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    Clinical Trial Results:
    A Phase 3, Randomized, Open-label Study of NKTR-214 Combined with Nivolumab Versus Nivolumab in Participants with Previously Untreated Unresectable or Metastatic Melanoma

    Summary
    EudraCT number
    		 2018-001423-40
    Trial protocol
    		 AT   FR   GB   ES   NL   GR   BE   PL   PT   Outside EU/EEA   SE   FI   IT   RO  
    Global end of trial date
    19 Mar 2024

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CA045-001
    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
    23 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Assess efficacy of bempegaldesleukin combined with nivolumab and that of nivolumab monotherapy in participants 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
    21 Sep 2018
    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
    United States: 75
    Country: Number of subjects enrolled
    Argentina: 35
    Country: Number of subjects enrolled
    Australia: 35
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 119
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Czechia: 18
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    Germany: 79
    Country: Number of subjects enrolled
    Greece: 61
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    Italy: 41
    Country: Number of subjects enrolled
    Mexico: 36
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Romania: 54
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Eswatini: 2
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    783
    EEA total number of subjects
    409
    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)
    458
    From 65 to 84 years
    325
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 783 randomized and 770 treated

    Period 1
    Period 1 title
    Pre-Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bempegaldesleukin + Nivolumab
    Arm description
    		 Bempegaldesleukin 0.006 mg/kg IV every 3 weeks + Nivolumab 360 mg IV every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    360 mg every 3 weeks

    Investigational medicinal product name
    Bempegaldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.006 mg/kg every 3 weeks

    Arm title
    		 Nivolumab
    Arm description
    		 Nivolumab 360 mg IV every 3 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    360 mg every 3 weeks

    Number of subjects in period 1
    		Bempegaldesleukin + Nivolumab Nivolumab
    Started
    391
    392
    Completed
    388
    382
    Not completed
    3
    10
         Consent withdrawn by subject
    -
    7
         Adverse Event unrelated to Study drug
    2
    1
         Participant no longer meets study criteria
    1
    -
         Other reasons
    -
    1
         Disease Progression
    -
    1
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bempegaldesleukin + Nivolumab
    Arm description
    		 Bempegaldesleukin 0.006 mg/kg IV every 3 weeks + Nivolumab 360 mg IV every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    360 mg every 3 weeks

    Investigational medicinal product name
    Bempegaldesleukin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.006 mg/kg every 3 weeks

    Arm title
    		 Nivolumab
    Arm description
    		 Nivolumab 360 mg IV every 3 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    360 mg every 3 weeks

    Number of subjects in period 2
    		Bempegaldesleukin + Nivolumab Nivolumab
    Started
    388
    382
    Completed
    82
    96
    Not completed
    306
    286
         Adverse event, serious fatal
    3
    5
         Consent withdrawn by subject
    3
    5
         Participant request to discontinue Study treatment
    6
    7
         Study drug toxicity
    35
    36
         Adverse Event unrelated to Study drug
    15
    15
         Maximum clinical benefit
    3
    5
         Participant no longer meets study criteria
    1
    4
         Poor/Non-compliance
    2
    1
         Other reasons
    7
    4
         Lost to follow-up
    -
    1
         Disease Progression
    230
    201
         Administrative reason by the sponsor
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bempegaldesleukin + Nivolumab
    Reporting group description
    		 Bempegaldesleukin 0.006 mg/kg IV every 3 weeks + Nivolumab 360 mg IV every 3 weeks

    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 360 mg IV every 3 weeks

    Reporting group values
    		 Bempegaldesleukin + Nivolumab Nivolumab Total
    Number of subjects
    		 391 392 783
    Age categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.3 ( 13.2 ) 60.4 ( 13.5 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 162 163 325
        Male
    		 229 229 458
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 379 379 758
        Black or African American
    		 2 4 6
        Asian
    		 1 0 1
        American Indian or Alaska Native
    		 5 2 7
        Other
    		 4 7 11
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 81 73 154
        Not Hispanic or Latino
    		 165 153 318
        Unknown or Not Reported
    		 145 166 311

    End points

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    End points reporting groups
    Reporting group title
    Bempegaldesleukin + Nivolumab
    Reporting group description
    		 Bempegaldesleukin 0.006 mg/kg IV every 3 weeks + Nivolumab 360 mg IV every 3 weeks

