (Grade 3-4)
    0
    2
        Platelet count (grade1-4)
    27
    25
        Platelet count ( grade 3-4)
    0
    1
        Leukocytes (grade1-4)
    62
    12
        Leukocytes (grade 3-4)
    0
    1
        Lymphocytes (grade1-4)
    118
    54
        Lymphocytes (grade 3-4)
    2
    4
        Absolute Neutrophil count (Grade1-4)
    56
    26
        Absolute Neutrophil count (Grade3-4)
    0
    2
        Alkaline Phosphatase (grade1-4)
    35
    69
        Alkaline Phosphatase (Grade3-4)
    1
    3
        Aspartate Aminotransferase (grade 1-4)
    105
    144
        Aspartate Aminotransferase(grade 3-4)
    6
    39
        Alkaline Aminotransferase (grade 1-4)
    113
    176
        Alkaline Aminotransferase(grade 3-4)
    8
    52
        Total Bilirubin (grade 1-4)
    33
    43
        Total Bilirubin (grade 3-4)
    0
    5
        Creatinine ( grade1-4)
    55
    56
        Creatinine (grade 3-4)
    0
    0
        Total Amylase ( grade1-4)
    68
    52
        Total Amylase (grade 3-4)
    13
    12
        Total Lipase ( grade1-4)
    109
    100
        Total Lipase (grade 3-4)
    31
    38
        Hypernatremia ( grade1-4)
    35
    20
        Hypernatremia (grade 3-4)
    0
    0
        Hyponatremia ( grade1-4)
    72
    96
        Hyponatremia (grade 3-4)
    5
    14
        Hyperkalemia ( grade1-4)
    55
    39
        Hyperkalemia (grade 3-4)
    1
    2
        Hypokalemia ( grade1-4)
    37
    45
        Hypokalemia(grade 3-4)
    5
    9
        Hypercalcemia ( grade1-4)
    14
    18
        Hypercalcemia(grade 3-4)
    0
    0
        Hypocalcemia ( grade1-4)
    46
    73
        Hypocalcemia(grade 3-4)
    3
    2
        Hypermagnesemia ( grade1-4)
    20
    7
        Hypermagnesemia(grade 3-4)
    2
    1
        Hypomagnesemia ( grade1-4)
    39
    32
        Hypomagnesemia(grade 3-4)
    1
    0
    No statistical analyses for this end point

    Secondary: Recurrence-free survival by PD-L1 Expression

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    End point title
    		 Recurrence-free survival by PD-L1 Expression
    End point description
    Recurrence-free survival by PD-L1 Expression(5% tumor cell membrane expression) Here "99999 and -99999" = NA
    End point type
    Secondary
    End point timeframe
    up to 106.6 months
    End point values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Number of subjects analysed
    453
    453
    Units: Months
    median (confidence interval 95%)
        Participants with >= 5% PD-L1 Expression,
    70.41 (67.65 to 84.80)
    54.67 (24.15 to 84.40)
        < 5% PD-L1 Expression,
    38.67 (22.05 to 61.04)
    16.56 (11.14 to 26.51)
        Non-quantifiable PD-L1 Expression
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Health Related Quality of Life (HRQoL) evaluation

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    End point title
    		 Health Related Quality of Life (HRQoL) evaluation
    End point description
    HRQoL was measured by mean changes from baseline in EORTC-QLQ-C30 global health status/QoL composite scale and in remaining EORTC QLQ-C30 scales in all randomized participants. EORTC QLQ-C30 is the most commonly used QoL instrument in melanoma clinical studies, is a 30-item instrument that has gained wide acceptance in oncology clinical studies and comprises 5 functional scales (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). Except for the overall health status and global quality of life items, responses for all items are 4 point categorical scales ranging from 1 (Not at all) to 4 (Very much). The overall health status/quality of life responses are 7-point Likert scales for which higher score reflects higher health status/quality of life for the 7-point Likert scale.
