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    Clinical Trial Results:
    A Phase IIIb/IV Safety Trial of Flat Dose Nivolumab in Combination with Ipilimumab in Participants with Non-Small Cell Lung Cancer CheckMate 817, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation

    Summary
    EudraCT number
    		 2016-002621-10
    Trial protocol
    		 HU   ES   DE   NL   GR   BE   GB   PL   FR   CZ   IT   RO  
    Global end of trial date
    13 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2023
    First version publication date
    19 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CA209-817
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb International Corporation, EU Study Start-Up Unit, 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
    29 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the safety of Nivolumab flat dosing in combination with weight-based Ipilimumab administration in participants with Non-Small Cell Lung Cancer (NSCLC)
    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
    05 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 21
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Canada: 54
    Country: Number of subjects enrolled
    Chile: 28
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    United States: 229
    Country: Number of subjects enrolled
    Belgium: 37
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    France: 92
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Greece: 23
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    Italy: 76
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Poland: 53
    Country: Number of subjects enrolled
    Romania: 75
    Country: Number of subjects enrolled
    Spain: 146
    Country: Number of subjects enrolled
    United Kingdom: 45
    Country: Number of subjects enrolled
    Switzerland: 23
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    Turkey: 6
    Worldwide total number of subjects
    1041
    EEA total number of subjects
    595
    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)
    488
    From 65 to 84 years
    546
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Analysis for the NSCLC special population cohort A1 is pre-specified as exploratory.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A
    Arm description
    		 First-line NSCLC: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    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
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg Q2W

    Arm title
    		 Cohort A1
    Arm description
    		 First-line NSCLC special population: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    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
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg Q2W

    Arm title
    		 Cohort B
    Arm description
    		 Second-line NSCLC: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    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
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg Q2W

    Arm title
    		 Cohort C
    Arm description
    		 First-line NSCLC high tumor mutational burden (H-TMB >= 10 mutations/MB): Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    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
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg Q2W

    Number of subjects in period 1
    		Cohort A Cohort A1 Cohort B Cohort C
    Started
    391
    198
    395
    57
    Completed
    56
    16
    30
    12
    Not completed
    335
    182
    365
    45
         Adverse event, serious fatal
    7
    3
    5
    1
         Consent withdrawn by subject
    5
    2
    7
    2
         Disease progression
    184
    109
    260
    19
         Adverse Event unrelated to study drug
    30
    18
    21
    6
         Study drug toxicity
    90
    32
    55
    14
         Maximum clinical benefit
    5
    2
    1
    -
         Participant no longer meets study criteria
    -
    1
    1
    -
         Other reasons
    4
    8
    6
    -
         Poor/Non-compliance
    -
    2
    1
    -
         Lost to follow-up
    -
    -
    2
    -
         Participant request to discontinue study treatment
    10
    5
    5
    3
         Administrative reason by sponsor
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 First-line NSCLC: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort A1
    Reporting group description
    		 First-line NSCLC special population: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort B
    Reporting group description
    		 Second-line NSCLC: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort C
    Reporting group description
    		 First-line NSCLC high tumor mutational burden (H-TMB >= 10 mutations/MB): Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group values
    		 Cohort A Cohort A1 Cohort B Cohort C Total
    Number of subjects
    		 391 198 395 57 1041
    Age Categorical
    Units: Participants
        < 65 years old
    		 183 81 200 24 488
        >= 65 and < 85 years old
    		 206 115 195 30 546
        >= 85 years old
    		 2 2 0 3 7
    Sex: Female, Male
    Units: Participants
        Female
    		 155 71 128 29 383
        Male
    		 236 127 267 28 658
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 3 0 4 0 7
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 6 3 5 8 22
        White
    		 379 194 382 47 1002
        More than one race
    		 0 0 0 0 0
        Unknown or Not Reported
    		 3 1 4 2 10
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 13 12 3 38
        Not Hispanic or Latino
    		 185 78 175 54 492
        Unknown or Not Reported
    		 196 107 208 0 511