    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 360 mg IV every 3 weeks
    Reporting group title
    Bempegaldesleukin + Nivolumab
    Reporting group description
    		 Bempegaldesleukin 0.006 mg/kg IV every 3 weeks + Nivolumab 360 mg IV every 3 weeks

    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 360 mg IV every 3 weeks

    Primary: Objective Response Rate (ORR) per Blinded Independent Central Review (BICR)

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    End point title
    		 Objective Response Rate (ORR) per Blinded Independent Central Review (BICR)
    End point description
    ORR is defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) using RECIST v 1.1 per blinded independent central review (BICR) assessment. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
    End point type
    Primary
    End point timeframe
    From date of randomization to disease progression (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    271
    272
    Units: Percentage of participants
        number (confidence interval 95%)
    27.7 (22.4 to 33.4)
    36.0 (30.3 to 42.0)
    Statistical analysis title
    		 Estimate of Odds Ratio (OR)
    Statistical analysis description
    Bempegaldesleukin+Nivolumab over Nivolumab
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0311
    Method
    		 Stratified Cochran-Mantel-Haenszel
    Parameter type
    		 Estimate of Odds Ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.96

    Primary: Progression-free Survival (PFS) per Blinded Independent Central Review (BICR)

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    End point title
    		 Progression-free Survival (PFS) per Blinded Independent Central Review (BICR)
    End point description
    PFS is defined as the time between the date of randomization and the first date of documented tumor progression using RECIST v 1.1 per blinded independent central review (BICR), or death due to any cause, whichever comes first. Progressive disease (PD)=At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Primary
    End point timeframe
    From date of randomization to disease progression, or death, whichever comes first (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    391
    392
    Units: Months
        median (confidence interval 95%)
    4.17 (3.52 to 5.55)
    4.99 (4.14 to 7.82)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    783
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3988 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.33
    Notes
    [1] - Log-rank stratified 2-sided. Boundary for statistical significance p-value < 0.03

    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 due to any cause. Participants who do not have a date of death will be censored on the last date for which a participant was known to be alive. 99999=NA
    End point type
    Primary
    End point timeframe
    From date of randomization to date of death (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    391
    392
    Units: Months
        median (confidence interval 95%)
    29.67 (22.14 to 99999)
    28.88 (21.32 to 99999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    783
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.6361
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.22
    Notes
    [2] - Bempegaldesleukin+Nivolumab over Nivolumab

    Secondary: Clinical Benefit Rate (CBR) per Blinded Independent Central Review (BICR)

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    End point title
    		 Clinical Benefit Rate (CBR) per Blinded Independent Central Review (BICR)
    End point description
    CBR, or equivalently the disease control rate (DCR) is defined as the percentage of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as assessed by blinded independent central review (BICR) using RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease.
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    271
    272
    Units: Percentage of participants
        number (confidence interval 95%)
    56.1 (50.0 to 62.1)
    58.5 (52.4 to 64.4)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) per Blinded Independent Central Review (BICR)

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    End point title
    		 Duration of Response (DoR) per Blinded Independent Central Review (BICR)
    End point description
    DOR is defined for participants who have a confirmed complete response (CR) or partial results (PR) as the date from first documented CR or PR using RECIST v 1.1 to the date of the documentation of disease progression per blinded independent central review (BICR) assessment or death due to any cause, whichever is earlier. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions. 99999=NA
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression, or death, whichever is earlier (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    75
    98
    Units: Months
        median (confidence interval 95%)
    29.67 (18.89 to 99999)
    99999 (26.74 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Objective Response (TTR) per Blinded Independent Central Review (BICR)

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    End point title
    		 Time to Objective Response (TTR) per Blinded Independent Central Review (BICR)
    End point description
    Time to response (TTR) is defined for participants who had a confirmed complete response (CR) or partial response (PR) as the time from the date of randomization to date of first documented CR or PR per blinded independent central review (BICR) assessment using RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    75
    98
    Units: Months
        median (full range (min-max))
    2.17 (1.0 to 15.3)
    2.20 (1.2 to 15.5)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) per Investigator