    End point type
    Secondary
    End point timeframe
    up to 36 months
    End point values
    		 Nivolumab 3 mg/kg Ipilimumab 10 mg/kg
    Number of subjects analysed
    334
    308
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Physical functioning
    -2.04 ( 15.134 )
    -4.88 ( 15.713 )
        Role functioning
    -2.43 ( 25.219 )
    -3.85 ( 29.951 )
        Emotional functioning
    0.18 ( 20.282 )
    1.43 ( 17.911 )
        Cognitive functioning
    -3.74 ( 18.364 )
    -4.67 ( 16.664 )
        Social functioning
    -0.51 ( 22.085 )
    -3.53 ( 26.391 )
        Global health status
    -5.81 ( 20.046 )
    -7.00 ( 23.109 )
        Fatigue
    6.45 ( 21.605 )
    9.05 ( 23.475 )
        Nausea and vomiting
    2.23 ( 12.622 )
    1.90 ( 11.473 )
        Pain
    1.66 ( 23.314 )
    4.38 ( 23.641 )
        Dyspnea
    7.32 ( 22.741 )
    5.45 ( 20.364 )
        Insomnia
    1.82 ( 28.692 )
    3.05 ( 28.785 )
        Appetite loss
    4.07 ( 22.660 )
    2.61 ( 19.257 )
        Constipation
    1.11 ( 17.904 )
    0.33 ( 18.373 )
        Diarrhea
    1.31 ( 20.831 )
    3.38 ( 21.242 )
        Financial difficulties
    -1.41 ( 23.348 )
    0.54 ( 20.282 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events and Serious Adverse Events: (From first dose to last dose + 100 days): approximately up to 16 Months All-Cause mortality (From first dose to end of study): Approximately up to 114 Months
    Adverse event reporting additional description
    The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Ipilimumab 10 mg/kg
    Reporting group description
    		 Radiotherapy: A total dose of 60 Gy [Gray (radiotherapy dose)], in 2 Gy daily fractions on 5 days/week, will be administered in 6 weeks (30 fractions). Placebo: administered intravenously (IV) as a 30 minute infusion every 2 weeks for 8 doses followed by a 30 minute infusion every 4 weeks beginning after 8 doses Temozolomide: 75 mg/m2 orally daily during radiation therapy followed by 4 week break then 6 (28-day) cycles temozolomide on Days 1-5 at 150 mg/m2 in Cycle 1 increasing to 200 mg/m2 as tolerated up to 6 cycles.

    Reporting group title
    Nivolumab 3 mg/kg
    Reporting group description
    		 Nivolumab: specified dose on specified days; IV (intravenous) infusion Temozolomide: 75 mg (milligram)/meter squared daily during Radiotherapy, 4 week treatment break, 150 mg/meter squared Day 1-5 for Cycle 1 and increased to 200 mg/meter squared Day 1-5 for Cycle2-Cycle 6 as tolerated; orally (additional cycles may be permitted with approval of sponsor) Radiotherapy: 2 gray units (joule of radiation energy per kilogram) 5 times per week for 6 weeks

    Serious adverse events
    		 Ipilimumab 10 mg/kg Nivolumab 3 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    215 / 453 (47.46%)
    106 / 452 (23.45%)
         number of deaths (all causes)
    142
    128
         number of deaths resulting from adverse events
    4
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 453 (0.66%)
    3 / 452 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 453 (0.00%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    3 / 453 (0.66%)
    4 / 452 (0.88%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Melanoma recurrent
         subjects affected / exposed
    1 / 453 (0.22%)
    10 / 452 (2.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 453 (0.22%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm malignant
         subjects affected / exposed
    0 / 453 (0.00%)
    3 / 452 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm recurrence
         subjects affected / exposed
    2 / 453 (0.44%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         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 / 453 (0.22%)
    5 / 452 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Giant cell arteritis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 453 (0.44%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Capillary leak syndrome
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 453 (2.43%)
    8 / 452 (1.77%)
         occurrences causally related to treatment / all
    7 / 11
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 453 (0.00%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune lung disease
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 453 (0.22%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 453 (0.00%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 453 (1.10%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 453 (0.88%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Dependence
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 453 (1.10%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecal volume increased
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    3 / 453 (0.66%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    5 / 453 (1.10%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 453 (0.44%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Bell's palsy