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 First-line NSCLC: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort A1
    Reporting group description
    		 First-line NSCLC special population: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort B
    Reporting group description
    		 Second-line NSCLC: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort C
    Reporting group description
    		 First-line NSCLC high tumor mutational burden (H-TMB >= 10 mutations/MB): Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Primary: Number of Participants with High Grade (Grade 3-4 and Grade 5) Drug-Related Select Adverse Events (AEs)

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    End point title
    		 Number of Participants with High Grade (Grade 3-4 and Grade 5) Drug-Related Select Adverse Events (AEs) [1] [2]
    End point description
    Drug related AEs are those events with relationship to study drug. If the relationship to study drug is missing, the AE will be considered as drug-related. The select AEs of interest are the following: Pulmonary, Renal, Gastrointestinal, Hepatic, Skin, Endocrine, and hypersensitivity/infusion reaction events. AEs are reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4. Grade 3= Prolonged severe reaction Grade 4= Life threatening Grade 5= Death
    End point type
    Primary
    End point timeframe
    From first dose to 30 days post last dose (Up to approximately 27 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only pre-specified arms planned for this endpoint.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    391
    395
    57
    Units: Participants
        Gastrointestinal AEs grade 3-4
    19
    15
    4
        Gastrointestinal AEs grade 5
    0
    0
    0
        Hepatic AEs grade 3-4
    25
    17
    3
        Hepatic AEs grade 5
    0
    0
    0
        Pulmonary AEs grade 3-4
    18
    11
    2
        Pulmonary AEs grade 5
    0
    1
    0
        Renal AEs grade 3-4
    2
    1
    1
        Renal AEs grade 5
    0
    0
    0
        Skin AEs grade 3-4
    14
    9
    2
        Skin AEs grade 5
    0
    0
    0
        Endocrine AEs grade 3-4
    18
    11
    2
        Endocrine AEs grade 5
    0
    0
    0
        Hypersensitivity/Infusion Reaction grade 3-4
    6
    3
    0
        Hypersensitivity/Infusion Reaction grade 5
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with High Grade (Grade 3-4 and Grade 5) Immune-Mediated Adverse Events (imAEs)