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    End point title
    		 Objective Response Rate (ORR) per Investigator
    End point description
    ORR is defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) using RECIST v 1.1 per investigator assessment. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    271
    272
    Units: Percentage of participants
        number (confidence interval 95%)
    29.2 (23.8 to 35.0)
    36.4 (30.7 to 42.4)
    Statistical analysis title
    		 Estimate of Odds Ratio (OR)
    Statistical analysis description
    Bempegaldesleukin+Nivolumab over Nivolumab
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0626
    Method
    		 Stratified Cochran-Mantel-Haenszel
    Parameter type
    		 Estimate of Odds Ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.02

    Secondary: Progression-free Survival (PFS) per Investigator

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    End point title
    		 Progression-free Survival (PFS) per Investigator
    End point description
    PFS is defined as the time between the date of randomization and the first date of documented tumor progression using RECIST v 1.1 per investigator, or death due to any cause, whichever comes first. Progressive disease (PD)=At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression, or death, whichever comes first (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    391
    392
    Units: Months
        median (confidence interval 95%)
    4.27 (4.04 to 6.14)
    6.21 (4.60 to 10.25)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    783
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3713 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.33
    Notes
    [3] - Log-rank stratified 2-sided. Boundary for statistical significance p-value < 0.03

    Secondary: Clinical Benefit Rate (CBR) per Investigator

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    End point title
    		 Clinical Benefit Rate (CBR) per Investigator
    End point description
    CBR, or equivalently the disease control rate (DCR) is defined as the percentage of participants with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as assessed by investigator using RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    271
    272
    Units: Percentage of participants
        number (confidence interval 95%)
    60.5 (54.4 to 66.4)
    61.8 (55.7 to 67.6)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) per Investigator

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    End point title
    		 Duration of Response (DoR) per Investigator
    End point description
    DOR is defined for participants who have a confirmed complete response (CR) or partial results (PR) as the date from first documented CR or PR using RECIST v 1.1 to the date of the documentation of disease progression per investigator assessment or death due to any cause, whichever is earlier. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions. 99999=NA
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression, or death, whichever is earlier (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    79
    99
    Units: Months
        median (confidence interval 95%)
    99999 (17.31 to 99999)
    99999 (21.68 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Objective Response (TTR) per Investigator

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    End point title
    		 Time to Objective Response (TTR) per Investigator
    End point description
    Time to response (TTR) is defined for participants who had a confirmed complete response (CR) or partial response (PR) as the time from the date of randomization to date of first documented CR or PR per investigator assessment using RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    79
    99
    Units: Months
        median (full range (min-max))
    2.14 (1.6 to 18.3)
    2.14 (1.8 to 12.2)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) per Blinded Independent Central Review (BICR) by Baseline PD-L1 Status

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    End point title
    		 Objective Response Rate (ORR) per Blinded Independent Central Review (BICR) by Baseline PD-L1 Status
    End point description
    ORR by baseline PD-L1 tumor cells expression (PD-L1 negative: <1%) vs. (PD-L1 positive: >=1%). ORR is defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR) using RECIST v 1.1 per blinded independent central review (BICR) assessment. CR=Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to < 10 mm. PR=At least a 30% decrease in the sum of diameters of target lesions.
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    242
    248
    Units: Percentage of participants
    number (confidence interval 95%)
        Participants with baseline PD-L1 expression <1%
    17.6 (10.8 to 26.4)
    25.2 (17.3 to 34.6)
        Participants with baseline PD-L1 expression >=1%
    36.4 (28.5 to 45.0)
    47.5 (39.1 to 56.1)
    Statistical analysis title
    		 Odds Ratio (OR)
    Statistical analysis description
    Bempegaldesleukin+Nivolumab vs. Nivolumab (PD-L1 Positive: >=1%)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9939
    Method
    		 Stratified Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.02
    Statistical analysis title
    		 Odds Ratio (OR)
    Statistical analysis description
    Bempegaldesleukin+Nivolumab vs. Nivolumab (PD-L1 Negative: <1%)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    490
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.24

    Secondary: Progression-free Survival (PFS) per Blinded Independent Central Review (BICR) by baseline PD-L1 Status

