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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind Study of BMS-936558 (Nivolumab) vs Dacarbazine in Subjects with Previously Untreated, Unresectable or Metastatic Melanoma

    Summary
    EudraCT number
    		 2012-003718-16
    Trial protocol
    		 DE   FI   SE   ES   DK   NO   IT   PL   GR  
    Global end of trial date
    14 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 May 2022
    First version publication date
    28 May 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-066
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01721772
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the clinical benefit, as measured by the duration of OS, provided by BMS-936558 (Nivolumab) vs. dacarbazine in subjects with previously untreated, 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
    18 Jan 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
    Canada: 25
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 66
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Italy: 72
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    Argentina: 10
    Country: Number of subjects enrolled
    Australia: 71
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Poland: 25
    Worldwide total number of subjects
    418
    EEA total number of subjects
    290
    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)
    199
    From 65 to 84 years
    214
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 418 were randomized (210 to nivolumab, 208 to dacarbazine) and 411 received treatment (206 with nivolumab, 205 with dacarbazine).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine
    Arm description
    		 Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg solution administered intravenously (IV)

    Arm title
    		 Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Arm description
    		 Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m^2 solution administered intravenously (IV)

    Number of subjects in period 1
    		Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Started
    210
    208
    Completed
    206
    205
    Not completed
    4
    3
         Participant withdrew consent
    -
    1
         Participant no longer meets study criteria
    3
    1
         Adverse event unrelated to study drug
    1
    -
         Poor/non-compliance
    -
    1
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine
    Arm description
    		 Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg solution administered intravenously (IV)

    Arm title
    		 Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Arm description
    		 Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dacarbazine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m^2 solution administered intravenously (IV)

    Number of subjects in period 2
    		Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Started
    206
    205
    Completed
    0
    0
    Not completed
    206
    205
         Adverse event, serious fatal
    1
    -
         Disease progression
    119
    168
         Participant withdrew consent
    2
    5
         Study drug toxicity
    19
    10
         Not reported
    1
    -
         Maximum clinical benefit
    16
    4
         Not specified
    19
    2
         Adverse event unrelated to study drug
    7
    7
         Lost to follow-up
    -
    1
         Poor/non-compliance
    1
    -
         Participant request to discontinue study treatment
    21
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine
    Reporting group description
    		 Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion

    Reporting group title
    Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Reporting group description
    		 Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion

    Reporting group values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab Total
    Number of subjects
    		 210 208 418
    Age Categorical
    Units:
        Younger than 65 years
    		 105 94 199
        65 to younger than 75 years
    		 78 74 152
        75 years and older
    		 27 40 67
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.6 ± 13.00 63.7 ± 12.60 -
    Sex: Female, Male
    Units:
        Female
    		 89 83 172
        Male
    		 121 125 246
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 209 207 416
        Black or African American
    		 0 0 0
        Asian
    		 0 1 1
        American Indian or Alaskan native
    		 0 0 0
        Other
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine
    Reporting group description
    		 Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion

    Reporting group title
    Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Reporting group description
    		 Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion
    Reporting group title
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine
    Reporting group description
    		 Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion

    Reporting group title
    Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Reporting group description
    		 Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion

    Primary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS is defined as the time between the date of randomization and the date of death or the last date the participant was known to be alive. "999"=N/A
    End point type
    Primary
    End point timeframe
    From date of randomization to date of death. For those without documentation of death, to the last date the participant was known to be alive, assessed up to 17 months.
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210 [1]
    208
    Units: Months
        median (confidence interval 95%)
    999 (999 to 999)
    10.84 (9.33 to 12.09)
    Notes
    [1] - Median, upper and lower limit survival were not reached due to insufficient number of events.
    Statistical analysis title
    		 Overall Survival Hazard Ratio
    Comparison groups
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine v Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Stratified Log Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.6

