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    Clinical Trial Results:
    versus Pemetrexed with Cisplatin or Carboplatin as First Line Therapy in unresectable Pleural Mesothelioma. CheckMate 743: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 743

    Summary
    EudraCT number
    		 2016-001859-43
    Trial protocol
    		 GR   NL   BE   DE   FR   PL   GB   IT  
    Global end of trial date
    28 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 May 2024
    First version publication date
    10 May 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-743
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Investigate efficacy of nivolumab combined with ipilimumab to pemetrexed plus cisplatin or carboplatin regimen as first line treatment in subjects with unresectable malignant pleural mesothelioma.
    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
    29 Nov 2016
    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
    Australia: 33
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Chile: 9
    Country: Number of subjects enrolled
    China: 5
    Country: Number of subjects enrolled
    Colombia: 16
    Country: Number of subjects enrolled
    France: 102
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Italy: 61
    Country: Number of subjects enrolled
    Japan: 60
    Country: Number of subjects enrolled
    Mexico: 39
    Country: Number of subjects enrolled
    Netherlands: 31
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    Switzerland: 9
    Country: Number of subjects enrolled
    Türkiye: 14
    Country: Number of subjects enrolled
    United Kingdom: 38
    Country: Number of subjects enrolled
    United States: 59
    Worldwide total number of subjects
    605
    EEA total number of subjects
    293
    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)
    167
    From 65 to 84 years
    432
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 605 participants randomized and 584 treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment A
    Arm description
    		 Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q2W

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q6W

    Arm title
    		 Treatment B
    Arm description
    		 Pemetrexed 500 mg/m^2 + Cisplatin 75 mg/m^2 or Carboplatin 5 AUC up to 6 cycles
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    as a 10-minute dose of 500 mg/m² on Day 1 of a q 21 day cycle

    Investigational medicinal product name
    Carboplatin Area Under the Curve (AUC) 5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 1 of every 21 days per cycle for 6 cycles.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m²

    Number of subjects in period 1
    		Treatment A Treatment B
    Started
    303
    302
    Completed
    300
    284
    Not completed
    3
    18
         Participant withdrew consent
    1
    11
         Not reported
    -
    1
         Participant no longer meets study criteria
    2
    3
         Participant request to discontinue study treatment
    -
    3
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment A
    Arm description
    		 Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg Q6W

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3 mg/kg Q2W

    Arm title
    		 Treatment B
    Arm description
    		 Pemetrexed 500 mg/m^2 + Cisplatin 75 mg/m^2 or Carboplatin 5 AUC up to 6 cycles
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    as a 10-minute dose of 500 mg/m² on Day 1 of a q 21 day cycle

    Investigational medicinal product name
    Carboplatin Area Under the Curve (AUC) 5
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 1 of every 21 days per cycle for 6 cycles.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m²

    Number of subjects in period 2
    		Treatment A Treatment B
    Started
    300
    284
    Completed
    0
    189
    Not completed
    300
    95
         Administrative reason by Sponsor
    2
    -
         Participant withdrew consent
    6
    3
         Not reported
    7
    -
         Maximum Clinical Benefit
    11
    2
         Participant no longer meets study criteria
    4
    -
         Adverse Event unrelated to Study Drug
    11
    9
         Poor/Non-compliance
    1
    -
         Other reasons
    12
    2
         Study Drug Toxicity
    60
    24
         Lost to follow-up
    -
    2
         Disease Progression
    182
    43
         Participant request to discontinue study treatment
    4
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W

    Reporting group title
    Treatment B
    Reporting group description
    		 Pemetrexed 500 mg/m^2 + Cisplatin 75 mg/m^2 or Carboplatin 5 AUC up to 6 cycles

    Reporting group values
    		 Treatment A Treatment B Total
    Number of subjects
    		 303 302 605
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.7 ( 8.5 ) 67.8 ( 9.7 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 69 69 138
        Male
    		 234 233 467
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 2 4 6
        Asian
    		 26 39 65
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 266 250 516
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 9 9 18
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 19 19 38
        Not Hispanic or Latino
    		 122 136 258
        Unknown or Not Reported
    		 162 147 309

    End points

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    End points reporting groups
    Reporting group title
    Treatment A
    Reporting group description
    		 Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W

    Reporting group title
    Treatment B
    Reporting group description
    		 Pemetrexed 500 mg/m^2 + Cisplatin 75 mg/m^2 or Carboplatin 5 AUC up to 6 cycles
    Reporting group title
    Treatment A
    Reporting group description
    		 Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W