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    End point title
    		 Number of Participants with High Grade (Grade 3-4 and Grade 5) Immune-Mediated Adverse Events (imAEs) [3] [4]
    End point description
    imAEs are specific events that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, and endocrine (adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis). AEs are reported using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4. Grade 3= Prolonged severe reaction Grade 4= Life threatening Grade 5= Death
    End point type
    Primary
    End point timeframe
    From first dose to 100 days post last dose (Up to approximately 29 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics planned for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only pre-specified arms planned for this endpoint.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    391
    395
    57
    Units: Participants
        Pneumonitis grade 3-4
    20
    14
    3
        Diarrhea/Colitis grade 3-4
    19
    15
    3
        Hepatitis grade 3-4
    18
    13
    1
        Adrenal Insufficiency grade 3-4
    5
    4
    1
        Hypothyroidism/Thyroiditis grade 3-4
    2
    2
    0
        Hypothyroidism grade 3-4
    1
    1
    0
        Thyroiditis grade 3-4
    1
    1
    0
        Diabetes Mellitus grade 3-4
    1
    0
    0
        Nephritis and Renal Dysfunction grade 3-4
    2
    1
    0
        Rash grade 3-4
    14
    8
    1
        Hypersensitivity grade 3-4
    4
    2
    0
        Hyperthyroidism grade 3-4
    0
    2
    0
        Hypophysitis grade 3-4
    3
    1
    1
        Any category imAEs grade 5
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS) [5]
    End point description
    PFS is defined as the time from first dosing date to the date of the first documented tumor progression, as determined by investigators (per RECIST v1.1), or death due to any cause, whichever occurs first. Progressive Disease (PD)= ≥ 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an absolute increase of ≥ 5 mm. The appearance of one or more new lesions is also considered progression.
    End point type
    Secondary
    End point timeframe
    From first dosing date to the date of first documented tumor progression or, death due to any cause, whichever occurs first (Up to approximately 67 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only pre-specified arms planned for this endpoint.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    391
    395
    57
    Units: Months
        median (confidence interval 95%)
    5.75 (4.50 to 7.62)
    3.91 (2.89 to 4.24)
    11.10 (6.47 to 18.40)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [6]
    End point description
    OS is defined as the time from first dosing date to the date of death. A participant who has not died will be censored at last known date alive. 99999=Not available
    End point type
    Secondary
    End point timeframe
    From first dosing date to the date of death (Up to approximately 67 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only pre-specified arms planned for this endpoint.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    391
    395
    57
    Units: Months
        median (confidence interval 95%)
    16.76 (16.65 to 22.41)
    10.45 (8.84 to 12.22)
    26.09 (21.85 to 99999)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR) [7]
    End point description
    ORR is defined as the percentage of participants with a best overall response of confirmed complete response (CR) or partial response (PR). CR= Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
    End point type
    Secondary
    End point timeframe
    From first dosing date up to approximately 67 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only pre-specified arms planned for this endpoint.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    391
    395
    57
    Units: Percentage of participants
        number (confidence interval 95%)
    37.3 (32.5 to 42.3)
    22.8 (18.7 to 27.2)
    45.6 (32.4 to 59.3)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR) [8]
    End point description