    Primary: Overall survival (OS) Rate

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    End point title
    		 Overall survival (OS) Rate [2]
    End point description
    OS rate is calculated as the percentage of participants alive at the indicated timepoints
    End point type
    Primary
    End point timeframe
    From randomization to 6 months and 12 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics were planned for this endpoint.
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210
    208
    Units: Percentage of participants
    number (confidence interval 95%)
        At 6 months
    84.1 (78.3 to 88.5)
    71.8 (64.9 to 77.6)
        At 12 months
    72.9 (65.5 to 78.9)
    42.1 (33.0 to 50.9)
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    Investigator-assessed PFS is defined as the time from randomization to the date of the first documented progression, as determined by the investigator, or death due to any cause, whichever occurs first. Patients who died without progressing were considered to have progressed on the date of their death. Those who did not progress or die were documented on the date of their last evaluable tumor assessment. Patients who did not have any on-study tumor assessments and did not die were documented on their date of randomization. Those who started any subsequent anticancer therapy without a prior reported progression were documented on the date of their last evaluable tumor assessment prior to initiation of subsequent anticancer therapy.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of disease progression or death, up to approximately 84 months
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210
    208
    Units: Months
        median (confidence interval 95%)
    5.06 (3.52 to 12.16)
    2.17 (2.10 to 2.50)
    Statistical analysis title
    		 Progression Free Survival Hazard Ratio
    Comparison groups
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine v Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.56

    Secondary: Progression-free survival (PFS) Rate

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    End point title
    		 Progression-free survival (PFS) Rate
    End point description
    The PFS rate is the percentage of participants alive at the indicated timepoints
    End point type
    Secondary
    End point timeframe
    From randomization to the specified timepoints, up to 84 months
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210
    208
    Units: Percentage of participants
    number (confidence interval 95%)
        At 6 months
    48.2 (41.0 to 55.0)
    20.0 (14.6 to 26.1)
        At 12 months
    43.3 (36.3 to 50.2)
    7.4 (3.9 to 12.4)
        At 18 months
    40.5 (33.5 to 47.4)
    5.2 (2.2 to 10.2)
        At 24 months
    35.8 (29.0 to 42.6)
    5.2 (2.2 to 10.2)
        At 36 months
    32.8 (26.1 to 39.6)
    3.9 (1.3 to 8.9)
        At 48 months
    29.7 (23.2 to 36.5)
    3.9 (1.3 to 8.9)
        At 60 months
    28.4 (22.0 to 35.2)
    3.9 (1.3 to 8.9)
        At 72 months
    27.8 (21.4 to 34.5)
    3.9 (1.3 to 8.9)
        At 84 months
    25.9 (19.5 to 32.7)
    3.9 (1.3 to 8.9)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR is defined as the percentage of participants with a best overall response of Response Evaluation Criteria in Solid Tumors (RECIST) defined complete response (CR) or partial response (PR). RECIST, volume 1.1 for target lesions: CR=disappearance of all target lesions; PR=at least a 30% decrease in the sum of the longest dimension (LD) of target lesions, taking as reference the baseline sum LD; stable disease=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; PD=at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions, and the sum LD must have an absolute increase of ≥5 mm.
    End point type
    Secondary
    End point timeframe
    Tumor assessments beginning at 9 weeks following randomization and continuing every 6 weeks for the first year, then every 12 weeks thereafter until disease progression or death, assessed up to 94 months
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210
    208
    Units: Percentage of participants
        number (confidence interval 95%)
    42.4 (35.6 to 49.4)
    14.4 (9.9 to 19.9)
    Statistical analysis title
    		 Objective Response Rate Odds Ratio
    Comparison groups
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine v Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.75
         upper limit
    		 7.13

    Secondary: Overall Survival by Programmed cell death ligand 1 (PD-L1) Expression Level