    Reporting group title
    Treatment B
    Reporting group description
    		 Pemetrexed 500 mg/m^2 + Cisplatin 75 mg/m^2 or Carboplatin 5 AUC up to 6 cycles

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival was defined as the time from randomization to the date of death due to any cause. A participant who has not died was censored at last known date alive.
    End point type
    Primary
    End point timeframe
    From randomization to the date of death (Up to 40 Months)
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    303
    302
    Units: Months
        median (confidence interval 95%)
    18.07 (16.82 to 21.45)
    14.09 (12.45 to 16.23)
    Statistical analysis title
    		 OS Hazard Ratio (HR)
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    605
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.002 [2]
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 96.6%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.91
    Notes
    [1] - Treatment A over Treatment B
    [2] - Boundary for statistical significance was a p-value < 0.0345

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    Objective Response Rate is defined as the percentage of randomized participants who achieve a best overall response of complete response (CR) or partial response (PR) per Blinded Independent Central Review (BICR) assessments. Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. Per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement.
    End point type
    Secondary
    End point timeframe
    From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months)
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    303
    302
    Units: Percentage of Participants
        number (confidence interval 95%)
    39.3 (33.7 to 45.0)
    44.4 (38.7 to 50.2)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    Disease Control Rate is defined as the percentage of all randomized participants whose Best Overall Response was complete response (CR), partial response (PR), stable disease (SD) or Non-CR/Non-PD as assessed by Blinded Independent Central Review (BICR). Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. Per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement; SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Non-CR/Non-PD: Persistence of one or more non-target lesion(s).
    End point type
    Secondary
    End point timeframe
    From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    303
    302
    Units: Percentage of Participants
        number (confidence interval 95%)
    76.6 (71.4 to 81.2)
    85.8 (81.3 to 89.5)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression Free Survival is defined as the time between the date of randomization and the date of first documented tumor progression per Blinded Independent Central Review (BICR) assessments (using adapted m-RECIST and RECIST 1.1), or death due to any cause, whichever occurs first. Participants who received subsequent anticancer therapy prior to documented progression were censored at the date of the last evaluable tumor assessment conducted on or prior to the date of initiation of the subsequent anticancer therapy. Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement.
    End point type
    Secondary
    End point timeframe
    From randomization date to the date of first documented tumor progression or death due to any cause, whichever occurs first. (up to 76 months)
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    303
    302
    Units: Months
        median (confidence interval 95%)
    6.77 (5.59 to 7.36)
    7.23 (6.93 to 8.05)
    Statistical analysis title
    		 PFS Hazard Ratio (HR)
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    605
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.13
    Notes
    [3] - Treatment A over Treatment B

    Secondary: Overall Survival (OS) According to PD-L1 Expression Level

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    End point title
    		 Overall Survival (OS) According to PD-L1 Expression Level
    End point description
    PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by overall survival (OS) analysis. OS was defined as the time from randomization to the date of death due to any cause. A participant who has not died was censored at last known date alive.
    End point type
    Secondary
    End point timeframe
    From randomization date to the date of death (Up to 76 Months)
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    289
    297
    Units: Months
    median (confidence interval 95%)
        <1% PD-L1
    17.3 (10.1 to 23.9)
    16.6 (13.4 to 20.8)
        ≥1% PD-L1
    18.0 (16.8 to 21.5)
    13.3 (11.6 to 15.4)
    Statistical analysis title
    		 OS Hazard Ratio (HR)
    Statistical analysis description
    <1% PD-L1
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.32
    Notes
    [4] - Treatment A vs Treatment B
    Statistical analysis title
    		 OS Hazard Ratio (HR)
    Statistical analysis description
    ≥1% PD-L1
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 0.88
    Notes
    [5] - Treatment A vs Treatment B