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    End point title
    		 Progression-free Survival (PFS) per Blinded Independent Central Review (BICR) by baseline PD-L1 Status
    End point description
    PFS by baseline PD-L1 tumor cells expression (PD-L1 negative: <1%) vs. (PD-L1 positive: >=1%). PFS is defined as the time between the date of randomization and the first date of documented tumor progression using RECIST v 1.1 per blinded independent central review (BICR), or death due to any cause, whichever comes first. Progressive disease (PD)=At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    From date of randomization to disease progression, or death, whichever comes first (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    349
    357
    Units: Months
    median (confidence interval 95%)
        Participants with baseline PD-L1 expression <1%
    3.25 (2.20 to 4.24)
    2.30 (2.17 to 4.17)
        Participants with baseline PD-L1 expression >=1%
    6.24 (4.47 to 10.45)
    10.51 (6.05 to 28.88)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Bempegaldesleukin+Nivolumab vs. Nivo (PD-L1 positive: >=1%)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.51
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Bempegaldesleukin+Nivolumab vs. Nivo (PD-L1 negative: <1%)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.43

    Secondary: Overall Survival (OS) by baseline PD-L1 Status

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    End point title
    		 Overall Survival (OS) by baseline PD-L1 Status
    End point description
    OS by baseline PD-L1 tumor cells expression (PD-L1 negative: <1%) vs. (PD-L1 positive: >=1%). OS is defined as the time between the date of randomization and the date of death due to any cause. Participants who do not have a date of death will be censored on the last date for which a participant was known to be alive. 99999=NA
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of death (Up to 37 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    349
    357
    Units: Months
    median (confidence interval 95%)
        Participants with baseline PD-L1 expression <1%
    21.16 (15.51 to 26.68)
    21.13 (16.62 to 99999)
        Participants with baseline PD-L1 expression >=1%
    99999 (29.67 to 99999)
    99999 (28.88 to 99999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Bempegaldesleukin+Nivolumab vs. Nivo (PD-L1 positive: >=1%)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.33
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Bempegaldesleukin+Nivolumab vs. Nivo (PD-L1 negative: <1%)
    Comparison groups
    Bempegaldesleukin + Nivolumab v Nivolumab
    Number of subjects included in analysis
    706
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.4

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    Number of participants with any grade adverse events (AEs) including treatment-related AEs, AEs leading to discontinuation of any drug, serious adverse events (SAEs), treatment-related SAEs, and deaths from first dose to 30 days post last dose. An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post last dose (Average of 11 months and a maximum up to 26 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    387
    382
    Units: Participants
        AEs
    378
    364
        Drug-related AEs
    351
    281
        SAEs
    132
    130
        Drug-related SAEs
    57
    32
        AEs leading to discontinuation of any Drug
    65
    56
        Deaths
    21
    21
    No statistical analyses for this end point

    Secondary: Number of Participants with On-Treatment Laboratory Parameters that Worsened Relative to Baseline