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    End point title
    		 Overall Survival by Programmed cell death ligand 1 (PD-L1) Expression Level
    End point description
    Overall Survival is defined as the time between the date of randomization and the date of death or the last date the participant was known to be alive. PD-L1 expression level is defined as the percent of tumor cells demonstrating plasma membrane PD-L1-staining in a minimum of 100 evaluable tumor cells per a Dako PD-L1 IHC (immunohistochemistry) assay (referred to as quantifiable PD-L1 expression). Assessment of OS by PD-L1 expression as measured by a validated assay and comparing OS in patients with tumor PD-L1 expression ≥5% (PD-L1 positive) versus patients with tumor PD-L1 expression <5% (PD-L1 negative). Tumor tissue samples for PD-L1 testing were collected at screening from metastatic or unresectable sites prior to randomization. "999"=N/A
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of disease progression or death, up to approximately 94 months
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210
    208
    Units: Months
    median (confidence interval 95%)
        PD-L1 positive participants
    53.36 (31.47 to 999)
    12.39 (9.33 to 18.99)
        PD-L1 negative/indeterminate participants
    26.97 (16.36 to 39.79)
    10.84 (8.38 to 12.25)
    Statistical analysis title
    		 Overall Survival by PD-L1 Hazard Ratio
    Comparison groups
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine v Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Unstratified Hazard Ratio
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.56
    Statistical analysis title
    		 Overall Survival by PD-L1 Hazard Ratio
    Comparison groups
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine v Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Unstratified Hazard Ratio
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.8

    Secondary: Change from Baseline in Health-related Quality of Life (HRQoL) Scores

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    End point title
    		 Change from Baseline in Health-related Quality of Life (HRQoL) Scores
    End point description
    HRQoL is evaluated by mean changes from baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/quality of life composite scale in all randomized patients. The QLQ-30 is a cancer-specific, self-administered questionnaire that contains 30 questions, covering global, functional, and symptom scales. Scores range from 0 to 100. Higher scores on global and functional scales indicate better quality of life (QoL), while higher scores on the symptom scales indicate declining QoL. "999"=N/A
    End point type
    Secondary
    End point timeframe
    At baseline and every 6 weeks for 12 months and at follow-up visits 1 and 2, assessed up to 93 months
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210
    208
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 7
    1.39 ± 19.46
    2.32 ± 20.52
        Week 13
    1.49 ± 18.91
    3.81 ± 16.33
        Week 19
    3.07 ± 16.58
    3.15 ± 17.16
        Week 25
    3.52 ± 20.25
    -0.76 ± 21.28