    DoR is defined as the time between the date of first confirmed complete response (CR) or partial response (PR) to the date of the first documented tumor progression per RECIST 1.1, or death due to any cause, whichever occurs first. CR= Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR= ≥ 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD)= ≥ 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an absolute increase of ≥ 5 mm. The appearance of one or more new lesions is also considered progression. 99999=Not available
    End point type
    Secondary
    End point timeframe
    From first dosing date to the date of first documented tumor progression or, death due to any cause, whichever occurs first (Up to approximately 67 months)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only pre-specified arms planned for this endpoint.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    146
    90
    26
    Units: Months
        median (confidence interval 95%)
    27.56 (20.40 to 36.04)
    13.01 (10.12 to 19.29)
    26.05 (12.22 to 99999)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Health-Related Quality of Life (HRQoL) using Functional Assessment of Cancer Therapy-Lung (FACT-L)

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    End point title
    		 Change from Baseline in Health-Related Quality of Life (HRQoL) using Functional Assessment of Cancer Therapy-Lung (FACT-L) [9]
    End point description
    FACT-L is a quality-of-life questionnaire which includes the Lung Cancer Subscale (LCS) that assesses the treatment impact on lung cancer related symptoms in 5 domains: Physical, social/family, emotional, and functional well-being using a 5-point scale (0=not at all) to (4=very much) added to obtain total score. The ranges of possible total scores are 0 - 136 for the FACT-L with a higher score representing better quality of life, improved symptomatology and enhanced physical/functional outcomes. According to Functional Assessment of Chronic Illness Therapy scoring guidelines, in the event of missing responses for some of the questions/items, scores will be prorated using the average of the other answers in that scale. Baseline is defined as evaluations or events that occur before the date and time of the first dose of study treatment. Post treatment follow-up includes 2 visits for safety and subsequent survival follow-up every 3 months. 99999=Not available
    End point type
    Secondary
    End point timeframe
    From baseline and up to survival follow-up 18 (Up to approximately 67 months)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only pre-specified arms planned for this endpoint.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    364 [10]
    365 [11]
    57 [12]
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Baseline
    94.89 ( 19.33 )
    91.20 ( 18.45 )
    93.96 ( 17.28 )
        Week 6
    -0.84 ( 13.82 )
    -0.30 ( 14.87 )
    2.72 ( 12.95 )
        Survival Follow-up 6
    14.68 ( 13.58 )
    3.81 ( 18.59 )
    15.33 ( 37.71 )
        Survival Follow-up 16
    5.28 ( 28.19 )
    -18.00 ( 99999 )
    99999 ( 99999 )
        Survival Follow-up 18
    -43.33 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    Notes
    [10] - Baseline= 364 Week 6= 245 Survival Follow-up 6= 22 Survival Follow-up 16= 3 Survival Follow-up 18= 1
    [11] - Baseline= 365 Week 6= 244 Survival Follow-up 6=16 Survival Follow-up 16=1 Survival Follow-up 18=0
    [12] - Baseline= 57 Week 6= 41 Survival Follow-up 6= 2 Survival Follow-up 16= 0 Survival Follow-up 18= 0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and AEs are assessed from first dose to 100 days post last dose (Up to approximately 29 months). Participants were assessed for deaths (all causes) from their first dose to study completion (Up to approximately 67 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 First-line NSCLC: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort C
    Reporting group description
    		 First-line NSCLC high tumor mutational burden (H-TMB >= 10 mutations/MB): Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort B
    Reporting group description
    		 Second-line NSCLC: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Reporting group title
    Cohort A1
    Reporting group description
    		 First-line NSCLC special population: Nivolumab 240 mg IV Q2W + Ipilimumab 1 mg/kg IV Q6W, starting on Day 1, until progression, unacceptable toxicity, withdrawal of consent, 24 months of treatment from the first dose, or the study ends, whichever occurs first