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    End point title
    		 Number of Participants with On-Treatment Laboratory Parameters that Worsened Relative to Baseline
    End point description
    Number of participants with on-treatment laboratory parameters that worsened relative to baseline. Parameters include hematology, chemistry, liver function, and renal function using worst grade (grade 1-4 and grade 3-4) per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) v5 criteria. Grade 1=Mild event Grade 2=Moderate event Grade 3=Severe event Grade 4=Life threatening event
    End point type
    Secondary
    End point timeframe
    From first dose to 100 days post last dose (Average of 13 months and a maximum up to 28 months)
    End point values
    		 Bempegaldesleukin + Nivolumab Nivolumab
    Number of subjects analysed
    383
    380
    Units: Participants
        Hemoglobin decreased grade 1-4
    194
    173
        Hemoglobin decreased grade 3-4
    17
    22
        Platelet count decreased grade 1-4
    36
    41
        Platelet count decreased grade 3-4
    2
    6
        Leukocytes decreased grade 1-4
    29
    46
        Leukocytes decreased grade 3-4
    2
    2
        Lymphocytes (absolute) decreased grade 1-4
    304
    194
        Lymphocytes (absolute) decreased grade 3-4
    199
    30
        Absolute Neutrophil count decreased grade 1-4
    71
    31
        Absolute Neutrophil, count decreased grade 3-4
    8
    2
        Neutrophils (absolute) decreased grade 1-4
    57
    29
        Neutrophils (absolute) decreased grade 3-4
    10
    2
        Alkaline Phosphatase increased grade 1-4
    96
    90
        Alkaline Phosphatase increased grade 3-4
    2
    6
        Aspartate Aminotransferase increased grade 1-4
    96
    115
        Aspartate Aminotransferase increased grade 3-4
    9
    17
        Alanine Aminotransferase increased grade 1-4
    104
    132
        Alanine Aminotransferase increased grade 3-4
    11
    13
        Bilirubin, total increased grade 1-4
    36
    46
        Bilirubin, total increased grade 3-4
    2
    4
        Creatinine increased grade 1-4
    81
    94
        Creatinine increased grade 3-4
    2
    6
        Amylase increased grade 1-4
    51
    78
        Amylase increased grade 3-4
    3
    6
        Lipase, total increased grade 1-4
    90
    126
        Lipase, total increased grade 3-4
    17
    17
        Hypernatremia grade 1-4
    29
    47
        Hypernatremia grade 3-4
    2
    0
        Hyponatremia grade 1-4
    112
    123
        Hyponatremia grade 3-4
    6
    11
        Hyperkalemia grade 1-4
    91
    85
        Hyperkalemia grade 3-4
    9
    6
        Hypokalemia grade 1-4
    32
    51
        Hypokalemia grade 3-4
    5
    2
        Hypercalcemia grade 1-4
    45
    45
        Hypercalcemia grade 3-4
    1
    0
        Hypocalcemia grade 1-4
    78
    82
        Hypocalcemia grade 3-4
    5
    0
        Hypoglycemia grade 1-4
    42
    39
        Hypoglycemia grade 3-4
    3
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs are collected from first dose to 100 days post last dose (Average of 13 months and a maximum up to 28 months). Participants for deaths from their date of randomization to study completion date (Up to approximately 65 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 360 mg IV every 3 weeks

    Reporting group title
    Bempegaldesleukin + Nivolumab
    Reporting group description
    		 Bempegaldesleukin 0.006 mg/kg IV every 3 weeks + Nivolumab 360 mg IV every 3 weeks

