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    Clinical Trial Results:
    An Open Label, Randomized Phase 3 Clinical Trial of Nivolumab vs Therapy of Investigator's Choice in Recurrent or Metastatic Platinum-refractory Squamous Cell Carcinoma of the Head and Neck (SCCHN)

    Summary
    EudraCT number
    		 2013-003622-86
    Trial protocol
    		 IT   GB   ES   DE   NL   FR  
    Global end of trial date
    10 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Sep 2022
    First version publication date
    22 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-141
    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
    19 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare OS of Nivolumab to Investigator’s Choice in subjects who have tumor progression within 6 months of last dose of platinum therapy in the primary, recurrent, or metastatic setting.
    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 May 2014
    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
    Argentina: 4
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    France: 52
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Japan: 27
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 1
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    United States: 139
    Worldwide total number of subjects
    361
    EEA total number of subjects
    130
    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)
    248
    From 65 to 84 years
    113
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 361 participants randomized and 347 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
    		 Nivolumab 3mg/kg
    Arm description
    		 Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3mg/kg every 2 weeks

    Arm title
    		 Investigators Choice
    Arm description
    		 Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligrams per square meter (mg/m^2) for the first dose followed that a doses of 250 mg/m^2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m^2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m^2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30mg/m^2 weekly

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400mg/m^2 once then 250mg/m^2 weekly

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40mg/m^2 weekly, may be increased to 60mg/m^2 if tolerated

    Number of subjects in period 1
    		Nivolumab 3mg/kg Investigators Choice
    Started
    240
    121
    Completed
    236
    111
    Not completed
    4
    10
         Participant withdrew consent
    -
    6
         Participant no longer meets study criteria
    2
    2
         Disease Progression
    1
    -
         Participant request to discontinue study treatment
    1
    2
    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
    		 Nivolumab 3mg/kg
    Arm description
    		 Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    3mg/kg every 2 weeks

    Arm title
    		 Investigators Choice
    Arm description
    		 Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligrams per square meter (mg/m^2) for the first dose followed that a doses of 250 mg/m^2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m^2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m^2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30mg/m^2 weekly

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40mg/m^2 weekly, may be increased to 60mg/m^2 if tolerated

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400mg/m^2 once then 250mg/m^2 weekly

    Number of subjects in period 2
    		Nivolumab 3mg/kg Investigators Choice
    Started
    236
    111
    Completed
    1
    0
    Not completed
    235
    111
         Participant withdrew consent
    5
    1
         Maximum Clinical Benefit
    1
    3
         Adverse event unrelated to study drug
    19
    3
         Participant no longer meets study criteria
    1
    -
         Other reasons
    1
    -
         Poor/Non-compliance
    -
    1
         Study Drug Toxicity
    14
    10
         Lost to follow-up
    1
    -
         Disease Progression
    185
    87
         Participant request to discontinue study treatment
    8
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab 3mg/kg
    Reporting group description
    		 Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.

    Reporting group title
    Investigators Choice
    Reporting group description
    		 Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligrams per square meter (mg/m^2) for the first dose followed that a doses of 250 mg/m^2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m^2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m^2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice

    Reporting group values
    		 Nivolumab 3mg/kg Investigators Choice Total
    Number of subjects
    		 240 121 361
    Age Categorical
    Units: Participants
        < 65 years
    		 172 76 248
        >=65 and <75 years
    		 56 39 95
        >=75 years
    		 12 6 18
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.0 ± 10.15 59.4 ± 11.00 -
    Sex: Female, Male
    Units:
        Female
    		 43 18 61
        Male
    		 197 103 300
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 196 104 300
        Black or African American
    		 10 3 13
        Asian
    		 29 14 43
        Other
    		 5 0 5
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic/Latino
    		 9 4 13
        Not Hispanic/Latino
    		 132 60 192
        Not Reported
    		 99 57 156

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab 3mg/kg
    Reporting group description
    		 Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.

    Reporting group title
    Investigators Choice
    Reporting group description
    		 Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligrams per square meter (mg/m^2) for the first dose followed that a doses of 250 mg/m^2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m^2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m^2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice
    Reporting group title
    Nivolumab 3mg/kg
    Reporting group description
    		 Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.