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial nerve disorder
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    4 / 453 (0.88%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IVth nerve disorder
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Miller Fisher syndrome
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosarcoidosis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 453 (0.66%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 453 (0.00%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node pain
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    3 / 453 (0.66%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Autoimmune colitis
         subjects affected / exposed
    5 / 453 (1.10%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 453 (0.66%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    41 / 453 (9.05%)
    5 / 452 (1.11%)
         occurrences causally related to treatment / all
    50 / 52
    3 / 6
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 453 (0.66%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glossitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 453 (0.66%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 453 (0.44%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    37 / 453 (8.17%)
    5 / 452 (1.11%)
         occurrences causally related to treatment / all
    39 / 43
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         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 / 453 (0.44%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    2 / 453 (0.44%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    2 / 453 (0.44%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 453 (0.44%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    7 / 453 (1.55%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disease
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    3 / 453 (0.66%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acne
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    4 / 453 (0.88%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 453 (0.22%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 453 (0.22%)
    3 / 452 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         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
    5 / 453 (1.10%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal suppression
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 453 (0.22%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    18 / 453 (3.97%)
    3 / 452 (0.66%)
         occurrences causally related to treatment / all
    19 / 19
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothalamo-pituitary disorder
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytic hypophysitis
         subjects affected / exposed
    5 / 453 (1.10%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 453 (0.00%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Temporomandibular pain and dysfunction syndrome
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 453 (0.66%)
    7 / 452 (1.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    3 / 453 (0.66%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucormycosis
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 453 (1.32%)
    4 / 452 (0.88%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 453 (0.22%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 453 (0.66%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinobronchitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 453 (0.00%)
    2 / 452 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 453 (0.66%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    4 / 453 (0.88%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fulminant type 1 diabetes mellitus
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 453 (0.44%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 453 (0.22%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 453 (0.44%)
    0 / 452 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 453 (0.44%)
    1 / 452 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 453 (0.00%)
    1 / 452 (0.22%)
         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 10 mg/kg Nivolumab 3 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    438 / 453 (96.69%)
    421 / 452 (93.14%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    24 / 453 (5.30%)
    33 / 452 (7.30%)
         occurrences all number
    48
    60
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    197 / 453 (43.49%)
    193 / 452 (42.70%)
         occurrences all number
    239
    263
    Asthenia
         subjects affected / exposed
    72 / 453 (15.89%)
    74 / 452 (16.37%)
         occurrences all number
    98
    105
    Chills
         subjects affected / exposed
    31 / 453 (6.84%)
    11 / 452 (2.43%)
         occurrences all number
    37
    11
    Pyrexia
         subjects affected / exposed