    Serious adverse events
    		 Nivolumab Bempegaldesleukin + Nivolumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    172 / 382 (45.03%)
    161 / 388 (41.49%)
         number of deaths (all causes)
    169
    168
         number of deaths resulting from adverse events
    56
    54
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    3 / 382 (0.79%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 382 (0.52%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal metastasis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    40 / 382 (10.47%)
    37 / 388 (9.54%)
         occurrences causally related to treatment / all
    0 / 42
    0 / 40
         deaths causally related to treatment / all
    0 / 32
    0 / 31
    Malignant pleural effusion
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    3 / 382 (0.79%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oncologic complication
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm malignant
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic neoplasm
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Ischaemia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 382 (0.52%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Drowning
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Face oedema
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 382 (1.05%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 382 (0.79%)
    4 / 388 (1.03%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Hanging
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Implant site haemorrhage
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 382 (1.05%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular mass
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         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
    Alveolitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma-chronic obstructive pulmonary disease overlap syndrome
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune lung disease
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 382 (0.79%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 382 (0.52%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 382 (0.26%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epiglottic polyp
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal congestion
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 382 (0.52%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    2 / 382 (0.52%)
    4 / 388 (1.03%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         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
    1 / 382 (0.26%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 382 (0.26%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    3 / 382 (0.79%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node palpable
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunisation reaction
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial tachycardia
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    4 / 382 (1.05%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopericarditis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    3 / 382 (0.79%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 382 (0.26%)
    7 / 388 (1.80%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis autoimmune
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         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
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 382 (1.05%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 382 (0.52%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    4 / 382 (1.05%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 382 (0.52%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node haemorrhage
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    0 / 382 (0.00%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Autoimmune colitis
         subjects affected / exposed
    2 / 382 (0.52%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 382 (0.79%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 382 (0.79%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune pancreatitis
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 382 (0.52%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    6 / 382 (1.57%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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 / 382 (0.26%)
    0 / 388 (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
    2 / 382 (0.52%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated pancreatitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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
    1 / 382 (0.26%)
    0 / 388 (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 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 382 (0.79%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 382 (0.52%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Hepatitis
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain of skin
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ingrowing nail
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated dermatitis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hidradenitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         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
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoid-like reaction
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 382 (0.79%)
    7 / 388 (1.80%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    3 / 382 (0.79%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvi-ureteric obstruction
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         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
    Groin pain
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         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 / 382 (0.52%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    2 / 382 (0.52%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Morphoea
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 382 (0.52%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    5 / 382 (1.31%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    3 / 382 (0.79%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    5 / 382 (1.31%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 382 (0.26%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis klebsiella
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (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 / 382 (0.00%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella urinary tract infection
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 382 (2.09%)
    4 / 388 (1.03%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 382 (1.05%)
    5 / 388 (1.29%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Septic shock
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Severe acute respiratory syndrome
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 382 (0.00%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         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
    1 / 382 (0.26%)
    2 / 388 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 382 (0.79%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 382 (0.26%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hyponatraemia
         subjects affected / exposed
    2 / 382 (0.52%)
    3 / 388 (0.77%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 382 (0.26%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 382 (0.52%)
    0 / 388 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 382 (0.00%)