    Reporting group title
    Investigators Choice
    Reporting group description
    		 Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligrams per square meter (mg/m^2) for the first dose followed that a doses of 250 mg/m^2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m^2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m^2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Median OS time was calculated using Kaplan-Meier (KM) method.
    End point type
    Primary
    End point timeframe
    From date of randomization to date of death (Up to approximately 18 months)
    End point values
    		 Nivolumab 3mg/kg Investigators Choice
    Number of subjects analysed
    240
    121
    Units: Months
        median (confidence interval 95%)
    7.49 (5.49 to 9.10)
    5.06 (4.04 to 6.05)
    Statistical analysis title
    		 OS HR
    Statistical analysis description
    Stratified Cox proportional hazard model. HR = Nivolumab over investigator’s choice therapy (Cetuximab, Methotrexate, or Docetaxel)
    Comparison groups
    Nivolumab 3mg/kg v Investigators Choice
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0101 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.92
    Notes
    [1] - Log-rank Test stratified by prior treatment with cetuximab (yes, no) as entered into the Interactive Voice Response System (IVRS). For OS the boundary for statistical significance requires the p-value to be less than 0.0227.

    Secondary: Investigator-Assessed Progression-Free Survival (PFS)

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    End point title
    		 Investigator-Assessed Progression-Free Survival (PFS)
    End point description
    PFS was defined as the time between the date of randomization and the first date of documented progression, as determined by the investigator (as per Response Evaluation Criteria In Solid Tumors (RECIST1.1)), or death due to any cause, whichever occurs first. Progressive Disease: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must demonstrate an absolute increase of at least 5mm. Participants who: - Die without a reported progression were considered to have progressed on the date of their death. - Did not progress or die were censored on the date of their last evaluable tumor assessment. - Without any on study tumor assessments and did not die were censored on their date of randomization. - Received subsequent systemic anti-cancer therapy prior to documented progression were censored at the date of the last tumor assessment prior to the initiation of the new therapy.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of disease progression or death, whichever occurs first (Up to approximately 87 months)
    End point values
    		 Nivolumab 3mg/kg Investigators Choice
    Number of subjects analysed
    240
    121
    Units: Months
        median (confidence interval 95%)
    2.04 (1.91 to 2.14)
    2.33 (1.94 to 3.06)
    Statistical analysis title
    		 PFS HR
    Comparison groups
    Nivolumab 3mg/kg v Investigators Choice
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.1

    Secondary: Investigator-Assessed Objective Response Rate (ORR)

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    End point title
    		 Investigator-Assessed Objective Response Rate (ORR)
    End point description
    ORR was defined as the percentage of randomized participants who achieved a best response of complete response (CR) or partial response (PR) using the RECIST1.1 criteria as per investigator assessment. Complete Response (CR): Disappearance of all target lesions. Partial Response (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 date of disease progression or study drug is discontinued, whichever occurs first (Up to approximately 87 months)
    End point values
    		 Nivolumab 3mg/kg Investigators Choice
    Number of subjects analysed
    240
    121
    Units: Percentage of Participants
        number (confidence interval 95%)
    13.3 (9.3 to 18.3)
    5.8 (2.4 to 11.6)
    Statistical analysis title
    		 Difference in ORR
    Comparison groups
    Nivolumab 3mg/kg v Investigators Choice
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in ORR
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.5
         upper limit
    		 13.6
    Statistical analysis title
    		 ORR Odds Ratio
    Comparison groups
    Nivolumab 3mg/kg v Investigators Choice
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 CMH Estimate of Common Odds Ratio
    Point estimate
    2.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 5.82

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

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    End point title
    		 Overall Survival (OS) - Extended Collection
    End point description
    OS was defined as the time from randomization to the date of death from any cause. Participants were censored at the date they were last known to be alive and at the date of randomization if they were randomized but had no follow-up. Median OS time was calculated using Kaplan-Meier (KM) method. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until 10-Sep-2021)
    End point type
    Post-hoc
    End point timeframe
    From date of randomization to date of death (Up to approximately 87 months)
    End point values
    		 Nivolumab 3mg/kg Investigators Choice
    Number of subjects analysed
    240
    121
    Units: Months
        median (confidence interval 95%)
    7.72 (5.68 to 8.74)
    5.06 (4.04 to 6.24)
    Statistical analysis title
    		 OS HR
    Comparison groups
    Nivolumab 3mg/kg v Investigators Choice
    Number of subjects included in analysis
    361
    Analysis specification
    Post-hoc
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.85