    105 / 453 (23.18%)
    39 / 452 (8.63%)
         occurrences all number
    146
    45
    Oedema peripheral
         subjects affected / exposed
    29 / 453 (6.40%)
    24 / 452 (5.31%)
         occurrences all number
    32
    29
    Influenza like illness
         subjects affected / exposed
    39 / 453 (8.61%)
    32 / 452 (7.08%)
         occurrences all number
    50
    41
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    37 / 453 (8.17%)
    30 / 452 (6.64%)
         occurrences all number
    47
    36
    Nasal congestion
         subjects affected / exposed
    17 / 453 (3.75%)
    24 / 452 (5.31%)
         occurrences all number
    19
    26
    Cough
         subjects affected / exposed
    83 / 453 (18.32%)
    84 / 452 (18.58%)
         occurrences all number
    106
    107
    Dyspnoea
         subjects affected / exposed
    45 / 453 (9.93%)
    34 / 452 (7.52%)
         occurrences all number
    52
    36
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    21 / 453 (4.64%)
    25 / 452 (5.53%)
         occurrences all number
    21
    25
    Insomnia
         subjects affected / exposed
    43 / 453 (9.49%)
    35 / 452 (7.74%)
         occurrences all number
    51
    36
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    88 / 453 (19.43%)
    38 / 452 (8.41%)
         occurrences all number
    109
    45
    Amylase increased
         subjects affected / exposed
    26 / 453 (5.74%)
    29 / 452 (6.42%)
         occurrences all number
    31
    49
    Aspartate aminotransferase increased
         subjects affected / exposed
    75 / 453 (16.56%)
    31 / 452 (6.86%)
         occurrences all number
    101
    37
    Blood alkaline phosphatase increased
         subjects affected / exposed
    26 / 453 (5.74%)
    4 / 452 (0.88%)
         occurrences all number
    33
    7
    Lipase increased
         subjects affected / exposed
    41 / 453 (9.05%)
    36 / 452 (7.96%)
         occurrences all number
    49
    55
    Weight decreased
         subjects affected / exposed
    35 / 453 (7.73%)
    11 / 452 (2.43%)
         occurrences all number
    39
    12
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    39 / 453 (8.61%)
    47 / 452 (10.40%)
         occurrences all number
    45
    58
    Headache
         subjects affected / exposed
    148 / 453 (32.67%)
    109 / 452 (24.12%)
         occurrences all number
    181
    149
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 453 (5.74%)
    13 / 452 (2.88%)
         occurrences all number
    45
    19
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    30 / 453 (6.62%)
    10 / 452 (2.21%)
         occurrences all number
    34
    10
    Constipation
         subjects affected / exposed
    46 / 453 (10.15%)
    47 / 452 (10.40%)
         occurrences all number
    47
    61
    Diarrhoea
         subjects affected / exposed
    250 / 453 (55.19%)
    171 / 452 (37.83%)
         occurrences all number
    471
    341
    Dry mouth
         subjects affected / exposed
    23 / 453 (5.08%)
    33 / 452 (7.30%)
         occurrences all number
    28
    34
    Dyspepsia
         subjects affected / exposed
    27 / 453 (5.96%)
    21 / 452 (4.65%)
         occurrences all number
    34
    23
    Nausea
         subjects affected / exposed
    135 / 453 (29.80%)
    110 / 452 (24.34%)
         occurrences all number
    171
    153
    Vomiting
         subjects affected / exposed
    68 / 453 (15.01%)
    39 / 452 (8.63%)
         occurrences all number
    88
    44
    Abdominal pain upper
         subjects affected / exposed
    21 / 453 (4.64%)
    33 / 452 (7.30%)
         occurrences all number
    25
    39
    Abdominal pain
         subjects affected / exposed
    78 / 453 (17.22%)
    53 / 452 (11.73%)
         occurrences all number
    99
    70
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    23 / 453 (5.08%)
    31 / 452 (6.86%)
         occurrences all number
    25
    42
    Rash maculo-papular
         subjects affected / exposed
    52 / 453 (11.48%)
    27 / 452 (5.97%)
         occurrences all number
    77
    35
    Rash
         subjects affected / exposed
    166 / 453 (36.64%)
    122 / 452 (26.99%)
         occurrences all number
    225
    157
    Pruritus
         subjects affected / exposed
    179 / 453 (39.51%)
    136 / 452 (30.09%)
         occurrences all number
    257
    188
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    35 / 453 (7.73%)
    53 / 452 (11.73%)
         occurrences all number
    36
    57
    Hypophysitis
         subjects affected / exposed
    42 / 453 (9.27%)
    6 / 452 (1.33%)
         occurrences all number
    45
    6
    Hyperthyroidism
         subjects affected / exposed
    22 / 453 (4.86%)
    37 / 452 (8.19%)
         occurrences all number
    22
    37
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    80 / 453 (17.66%)
    103 / 452 (22.79%)
         occurrences all number
    94
    122
    Back pain