    Secondary: Progression Free Survival (PFS) According to PD-L1 Expression Level

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    End point title
    		 Progression Free Survival (PFS) According to PD-L1 Expression Level
    End point description
    PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by progression free survival (PFS) analysis. PFS is defined as the time between the date of randomization and the date of first documented tumor progression per Blinded Independent Central Review (BICR) assessments (using adapted m-RECIST and RECIST 1.1), or death due to any cause, whichever occurs first. Participants who received subsequent anticancer therapy prior to documented progression were censored at the date of the last evaluable tumor assessment conducted on or prior to the date of initiation of the subsequent anticancer therapy. Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement.
    End point type
    Secondary
    End point timeframe
    From randomization date to the date of first documented tumor progression or death due to any cause, whichever occurs first. (up to 76 months)
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    289
    297
    Units: Months
    median (confidence interval 95%)
        <1% PD-L1
    4.1 (2.7 to 5.6)
    8.3 (7.0 to 11.1)
        ≥1% PD-L1
    7.0 (5.8 to 8.5)
    7.1 (6.2 to 7.6)
    Statistical analysis title
    		 PFS Hazard Ratio (HR)
    Statistical analysis description
    ≥1% PD-L1
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.96
    Notes
    [6] - Treatment A vs Treatment B
    Statistical analysis title
    		 PFS Hazard Ratio (HR)
    Statistical analysis description
    < 1% PD-L1
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.22
         upper limit
    		 2.63
    Notes
    [7] - Treatment A vs Treatment B

    Secondary: Objective Response Rate (ORR) According to PD-L1 Expression Level

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    End point title
    		 Objective Response Rate (ORR) According to PD-L1 Expression Level
    End point description
    PD-L1 Expression is defined as the percent of tumor cells membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 immunohistochemistry (IHC) assay. This is referred to as quantifiable PD-L1 expression and efficacy is determined by objective response rate (ORR) analysis. ORR is defined as the percentage of participants who achieve a best overall response of complete response (CR) or partial response (PR) per Blinded Independent Central Review (BICR) assessments. Per adapted m-RECIST for pleural mesothelioma, each single tumor measurement must be at least 10 mm in length to qualify as measureable disease and contribute to the sum that defines the pleural uni-variate measure. per RECIST 1.1 for solid tumors, confirmation of response required: CR=Disappearance of all target lesions; PR=At least a 30% decrease in the sum of the Total Tumor Measurement; Progressive disease (PD)=At least a 20% increase in the sum of the Total Tumor Measurement.
    End point type
    Secondary
    End point timeframe
    From randomization date to the date of objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first (Up to 76 months)
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    289
    297
    Units: Percentage of Participants
    number (confidence interval 95%)
        <1% PD-L1
    21.1 (11.4 to 33.9)
    41.0 (30.0 to 52.7)
        ≥1% PD-L1
    43.1 (36.6 to 49.7)
    45.7 (38.9 to 52.5)
    No statistical analyses for this end point

    Post-hoc: Extended Collection: Overall Survival (OS)

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    End point title
    		 Extended Collection: Overall Survival (OS)
    End point description
    Overall Survival was defined as the time from randomization to the date of death due to any cause. A participant who has not died was censored at last known date alive.
    End point type
    Post-hoc
    End point timeframe
    From randomization date to the date of death (Up to 76 Months)
    End point values
    		 Treatment A Treatment B
    Number of subjects analysed
    303
    302
    Units: Months
        median (confidence interval 95%)
    18.07 (16.82 to 20.99)
    14.09 (12.45 to 16.33)
    Statistical analysis title
    		 OS Hazard Ratio (HR)
    Comparison groups
    Treatment A v Treatment B
    Number of subjects included in analysis
    605
    Analysis specification
    Post-hoc
    Analysis type
    		 [8]
    P-value
    		 = 0.0008
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.88
    Notes
    [8] - Treatment A over Treatment B

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Subjects were assessed for deaths (all-causes) from their first dose to their study completion (up to approximately 76 months.) SAEs and NSAEs were assessed from first dose to 100 days post the last dose of study therapy (up to approximately 29 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Treatment B
    Reporting group description
    		 Pemetrexed 500 mg/m^2 + Cisplatin 75 mg/m^2 or Carboplatin 5 AUC up to 6 cycles

    Reporting group title
    Treatment A
    Reporting group description
    		 Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W