        Week 31
    2.53 ± 20.46
    4.17 ± 17.83
        Week 37
    3.26 ± 17.61
    7.14 ± 18.45
        Week 43
    1.69 ± 20.24
    -1.04 ± 18.06
        Week 49
    4.31 ± 18.95
    3.33 ± 13.94
        Week 55
    2.92 ± 18.26
    12.50 ± 23.42
        Week 61
    1.79 ± 18.72
    13.89 ± 17.35
        Week 67
    2.08 ± 21.92
    8.33 ± 11.79
        Week 73
    4.69 ± 17.10
    12.50 ± 5.89
        Week 79
    5.62 ± 18.84
    8.33 ± 11.79
        Week 85
    3.05 ± 19.43
    12.50 ± 5.89
        Week 91
    3.66 ± 20.92
    16.67 ± 0.00
        Week 97
    4.27 ± 19.48
    8.33 ± 11.79
        Week 103
    6.20 ± 19.56
    0.00 ± 0.00
        Week 109
    3.83 ± 20.75
    8.33 ± 11.79
        Week 115
    4.17 ± 21.15
    0.00 ± 0.00
        Week 121
    1.47 ± 20.25
    0.00 ± 0.00
        Week 127
    -0.26 ± 19.91
    999 ± 999
        Week 133
    3.16 ± 22.09
    16.67 ± 999
        Week 139
    1.11 ± 21.86
    16.67 ± 999
        Week 145
    4.69 ± 20.07
    16.67 ± 999
        Week 151
    1.67 ± 20.34
    16.67 ± 999
        Week 157
    3.53 ± 22.99
    33.33 ± 999
        Week 163
    7.94 ± 20.83
    16.67 ± 999
        Week 169
    13.33 ± 17.61
    33.33 ± 999
        Week 175
    7.84 ± 23.66
    50.00 ± 999
        Week 181
    5.42 ± 21.16
    999 ± 999
        Week 187
    1.85 ± 22.06
    33.33 ± 999
        Week 193
    2.50 ± 20.96
    16.67 ± 999
        Week 199
    6.77 ± 21.13
    33.33 ± 999
        Week 205
    0.93 ± 24.07
    33.33 ± 999
        Week 211
    0.49 ± 18.97
    999 ± 999
        Week 217
    1.19 ± 23.32
    33.33 ± 999
        Week 223
    5.26 ± 25.49
    33.33 ± 999
        Week 229
    5.56 ± 23.77
    16.67 ± 999
        Week 235
    5.39 ± 24.82
    999 ± 999
        Week 241
    2.78 ± 25.72
    999 ± 999
        Week 247
    5.36 ± 25.45
    16.67 ± 999
        Week 253
    3.89 ± 26.89
    16.67 ± 999
        Week 259
    7.05 ± 24.26
    25.00 ± 999
        Week 265
    8.93 ± 21.55
    33.33 ± 999
        Week 271
    6.25 ± 21.94
    999 ± 999
        Week 277
    4.17 ± 21.12
    25.00 ± 999
        Week 283
    5.56 ± 21.42
    33.33 ± 999
        Week 289
    3.57 ± 20.86
    33.33 ± 999
        Week 295
    3.47 ± 23.15
    16.67 ± 999
        Week 301
    2.78 ± 23.92
    16.67 ± 999
        Week 307
    1.52 ± 24.95
    33.33 ± 999
        Week 313
    9.17 ± 24.04
    999 ± 999
        Week 319
    3.33 ± 26.70
    33.33 ± 999
        Week 325
    9.38 ± 25.37
    999 ± 999
        Week 331
    10.71 ± 27.09
    33.33 ± 999
        Week 337
    11.90 ± 26.29
    999 ± 999
        Week 343
    16.67 ± 26.35
    999 ± 999
        Week 349
    9.52 ± 26.54
    999 ± 999
        Week 355
    0 ± 10.21
    999 ± 999
        Week 361
    20.83 ± 30.81
    999 ± 999
        Week 367
    25.00 ± 36.32
    999 ± 999
        Week 373
    25.00 ± 36.32
    999 ± 999
        Week 379
    8.33 ± 999
    999 ± 999
        Week 385
    8.33 ± 999
    999 ± 999
        Week 391
    8.33 ± 999
    999 ± 999
        Week 397
    8.33 ± 999
    999 ± 999
        Week 403
    8.33 ± 999
    999 ± 999
    No statistical analyses for this end point