         subjects affected / exposed
    46 / 453 (10.15%)
    49 / 452 (10.84%)
         occurrences all number
    51
    59
    Myalgia
         subjects affected / exposed
    35 / 453 (7.73%)
    60 / 452 (13.27%)
         occurrences all number
    39
    69
    Pain in extremity
         subjects affected / exposed
    36 / 453 (7.95%)
    42 / 452 (9.29%)
         occurrences all number
    41
    46
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    32 / 453 (7.06%)
    43 / 452 (9.51%)
         occurrences all number
    46
    54
    Nasopharyngitis
         subjects affected / exposed
    24 / 453 (5.30%)
    53 / 452 (11.73%)
         occurrences all number
    33
    65
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    69 / 453 (15.23%)
    43 / 452 (9.51%)
         occurrences all number
    85
    46

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2015
    1) The main purpose of this global amendment is to clarify the age requirement to participate in the study as the inclusion of adolescents may not be appropriate per local regulations. 2) Additional clarifications have been made to other inclusion/exclusion criteria. 3) There is also a new requirement regarding additional sample collection (serum, and biopsy of affected organ) for biomarker analysis. This collection will be done upon occurrence of  Grade 3 drug-related AE and lab abnormalities regarded as a drug related SAE when clinically safe and feasible 4) This amendment will also be used to implement recent changes in the program level protocol template as well as changes to the standard protocol model document 5) This amendment applies to all subjects
    24 Feb 2016
    The main purpose of this global amendment is to: 1) Increase the visit window from  2 days to  3 days for all dosing visits, except for Week 24, Week 36 and Week 48 where the visit window will increase from  2 days to  7 days. 2) Clarify that the minimum time between dosing visits is 12 days 3) Revise and clarify the Prohibited and /or Restricted Treatments 4) Update the acceptable methods of contraception
    04 Aug 2016
    The main purpose of this global amendment is to:  Addition of Adrenocorticotropic hormone (ACTH) test at Week 45 in subjects receiving ipilimumab/ipilimumab-placebo at Week 48 (Note: All subjects will have completed 36 weeks of treatment prior to implementation of this amendment.)  Clarify that the minimum time between dosing visits is 12 days between Nivolumab administrations  Add information on surveillance scan requirements in case the patient discontinues and starts new systemic therapy.  Update the contraception section  Updates in the treatment algorithms
    06 Aug 2016
    The main purpose of this global amendment is to: 1) Incorporate the definition of immune-mediated adverse events 2) Incorporate the Adverse Event Management Algorithms for Immuno-oncology Agents as an appendix, and updated terminology to be consistent throughout document 3) Clarify that follow-up of laboratory toxicities will continue until toxicities resolve, return to baseline, or are deemed irreversible based on on-site/local laboratory results. 4) Clarify that follow-up of immune-mediated adverse drug reactions will continue until toxicities resolve, return to baseline, or are deemed irreversible 5) Revise the discontinuation criteria to be consistent with the Nivolumab USPI 6) Revise the definition of recurrence free survival to include new primary melanoma 7) Add censoring rules for primary analysis of recurrence free survival 8) Clarify that subjects will continue to be followed for recurrences (until local or regional recurrences for all subjects and until distant recurrence for Stage III subjects) and survival
    26 Jan 2017
    The main purpose of this global amendment is to:  Add an interim analysis of RFS after all subjects have a minimum of 18 months of follow-up (approximately 350 RFS events are anticipated at this analysis).  Change the name and coordinates of the new Medical Monitor  Add the Mechanism for Action for Ipilimumab  Confirm that also blood samples from subjects receiving Ipilimumab will also be evaluated for development of Anti-Drug Antibody (ADA).
    14 Oct 2020
    The primary purpose of Revised Protocol 06 is to extend the collection of Overall Survival (OS) data for approximately 5 additional years. In addition, data associated with the primary, secondary, and exploratory efficacy outcomes (eg, melanoma recurrence data, data on development of new primary melanomas and non-melanoma cancers, subsequent anticancer therapies) will continue to be collected on Case Report Forms. Study drug-related serious adverse events (SAEs) will continue to be collected, whereas follow-up surveillance imaging assessments, plasma biomarker samples, and the EQ-5D questionnaire will no longer be required during extended follow-up.

    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
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