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were monitored from first dose to 100 days post last dose (Up to a max of approximately 70 months). Participants were assessed for Deaths (all causes) from their date of first treatment until study completion (up to approximately 87 months)
    Adverse event reporting additional description
    Total number of subjects exposed represents all participants that received at least 1 dose of study medication. Of the randomized population that did not receive any study medication, 1 participant randomized in Nivolumab arm died and 9 participants randomized in Investigator's Choice arm died.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Investigators Choice
    Reporting group description
    		 Participants were provided a dose of Cetuximab intravenous (IV) solution for injection at a dose of 400 milligrams per square meter (mg/m^2) for the first dose followed that a doses of 250 mg/m^2 weekly until disease progression OR a Methotrexate intravenous (IV) solution for Injection at a dose of 40 or 60 mg/m^2 weekly until disease progression OR a Docetaxel intravenous (IV) solution for Injection at a dose of 30 or 40 mg/m^2 weekly until disease progression. The decision regarding which treatment the participant received was at the discretion of the investigator and referred to as Investigators Choice

    Reporting group title
    Nivolumab 3mg/kg
    Reporting group description
    		 Nivolumab was provided at a dose of 3 milligrams/kilogram (mg/kg) using an intravenous (IV) solution for Injection every 2 weeks until disease progression.