    Post-hoc: Overall Survival (OS) Extended

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    End point title
    		 Overall Survival (OS) Extended
    End point description
    OS is defined as the time between the date of randomization and the date of death. For those without documentation of death, OS will be censored on the last date the participant was known to be alive. OS data for this endpoint was collected past the primary completion date up until study completion.
    End point type
    Post-hoc
    End point timeframe
    From date of randomization to date of death. For those without documentation of death, to the last date the participant was known to be alive, assessed up to 94 months.
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210
    208
    Units: Months
        median (confidence interval 95%)
    37.29 (25.40 to 51.55)
    11.17 (9.56 to 12.98)
    Statistical analysis title
    		 Overall Survival Extended Hazard Ratio
    Comparison groups
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine v Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects included in analysis
    418
    Analysis specification
    Post-hoc
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.65

    Post-hoc: Overall Survival (OS) Rate Extended

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    End point title
    		 Overall Survival (OS) Rate Extended
    End point description
    OS rate is calculated as the percentage of participants alive at the indicated timepoints. Data for this endpoint was collected after the primary completion date up until study completion. The OS rate for the 6 month and 12 month timepoints reflect updated data that was collected after the primary completion date.
    End point type
    Post-hoc
    End point timeframe
    From randomization to the specified timepoints, up to 84 months
    End point values
    		 Nivolumab, 3 mg/kg + placebo-matching dacarbazine Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Number of subjects analysed
    210
    208
    Units: Percentage of participants
    median (confidence interval 95%)
        6 months
    48.2 (41.0 to 55.0)
    20.0 (14.6 to 26.1)
        12 months
    43.3 (36.3 to 50.2)
    7.4 (3.9 to 12.4)
        18 months
    63.8 (56.8 to 70.0)
    36.7 (30.0 to 43.3)
        24 months
    57.8 (50.7 to 64.2)
    26.3 (20.4 to 32.6)
        36 months
    50.8 (43.7 to 57.5)
    21.6 (16.1 to 27.6)
        48 months
    43.8 (36.9 to 50.5)
    17.9 (12.9 to 23.6)
        60 months
    39.3 (32.6 to 46.0)
    17.4 (12.4 to 23.0)
        72 months
    37.3 (30.7 to 43.9)
    16.9 (12.0 to 22.5)
        84 months
    36.2 (29.5 to 42.8)
    16.9 (12.0 to 22.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first dose to 100 days following date of last dose (up to approximately 97 months).
    Adverse event reporting additional description
    All randomized subjects
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab
    Reporting group description
    		 Participants received dacarbazine 1000 mg/m^2, solution administered IV every 3 weeks with placebo-matching nivolumab solution administered IV every 2 weeks until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion

    Reporting group title
    Nivolumab, 3 mg/kg + placebo-matching dacarbazine
    Reporting group description
    		 Participants received nivolumab, 3 mg/kg, solution administered Intravenously (IV) every 2 weeks with placebo-matching dacarbazine solution administered IV every 3 weeks, until disease progression, discontinuation due to toxicity, withdrawal of consent, or study completion