    1 / 388 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nivolumab Bempegaldesleukin + Nivolumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    336 / 382 (87.96%)
    357 / 388 (92.01%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 382 (1.57%)
    33 / 388 (8.51%)
         occurrences all number
    8
    48
    Hypertension
         subjects affected / exposed
    34 / 382 (8.90%)
    27 / 388 (6.96%)
         occurrences all number
    53
    39
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    39 / 382 (10.21%)
    147 / 388 (37.89%)
         occurrences all number
    44
    370
    Oedema peripheral
         subjects affected / exposed
    30 / 382 (7.85%)
    40 / 388 (10.31%)
         occurrences all number
    32
    49
    Influenza like illness
         subjects affected / exposed
    9 / 382 (2.36%)
    71 / 388 (18.30%)
         occurrences all number
    11
    235
    Fatigue
         subjects affected / exposed
    104 / 382 (27.23%)
    128 / 388 (32.99%)
         occurrences all number
    126
    206
    Face oedema
         subjects affected / exposed
    0 / 382 (0.00%)
    20 / 388 (5.15%)
         occurrences all number
    0
    38
    Chills
         subjects affected / exposed
    5 / 382 (1.31%)
    36 / 388 (9.28%)
         occurrences all number
    6
    60
    Asthenia
         subjects affected / exposed
    42 / 382 (10.99%)
    68 / 388 (17.53%)
         occurrences all number
    46
    116
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    45 / 382 (11.78%)
    53 / 388 (13.66%)
         occurrences all number
    50
    75
    Dyspnoea
         subjects affected / exposed
    31 / 382 (8.12%)
    31 / 388 (7.99%)
         occurrences all number
    38
    37
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    24 / 382 (6.28%)
    31 / 388 (7.99%)
         occurrences all number
    26
    33
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    39 / 382 (10.21%)
    31 / 388 (7.99%)
         occurrences all number
    52
    32
    Amylase increased
         subjects affected / exposed
    29 / 382 (7.59%)
    20 / 388 (5.15%)
         occurrences all number
    55
    27
    Aspartate aminotransferase increased
         subjects affected / exposed
    34 / 382 (8.90%)
    26 / 388 (6.70%)
         occurrences all number
    45
    30
    Blood alkaline phosphatase increased
         subjects affected / exposed
    20 / 382 (5.24%)
    10 / 388 (2.58%)
         occurrences all number
    23
    11
    Weight decreased
         subjects affected / exposed
    22 / 382 (5.76%)
    16 / 388 (4.12%)
         occurrences all number
    24
    16
    Lipase increased
         subjects affected / exposed
    37 / 382 (9.69%)
    22 / 388 (5.67%)
         occurrences all number
    60
    36
    Blood creatinine increased
         subjects affected / exposed
    28 / 382 (7.33%)
    20 / 388 (5.15%)
         occurrences all number
    36
    23
    Blood creatine phosphokinase increased
         subjects affected / exposed
    38 / 382 (9.95%)
    23 / 388 (5.93%)
         occurrences all number
    57
    29
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    15 / 382 (3.93%)
    48 / 388 (12.37%)
         occurrences all number
    19
    77
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    20 / 382 (5.24%)
    38 / 388 (9.79%)
         occurrences all number
    22
    45
    Headache
         subjects affected / exposed
    56 / 382 (14.66%)
    64 / 388 (16.49%)
         occurrences all number
    81
    100
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    63 / 382 (16.49%)
    61 / 388 (15.72%)
         occurrences all number
    74
    68
    Eosinophilia
         subjects affected / exposed
    7 / 382 (1.83%)
    60 / 388 (15.46%)
         occurrences all number
    13
    77
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    16 / 382 (4.19%)
    29 / 388 (7.47%)
         occurrences all number
    18
    35
    Abdominal pain
         subjects affected / exposed
    34 / 382 (8.90%)
    33 / 388 (8.51%)
         occurrences all number
    41
    41
    Constipation
         subjects affected / exposed
    51 / 382 (13.35%)
    39 / 388 (10.05%)
         occurrences all number
    57
    51
    Dry mouth
         subjects affected / exposed
    13 / 382 (3.40%)
    21 / 388 (5.41%)
         occurrences all number
    15
    24
    Diarrhoea
         subjects affected / exposed
    80 / 382 (20.94%)
    96 / 388 (24.74%)
         occurrences all number
    113
    166
    Vomiting
         subjects affected / exposed
    37 / 382 (9.69%)
    64 / 388 (16.49%)
         occurrences all number
    41
    103
    Nausea
         subjects affected / exposed
    67 / 382 (17.54%)
    113 / 388 (29.12%)
         occurrences all number
    82
    201
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    14 / 382 (3.66%)
    30 / 388 (7.73%)
         occurrences all number
    14
    31
    Erythema
         subjects affected / exposed
    7 / 382 (1.83%)
    28 / 388 (7.22%)
         occurrences all number
    8
    37
    Pruritus
         subjects affected / exposed
    80 / 382 (20.94%)
    121 / 388 (31.19%)
         occurrences all number
    99
    181
    Vitiligo
         subjects affected / exposed
    34 / 382 (8.90%)
    35 / 388 (9.02%)
         occurrences all number
    34
    37
    Rash maculo-papular
         subjects affected / exposed
    18 / 382 (4.71%)
    30 / 388 (7.73%)
         occurrences all number
    25
    42
    Rash
         subjects affected / exposed
    63 / 382 (16.49%)
    108 / 388 (27.84%)
         occurrences all number
    77
    173
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    52 / 382 (13.61%)
    74 / 388 (19.07%)
         occurrences all number
    54
    78
    Hyperthyroidism
         subjects affected / exposed
    28 / 382 (7.33%)
    49 / 388 (12.63%)
         occurrences all number
    29
    50
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    67 / 382 (17.54%)
    99 / 388 (25.52%)
         occurrences all number
    88
    183
    Back pain
         subjects affected / exposed
    47 / 382 (12.30%)
    35 / 388 (9.02%)
         occurrences all number
    54
    47
    Myalgia
         subjects affected / exposed
    28 / 382 (7.33%)
    55 / 388 (14.18%)
         occurrences all number
    38
    109
    Pain in extremity
         subjects affected / exposed
    36 / 382 (9.42%)
    34 / 388 (8.76%)
         occurrences all number
    42
    44
    Infections and infestations
    COVID-19
         subjects affected / exposed
    31 / 382 (8.12%)
    32 / 388 (8.25%)
         occurrences all number
    33
    33
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 382 (5.24%)
    9 / 388 (2.32%)
         occurrences all number
    26
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    35 / 382 (9.16%)
    68 / 388 (17.53%)
         occurrences all number
    39
    86
    Hyponatraemia
         subjects affected / exposed
    20 / 382 (5.24%)
    15 / 388 (3.87%)
         occurrences all number
    26
    16
    Hyperglycaemia
         subjects affected / exposed
    28 / 382 (7.33%)
    20 / 388 (5.15%)
         occurrences all number
    40
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2020
    statistical analysis for OS was updated
    26 Aug 2021
    Updated study treatment dose delay, resumption, and discontinuation
    19 May 2022
    treatment discontinuation update

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

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

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