    Serious adverse events
    		 Investigators Choice Nivolumab 3mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 111 (78.38%)
    165 / 236 (69.92%)
         number of deaths (all causes)
    110
    219
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cancer pain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Head and neck cancer
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    55 / 111 (49.55%)
    94 / 236 (39.83%)
         occurrences causally related to treatment / all
    0 / 57
    0 / 96
         deaths causally related to treatment / all
    0 / 55
    0 / 92
    Malignant pleural effusion
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    3 / 111 (2.70%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Tumour pain
         subjects affected / exposed
    4 / 111 (3.60%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertensive urgency
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (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
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Venous thrombosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site pain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 111 (3.60%)
    5 / 236 (2.12%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilic granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumopathy
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cough
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 111 (1.80%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 111 (1.80%)
    11 / 236 (4.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Laryngeal oedema
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 111 (2.70%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    4 / 111 (3.60%)
    10 / 236 (4.24%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    3 / 111 (2.70%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 111 (0.90%)
    5 / 236 (2.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agoraphobia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Suicide attempt
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Product issues
    Device leakage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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
    Humerus fracture
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (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
    1 / 111 (0.90%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Procedural haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm ruptured
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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
    3 / 111 (2.70%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiovascular disorder
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericarditis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (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
    Cerebrovascular accident
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (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
    2 / 111 (1.80%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neuralgia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Radiculopathy
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 111 (3.60%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual acuity reduced
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 111 (2.70%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 111 (2.70%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dysphagia
         subjects affected / exposed
    3 / 111 (2.70%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Gastric disorder
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotid gland haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin mass
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary adrenocortical insufficiency
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary hypothyroidism
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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
    Fistula
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Localised infection
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 111 (2.70%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lymphangitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 111 (4.50%)
    17 / 236 (7.20%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 21
         deaths causally related to treatment / all
    2 / 2
    0 / 3
    Pneumonia bacterial
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Purulent discharge
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 111 (0.90%)
    5 / 236 (2.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 111 (3.60%)
    6 / 236 (2.54%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular device infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 111 (1.80%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 111 (0.90%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 111 (0.90%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperamylasaemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 236 (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
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hyponatraemia
         subjects affected / exposed
    1 / 111 (0.90%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 236 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypophosphataemia
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 236 (0.42%)
         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
    		 Investigators Choice Nivolumab 3mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    108 / 111 (97.30%)
    210 / 236 (88.98%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    8 / 111 (7.21%)
    13 / 236 (5.51%)
         occurrences all number
    10
    16
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 111 (3.60%)
    16 / 236 (6.78%)
         occurrences all number
    5
    27
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    24 / 111 (21.62%)
    27 / 236 (11.44%)
         occurrences all number
    32
    32
    Face oedema
         subjects affected / exposed
    8 / 111 (7.21%)
    11 / 236 (4.66%)
         occurrences all number
    10
    11
    Fatigue
         subjects affected / exposed
    37 / 111 (33.33%)
    67 / 236 (28.39%)
         occurrences all number
    43
    73
    Mucosal inflammation
         subjects affected / exposed
    19 / 111 (17.12%)
    11 / 236 (4.66%)
         occurrences all number
    24
    11
    Oedema peripheral
         subjects affected / exposed
    5 / 111 (4.50%)
    19 / 236 (8.05%)
         occurrences all number
    6
    26
    Pyrexia
         subjects affected / exposed
    16 / 111 (14.41%)
    37 / 236 (15.68%)
         occurrences all number
    23
    46
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 111 (10.81%)
    32 / 236 (13.56%)
         occurrences all number
    14
    36
    Cough
         subjects affected / exposed
    13 / 111 (11.71%)
    37 / 236 (15.68%)
         occurrences all number
    16
    47
    Epistaxis
         subjects affected / exposed
    11 / 111 (9.91%)
    5 / 236 (2.12%)