    Serious adverse events
    		 Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab Nivolumab, 3 mg/kg + placebo-matching dacarbazine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    119 / 205 (58.05%)
    125 / 206 (60.68%)
         number of deaths (all causes)
    165
    126
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 205 (0.00%)
    8 / 206 (3.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         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 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal adenocarcinoma
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         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
    1 / 205 (0.49%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    69 / 205 (33.66%)
    32 / 206 (15.53%)
         occurrences causally related to treatment / all
    0 / 72
    0 / 35
         deaths causally related to treatment / all
    0 / 61
    0 / 26
    Melanoma recurrent
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 205 (0.49%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    3 / 205 (1.46%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodular melanoma
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin neoplasm bleeding
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 205 (0.98%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhage
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (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
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Chills
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 205 (1.46%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    6 / 205 (2.93%)
    6 / 206 (2.91%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Injection site reaction
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site reaction
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    6 / 205 (2.93%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pyrexia
         subjects affected / exposed
    2 / 205 (0.98%)
    4 / 206 (1.94%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 205 (0.00%)
    4 / 206 (1.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    7 / 205 (3.41%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 205 (3.41%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 205 (0.98%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    4 / 205 (1.95%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mania
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic enzymes abnormal
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation skin injury
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tachycardia
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         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
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neurological decompensation
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 205 (0.98%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 205 (0.98%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         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
    2 / 205 (0.98%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 205 (0.98%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    4 / 205 (1.95%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 205 (1.95%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eyelid retraction
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    2 / 205 (0.98%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 205 (1.95%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 205 (0.49%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 205 (0.49%)
    4 / 206 (1.94%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 205 (1.95%)
    6 / 206 (2.91%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 205 (0.98%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric mucosal lesion
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 205 (0.98%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 205 (0.00%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoid-like reaction
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 205 (0.98%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 205 (0.98%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 205 (0.98%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Infections and infestations
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 205 (0.98%)
    3 / 206 (1.46%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 205 (0.98%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site infection
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (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 / 205 (0.00%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 205 (0.49%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         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 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin infection
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 205 (0.98%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 205 (0.49%)
    0 / 206 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 205 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 205 (0.49%)
    2 / 206 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 205 (0.49%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    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
    		 Dacarbazine, 1000 mg/m^2 + placebo-matching nivolumab Nivolumab, 3 mg/kg + placebo-matching dacarbazine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    187 / 205 (91.22%)
    191 / 206 (92.72%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 205 (2.44%)
    22 / 206 (10.68%)
         occurrences all number
    5
    26
    Hypotension
         subjects affected / exposed
    11 / 205 (5.37%)
    5 / 206 (2.43%)
         occurrences all number
    11
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    38 / 205 (18.54%)
    43 / 206 (20.87%)
         occurrences all number
    60
    86
    Influenza like illness
         subjects affected / exposed
    4 / 205 (1.95%)
    13 / 206 (6.31%)
         occurrences all number
    4
    16
    Fatigue
         subjects affected / exposed
    60 / 205 (29.27%)
    77 / 206 (37.38%)
         occurrences all number
    77
    113
    Oedema peripheral
         subjects affected / exposed
    11 / 205 (5.37%)
    26 / 206 (12.62%)
         occurrences all number
    12
    31
    Pyrexia
         subjects affected / exposed
    29 / 205 (14.15%)
    36 / 206 (17.48%)
         occurrences all number
    37
    65
    Pain
         subjects affected / exposed
    13 / 205 (6.34%)
    13 / 206 (6.31%)
         occurrences all number
    13
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    29 / 205 (14.15%)
    40 / 206 (19.42%)
         occurrences all number
    32
    59
    Dyspnoea
         subjects affected / exposed
    25 / 205 (12.20%)
    25 / 206 (12.14%)
         occurrences all number
    28
    27
    Oropharyngeal pain
         subjects affected / exposed
    4 / 205 (1.95%)
    11 / 206 (5.34%)
         occurrences all number
    6
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    12 / 205 (5.85%)