    Serious adverse events
    		 Treatment B Treatment A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    106 / 284 (37.32%)
    188 / 300 (62.67%)
         number of deaths (all causes)
    259
    251
         number of deaths resulting from adverse events
    49
    58
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesothelioma malignant
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesothelioma
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    42 / 284 (14.79%)
    51 / 300 (17.00%)
         occurrences causally related to treatment / all
    0 / 45
    0 / 52
         deaths causally related to treatment / all
    0 / 40
    0 / 44
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Embolism
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Giant cell arteritis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (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
    Asthenia
         subjects affected / exposed
    2 / 284 (0.70%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 284 (1.41%)
    4 / 300 (1.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hyperpyrexia
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Illness
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mucosal inflammation
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 284 (0.35%)
    4 / 300 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 284 (1.41%)
    16 / 300 (5.33%)
         occurrences causally related to treatment / all
    1 / 4
    3 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related hypersensitivity reaction
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 284 (2.82%)
    9 / 300 (3.00%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 284 (0.70%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 284 (0.35%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pleural effusion
         subjects affected / exposed
    3 / 284 (1.06%)
    9 / 300 (3.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleurisy
         subjects affected / exposed
    0 / 284 (0.00%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 284 (0.00%)
    9 / 300 (3.00%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 10
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    2 / 284 (0.70%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 284 (1.06%)
    6 / 300 (2.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary oedema
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 284 (0.35%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    General physical condition abnormal
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heat exhaustion
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 284 (0.00%)
    6 / 300 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (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
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 284 (0.35%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocarditis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limbic encephalitis
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelitis transverse
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 284 (0.00%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenic syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 284 (3.17%)
    5 / 300 (1.67%)
         occurrences causally related to treatment / all
    11 / 16
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myelosuppression
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haematotoxicity
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 284 (1.06%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenic purpura
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    3 / 284 (1.06%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Opsoclonus myoclonus
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 284 (0.70%)
    5 / 300 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 284 (0.00%)
    9 / 300 (3.00%)
         occurrences causally related to treatment / all
    0 / 0
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 284 (0.35%)
    5 / 300 (1.67%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         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 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastritis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overflow diarrhoea
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 284 (0.00%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior mesenteric artery dissection
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 284 (0.70%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 284 (0.00%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 284 (0.00%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 284 (0.00%)
    5 / 300 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 284 (0.00%)
    5 / 300 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous vasculitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal haemorrhage
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 284 (0.70%)
    7 / 300 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypophysitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 284 (0.00%)
    4 / 300 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 284 (0.00%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Back pain
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 284 (0.00%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Candida sepsis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella urinary tract infection
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa fungal
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy bacterial
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 284 (2.11%)
    14 / 300 (4.67%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 14
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 284 (0.70%)
    3 / 300 (1.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 284 (0.00%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         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 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 284 (0.35%)
    2 / 300 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 284 (0.35%)
    4 / 300 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    1 / 284 (0.35%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 284 (0.35%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 284 (0.70%)
    0 / 300 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 284 (0.00%)
    1 / 300 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment B Treatment A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    264 / 284 (92.96%)
    277 / 300 (92.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 284 (2.82%)