         occurrences all number
    11
    7
    Pleural effusion
         subjects affected / exposed
    6 / 111 (5.41%)
    5 / 236 (2.12%)
         occurrences all number
    7
    5
    Productive cough
         subjects affected / exposed
    2 / 111 (1.80%)
    14 / 236 (5.93%)
         occurrences all number
    2
    15
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 111 (8.11%)
    9 / 236 (3.81%)
         occurrences all number
    9
    9
    Insomnia
         subjects affected / exposed
    7 / 111 (6.31%)
    13 / 236 (5.51%)
         occurrences all number
    7
    13
    Depression
         subjects affected / exposed
    3 / 111 (2.70%)
    12 / 236 (5.08%)
         occurrences all number
    3
    13
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 111 (5.41%)
    9 / 236 (3.81%)
         occurrences all number
    9
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 111 (5.41%)
    14 / 236 (5.93%)
         occurrences all number
    9
    17
    Lipase increased
         subjects affected / exposed
    2 / 111 (1.80%)
    13 / 236 (5.51%)
         occurrences all number
    2
    20
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 111 (2.70%)
    18 / 236 (7.63%)
         occurrences all number
    3
    20
    Lymphocyte count decreased
         subjects affected / exposed
    6 / 111 (5.41%)
    8 / 236 (3.39%)
         occurrences all number
    7
    20
    Weight decreased
         subjects affected / exposed
    19 / 111 (17.12%)
    35 / 236 (14.83%)
         occurrences all number
    22
    38
    White blood cell count decreased
         subjects affected / exposed
    8 / 111 (7.21%)
    3 / 236 (1.27%)
         occurrences all number
    11
    3
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    7 / 111 (6.31%)
    7 / 236 (2.97%)
         occurrences all number
    7
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 111 (6.31%)
    9 / 236 (3.81%)
         occurrences all number
    9
    12
    Neuropathy peripheral
         subjects affected / exposed
    9 / 111 (8.11%)
    6 / 236 (2.54%)
         occurrences all number
    9
    6
    Headache
         subjects affected / exposed
    4 / 111 (3.60%)
    23 / 236 (9.75%)
         occurrences all number
    5
    35
    Paraesthesia
         subjects affected / exposed
    6 / 111 (5.41%)
    4 / 236 (1.69%)
         occurrences all number
    6
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    42 / 111 (37.84%)
    53 / 236 (22.46%)
         occurrences all number
    52
    63
    Neutropenia
         subjects affected / exposed
    9 / 111 (8.11%)
    2 / 236 (0.85%)
         occurrences all number
    18
    2
    Thrombocytopenia
         subjects affected / exposed
    6 / 111 (5.41%)
    4 / 236 (1.69%)
         occurrences all number
    9
    5
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    6 / 111 (5.41%)
    1 / 236 (0.42%)
         occurrences all number
    6
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    27 / 111 (24.32%)
    47 / 236 (19.92%)
         occurrences all number
    40
    65
    Constipation
         subjects affected / exposed
    21 / 111 (18.92%)
    43 / 236 (18.22%)
         occurrences all number
    23
    48
    Dry mouth
         subjects affected / exposed
    8 / 111 (7.21%)
    8 / 236 (3.39%)
         occurrences all number
    8
    9
    Dysphagia
         subjects affected / exposed
    17 / 111 (15.32%)
    30 / 236 (12.71%)
         occurrences all number
    18
    32
    Dyspepsia
         subjects affected / exposed
    6 / 111 (5.41%)
    7 / 236 (2.97%)
         occurrences all number
    7
    9
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 111 (7.21%)
    3 / 236 (1.27%)
         occurrences all number
    8
    3
    Stomatitis
         subjects affected / exposed
    12 / 111 (10.81%)
    14 / 236 (5.93%)
         occurrences all number
    18
    16
    Nausea
         subjects affected / exposed
    37 / 111 (33.33%)
    55 / 236 (23.31%)
         occurrences all number
    53
    75
    Vomiting
         subjects affected / exposed
    16 / 111 (14.41%)
    28 / 236 (11.86%)
         occurrences all number
    23
    43
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    16 / 111 (14.41%)
    4 / 236 (1.69%)
         occurrences all number
    16
    4
    Erythema
         subjects affected / exposed
    6 / 111 (5.41%)
    3 / 236 (1.27%)
         occurrences all number
    6
    3
    Dry skin
         subjects affected / exposed
    12 / 111 (10.81%)
    14 / 236 (5.93%)
         occurrences all number
    12
    14
    Pruritus
         subjects affected / exposed
    1 / 111 (0.90%)
    23 / 236 (9.75%)
         occurrences all number
    1
    24
    Rash
         subjects affected / exposed
    6 / 111 (5.41%)
    22 / 236 (9.32%)
         occurrences all number
    7
    29
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    7 / 111 (6.31%)
    21 / 236 (8.90%)
         occurrences all number
    10
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 111 (1.80%)
    19 / 236 (8.05%)
         occurrences all number
    2
    22
    Back pain
         subjects affected / exposed
    0 / 111 (0.00%)
    17 / 236 (7.20%)
         occurrences all number
    0
    17
    Neck pain
         subjects affected / exposed
    9 / 111 (8.11%)
    17 / 236 (7.20%)
         occurrences all number
    9
    18
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    6 / 111 (5.41%)
    11 / 236 (4.66%)
         occurrences all number
    6
    11
    Respiratory tract infection
         subjects affected / exposed
    6 / 111 (5.41%)
    6 / 236 (2.54%)
         occurrences all number
    7
    8
    Pneumonia
         subjects affected / exposed
    5 / 111 (4.50%)
    16 / 236 (6.78%)
         occurrences all number
    5
    16
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    8 / 111 (7.21%)
    17 / 236 (7.20%)
         occurrences all number
    8
    23
    Decreased appetite
         subjects affected / exposed
    21 / 111 (18.92%)
    46 / 236 (19.49%)
         occurrences all number
    23
    54
    Hyperglycaemia
         subjects affected / exposed
    9 / 111 (8.11%)
    16 / 236 (6.78%)
         occurrences all number
    9
    36
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 111 (3.60%)
    12 / 236 (5.08%)
         occurrences all number
    4
    16
    Hypokalaemia
         subjects affected / exposed
    7 / 111 (6.31%)
    11 / 236 (4.66%)
         occurrences all number
    9
    12
    Hyponatraemia
         subjects affected / exposed
    15 / 111 (13.51%)
    25 / 236 (10.59%)
         occurrences all number
    19
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2014
    Update to investigational product description
    30 Jan 2015
    Update to Endpoints
    09 Jun 2015
    Update to OS interim analysis trigger
    11 Feb 2016
    Update to Study Design
    03 Nov 2016
    Update to the treatment management algorithms and study treatment dose options

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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