    16 / 206 (7.77%)
         occurrences all number
    12
    17
    Insomnia
         subjects affected / exposed
    9 / 205 (4.39%)
    15 / 206 (7.28%)
         occurrences all number
    9
    16
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 205 (3.41%)
    17 / 206 (8.25%)
         occurrences all number
    8
    21
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 205 (3.90%)
    12 / 206 (5.83%)
         occurrences all number
    8
    17
    Blood alkaline phosphatase increased
         subjects affected / exposed
    7 / 205 (3.41%)
    12 / 206 (5.83%)
         occurrences all number
    7
    14
    Blood creatinine increased
         subjects affected / exposed
    6 / 205 (2.93%)
    12 / 206 (5.83%)
         occurrences all number
    6
    15
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 205 (2.93%)
    13 / 206 (6.31%)
         occurrences all number
    6
    13
    Platelet count decreased
         subjects affected / exposed
    11 / 205 (5.37%)
    0 / 206 (0.00%)
         occurrences all number
    16
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 205 (7.32%)
    14 / 206 (6.80%)
         occurrences all number
    20
    21
    Headache
         subjects affected / exposed
    32 / 205 (15.61%)
    45 / 206 (21.84%)
         occurrences all number
    52
    72
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    26 / 205 (12.68%)
    1 / 206 (0.49%)
         occurrences all number
    48
    2
    Anaemia
         subjects affected / exposed
    24 / 205 (11.71%)
    26 / 206 (12.62%)
         occurrences all number
    34
    39
    Thrombocytopenia
         subjects affected / exposed
    22 / 205 (10.73%)
    2 / 206 (0.97%)
         occurrences all number
    48
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    21 / 205 (10.24%)
    30 / 206 (14.56%)
         occurrences all number
    26
    35
    Abdominal pain upper
         subjects affected / exposed
    12 / 205 (5.85%)
    17 / 206 (8.25%)
         occurrences all number
    12
    21
    Constipation
         subjects affected / exposed
    57 / 205 (27.80%)
    57 / 206 (27.67%)
         occurrences all number
    81
    89
    Diarrhoea
         subjects affected / exposed
    58 / 205 (28.29%)
    75 / 206 (36.41%)
         occurrences all number
    94
    159
    Dyspepsia
         subjects affected / exposed
    7 / 205 (3.41%)
    11 / 206 (5.34%)
         occurrences all number
    7
    15
    Nausea
         subjects affected / exposed
    104 / 205 (50.73%)
    59 / 206 (28.64%)
         occurrences all number
    180
    95
    Vomiting
         subjects affected / exposed
    54 / 205 (26.34%)
    34 / 206 (16.50%)
         occurrences all number
    72
    53
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 205 (0.49%)
    14 / 206 (6.80%)
         occurrences all number
    1
    17
    Dry skin
         subjects affected / exposed
    5 / 205 (2.44%)
    21 / 206 (10.19%)
         occurrences all number
    5
    24
    Erythema
         subjects affected / exposed
    7 / 205 (3.41%)
    29 / 206 (14.08%)
         occurrences all number
    7
    41
    Pruritus
         subjects affected / exposed
    40 / 205 (19.51%)
    64 / 206 (31.07%)
         occurrences all number
    45
    100
    Photosensitivity reaction
         subjects affected / exposed
    12 / 205 (5.85%)
    5 / 206 (2.43%)
         occurrences all number
    13
    5
    Rash
         subjects affected / exposed
    29 / 205 (14.15%)
    63 / 206 (30.58%)
         occurrences all number
    32
    99
    Vitiligo
         subjects affected / exposed
    3 / 205 (1.46%)
    37 / 206 (17.96%)
         occurrences all number
    3
    38
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    3 / 205 (1.46%)
    11 / 206 (5.34%)
         occurrences all number
    3
    11
    Hypothyroidism
         subjects affected / exposed
    8 / 205 (3.90%)
    20 / 206 (9.71%)
         occurrences all number
    9
    21
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    29 / 205 (14.15%)
    46 / 206 (22.33%)
         occurrences all number
    35
    69
    Back pain
         subjects affected / exposed
    23 / 205 (11.22%)
    39 / 206 (18.93%)
         occurrences all number
    26
    51
    Myalgia
         subjects affected / exposed
    13 / 205 (6.34%)
    18 / 206 (8.74%)
         occurrences all number
    17
    28
    Pain in extremity
         subjects affected / exposed
    20 / 205 (9.76%)
    34 / 206 (16.50%)
         occurrences all number
    22
    52
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 205 (1.95%)
    12 / 206 (5.83%)
         occurrences all number
    4
    15
    Influenza
         subjects affected / exposed
    3 / 205 (1.46%)
    15 / 206 (7.28%)
         occurrences all number
    4
    22
    Nasopharyngitis
         subjects affected / exposed
    10 / 205 (4.88%)
    34 / 206 (16.50%)
         occurrences all number
    13
    67
    Rhinitis
         subjects affected / exposed
    3 / 205 (1.46%)
    12 / 206 (5.83%)
         occurrences all number
    3
    14
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 205 (6.34%)
    20 / 206 (9.71%)
         occurrences all number
    13
    28
    Urinary tract infection
         subjects affected / exposed
    11 / 205 (5.37%)
    13 / 206 (6.31%)
         occurrences all number
    11
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    37 / 205 (18.05%)
    40 / 206 (19.42%)
         occurrences all number
    40
    51
    Hyperglycaemia
         subjects affected / exposed
    0 / 205 (0.00%)
    14 / 206 (6.80%)
         occurrences all number
    0
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2013
    Inclusion of non-clinical safety findings related to reproductive toxicology data.
    08 May 2013
    Removes the specified timeframe around the timing of tumor tissue collection for inclusion. Inclusion of recommendations for adverse events management in subjects requiring treatment with high dose steroids or other immunosuppressive agents. Expanded allowance for palliative therapy at time of treatment beyond progression.
    09 Jul 2014
    This amendment provides modifications to the protocol based on recommendations of the study’s Data Monitoring Committee (DMC).
    06 May 2015
    Update to follow-up data collection of the overall survival endpoint and the definition of the protocol defined window.
    23 Sep 2016
    Update to nivolumab dosing and schedule, added contraception requirements, change in tumor assessment frequency for the dacarbazine arm, EQ-5D assessment frequency changed, Immunogenicity/PK assessment requirement removed, Efficacy Assessments changed, and Pharmacokinetic/Immunogenicity Assessments changed.

    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.
    An independent data monitoring committee (DMC) found that data from a DMC-requested database lock showed clear survival benefit with nivolumab and thus recommended unblinding the study and switching patients randomized to dacarbazine to nivolumab.
    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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