    16 / 300 (5.33%)
         occurrences all number
    8
    20
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 284 (4.93%)
    50 / 300 (16.67%)
         occurrences all number
    19
    79
    Pain
         subjects affected / exposed
    11 / 284 (3.87%)
    20 / 300 (6.67%)
         occurrences all number
    14
    21
    Oedema peripheral
         subjects affected / exposed
    19 / 284 (6.69%)
    47 / 300 (15.67%)
         occurrences all number
    19
    49
    Non-cardiac chest pain
         subjects affected / exposed
    16 / 284 (5.63%)
    39 / 300 (13.00%)
         occurrences all number
    16
    47
    Malaise
         subjects affected / exposed
    17 / 284 (5.99%)
    8 / 300 (2.67%)
         occurrences all number
    20
    9
    Fatigue
         subjects affected / exposed
    78 / 284 (27.46%)
    90 / 300 (30.00%)
         occurrences all number
    96
    110
    Chest pain
         subjects affected / exposed
    21 / 284 (7.39%)
    22 / 300 (7.33%)
         occurrences all number
    23
    23
    Asthenia
         subjects affected / exposed
    58 / 284 (20.42%)
    52 / 300 (17.33%)
         occurrences all number
    63
    74
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 284 (8.80%)
    65 / 300 (21.67%)
         occurrences all number
    25
    79
    Hiccups
         subjects affected / exposed
    17 / 284 (5.99%)
    2 / 300 (0.67%)
         occurrences all number
    28
    2
    Dyspnoea
         subjects affected / exposed
    41 / 284 (14.44%)
    77 / 300 (25.67%)
         occurrences all number
    42
    92
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 284 (5.63%)
    27 / 300 (9.00%)
         occurrences all number
    17
    29
    Investigations
    Weight decreased
         subjects affected / exposed
    24 / 284 (8.45%)
    17 / 300 (5.67%)
         occurrences all number
    25
    17
    Lipase increased
         subjects affected / exposed
    4 / 284 (1.41%)
    27 / 300 (9.00%)
         occurrences all number
    4
    42
    Blood creatinine increased
         subjects affected / exposed
    19 / 284 (6.69%)
    26 / 300 (8.67%)
         occurrences all number
    20
    49
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 284 (1.06%)
    18 / 300 (6.00%)
         occurrences all number
    3
    22
    Amylase increased
         subjects affected / exposed
    4 / 284 (1.41%)
    24 / 300 (8.00%)
         occurrences all number
    4
    36
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 284 (1.41%)
    22 / 300 (7.33%)
         occurrences all number
    4
    36
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 284 (0.70%)
    22 / 300 (7.33%)
         occurrences all number
    2
    26
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    15 / 284 (5.28%)
    3 / 300 (1.00%)
         occurrences all number
    15
    3
    Headache
         subjects affected / exposed
    12 / 284 (4.23%)
    24 / 300 (8.00%)
         occurrences all number
    12
    28
    Dysgeusia
         subjects affected / exposed
    22 / 284 (7.75%)
    15 / 300 (5.00%)
         occurrences all number
    23
    16
    Dizziness
         subjects affected / exposed
    10 / 284 (3.52%)
    16 / 300 (5.33%)
         occurrences all number
    11
    16
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    118 / 284 (41.55%)
    41 / 300 (13.67%)
         occurrences all number
    136
    56
    Leukopenia
         subjects affected / exposed
    25 / 284 (8.80%)
    0 / 300 (0.00%)
         occurrences all number
    31
    0
    Neutropenia
         subjects affected / exposed
    79 / 284 (27.82%)
    5 / 300 (1.67%)
         occurrences all number
    137
    5
    Thrombocytopenia
         subjects affected / exposed
    32 / 284 (11.27%)
    5 / 300 (1.67%)
         occurrences all number
    54
    6
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    19 / 284 (6.69%)
    1 / 300 (0.33%)
         occurrences all number
    19
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    55 / 284 (19.37%)
    47 / 300 (15.67%)
         occurrences all number
    78
    56
    Nausea
         subjects affected / exposed
    124 / 284 (43.66%)
    76 / 300 (25.33%)
         occurrences all number
    200
    95
    Diarrhoea
         subjects affected / exposed
    34 / 284 (11.97%)
    96 / 300 (32.00%)
         occurrences all number
    45
    152
    Abdominal pain
         subjects affected / exposed
    13 / 284 (4.58%)
    30 / 300 (10.00%)
         occurrences all number
    15
    30
    Constipation
         subjects affected / exposed
    86 / 284 (30.28%)
    57 / 300 (19.00%)
         occurrences all number
    104
    73
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    5 / 284 (1.76%)
    18 / 300 (6.00%)
         occurrences all number
    5
    21
    Rash
         subjects affected / exposed
    21 / 284 (7.39%)
    60 / 300 (20.00%)
         occurrences all number
    23
    76
    Pruritus
         subjects affected / exposed
    5 / 284 (1.76%)
    62 / 300 (20.67%)
         occurrences all number
    5
    70
    Dry skin
         subjects affected / exposed
    7 / 284 (2.46%)
    16 / 300 (5.33%)
         occurrences all number
    7
    16
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    3 / 284 (1.06%)
    37 / 300 (12.33%)
         occurrences all number
    3
    38
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    9 / 284 (3.17%)
    18 / 300 (6.00%)
         occurrences all number
    9
    19
    Myalgia
         subjects affected / exposed
    7 / 284 (2.46%)
    24 / 300 (8.00%)
         occurrences all number
    7
    27
    Back pain
         subjects affected / exposed
    13 / 284 (4.58%)
    21 / 300 (7.00%)
         occurrences all number
    14
    23
    Arthralgia
         subjects affected / exposed
    9 / 284 (3.17%)
    49 / 300 (16.33%)
         occurrences all number
    10
    55
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 284 (2.82%)
    21 / 300 (7.00%)
         occurrences all number
    8
    32
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    11 / 284 (3.87%)
    19 / 300 (6.33%)
         occurrences all number
    11
    23
    Hypoalbuminaemia
         subjects affected / exposed
    11 / 284 (3.87%)
    19 / 300 (6.33%)
         occurrences all number
    13
    24
    Decreased appetite
         subjects affected / exposed
    75 / 284 (26.41%)
    72 / 300 (24.00%)
         occurrences all number
    109
    78

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2017
    inclusion and exclusion criteria updated
    25 Apr 2019
    Endpoints updated

    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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