    Serious adverse events
    		 Cohort A Cohort C Cohort B Cohort A1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    264 / 391 (67.52%)
    42 / 57 (73.68%)
    282 / 395 (71.39%)
    149 / 198 (75.25%)
         number of deaths (all causes)
    294
    32
    334
    166
         number of deaths resulting from adverse events
    101
    15
    159
    85
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    81 / 391 (20.72%)
    6 / 57 (10.53%)
    144 / 395 (36.46%)
    64 / 198 (32.32%)
         occurrences causally related to treatment / all
    0 / 82
    0 / 6
    0 / 151
    0 / 68
         deaths causally related to treatment / all
    0 / 73
    0 / 4
    0 / 134
    0 / 63
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour obstruction
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour compression
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract neoplasm
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroma
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Brachiocephalic vein thrombosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infarction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exsanguination
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    Chills
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    4 / 391 (1.02%)
    1 / 57 (1.75%)
    2 / 395 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    4 / 395 (1.01%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    6 / 391 (1.53%)
    2 / 57 (3.51%)
    4 / 395 (1.01%)
    4 / 198 (2.02%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 6
    0 / 2
    0 / 4
    0 / 4
    Pyrexia
         subjects affected / exposed
    5 / 391 (1.28%)
    0 / 57 (0.00%)
    7 / 395 (1.77%)
    8 / 198 (4.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    2 / 8
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    3 / 395 (0.76%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Performance status decreased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    3 / 395 (0.76%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Ulcer
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast inflammation
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast pain
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    6 / 391 (1.53%)
    1 / 57 (1.75%)
    7 / 395 (1.77%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
    1 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Bronchostenosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diaphragmatic paralysis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alveolitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 391 (0.26%)
    2 / 57 (3.51%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 57 (1.75%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    5 / 391 (1.28%)
    1 / 57 (1.75%)
    5 / 395 (1.27%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    Dyspnoea
         subjects affected / exposed
    14 / 391 (3.58%)
    2 / 57 (3.51%)
    22 / 395 (5.57%)
    9 / 198 (4.55%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 2
    0 / 22
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    Interstitial lung disease
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 57 (1.75%)
    4 / 395 (1.01%)
    6 / 198 (3.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    23 / 391 (5.88%)
    3 / 57 (5.26%)
    17 / 395 (4.30%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    22 / 24
    3 / 3
    18 / 18
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 0
    Pleural effusion
         subjects affected / exposed
    8 / 391 (2.05%)
    0 / 57 (0.00%)
    4 / 395 (1.01%)
    4 / 198 (2.02%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    9 / 391 (2.30%)
    2 / 57 (3.51%)
    2 / 395 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device loosening
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood gases abnormal
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza B virus test positive
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incision site impaired healing
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anastomotic stenosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Recall phenomenon
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Poisoning
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound evisceration
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 57 (3.51%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    3 / 395 (0.76%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    7 / 391 (1.79%)
    2 / 57 (3.51%)
    2 / 395 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 2
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    6 / 391 (1.53%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 391 (0.77%)
    2 / 57 (3.51%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 57 (1.75%)
    3 / 395 (0.76%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burning sensation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 391 (0.26%)
    2 / 57 (3.51%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis autoimmune
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cluster headache
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 391 (0.77%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated encephalitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemianopia homonymous
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myasthenic syndrome
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Motor dysfunction
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient aphasia
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 391 (0.51%)
    2 / 57 (3.51%)
    4 / 395 (1.01%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Autoimmune anaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 57 (0.00%)
    3 / 395 (0.76%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Ophthalmoplegia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Chronic gastritis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Barrett's oesophagus
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 57 (1.75%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 391 (1.79%)
    1 / 57 (1.75%)
    11 / 395 (2.78%)
    4 / 198 (2.02%)
         occurrences causally related to treatment / all
    6 / 8
    1 / 1
    10 / 11
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    5 / 391 (1.28%)
    0 / 57 (0.00%)
    6 / 395 (1.52%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    7 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 57 (0.00%)
    5 / 395 (1.27%)
    4 / 198 (2.02%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
    7 / 7
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 391 (0.77%)
    1 / 57 (1.75%)
    2 / 395 (0.51%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Subileus
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary cirrhosis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cholangitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Toxic skin eruption
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pustular psoriasis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eosinophilic cellulitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 57 (0.00%)
    8 / 395 (2.03%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    3 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated nephritis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypophysitis
         subjects affected / exposed
    3 / 391 (0.77%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Euthyroid sick syndrome
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    6 / 391 (1.53%)
    1 / 57 (1.75%)
    4 / 395 (1.01%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 1
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hyperthyroidism
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    3 / 395 (0.76%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocytic hypophysitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    5 / 198 (2.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Arthritis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polymyositis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    7 / 395 (1.77%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal oesophagitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Diverticulitis intestinal perforated
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    4 / 198 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective spondylitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    21 / 391 (5.37%)
    2 / 57 (3.51%)
    26 / 395 (6.58%)
    6 / 198 (3.03%)
         occurrences causally related to treatment / all
    1 / 26
    0 / 2
    3 / 27
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    7 / 391 (1.79%)
    0 / 57 (0.00%)
    3 / 395 (0.76%)
    4 / 198 (2.02%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 1
    Sepsis
         subjects affected / exposed
    7 / 391 (1.79%)
    2 / 57 (3.51%)
    5 / 395 (1.27%)
    4 / 198 (2.02%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    2 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    1 / 2
    0 / 4
    Septic shock
         subjects affected / exposed
    5 / 391 (1.28%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    Skin infection
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 57 (1.75%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 57 (1.75%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 391 (0.51%)
    2 / 57 (3.51%)
    2 / 395 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acidosis
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 391 (1.02%)
    2 / 57 (3.51%)
    3 / 395 (0.76%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Steroid diabetes
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    1 / 395 (0.25%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 391 (0.00%)
    0 / 57 (0.00%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A Cohort C Cohort B Cohort A1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    362 / 391 (92.58%)
    56 / 57 (98.25%)
    346 / 395 (87.59%)
    174 / 198 (87.88%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    20 / 391 (5.12%)
    7 / 57 (12.28%)
    12 / 395 (3.04%)
    5 / 198 (2.53%)
         occurrences all number
    23
    7
    12
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    66 / 391 (16.88%)
    7 / 57 (12.28%)
    51 / 395 (12.91%)
    25 / 198 (12.63%)
         occurrences all number
    96
    8
    66
    29
    Pain
         subjects affected / exposed
    20 / 391 (5.12%)
    5 / 57 (8.77%)
    10 / 395 (2.53%)
    6 / 198 (3.03%)
         occurrences all number
    21
    5
    11
    6
    Oedema peripheral
         subjects affected / exposed
    39 / 391 (9.97%)
    9 / 57 (15.79%)
    32 / 395 (8.10%)
    14 / 198 (7.07%)
         occurrences all number
    47
    9
    36
    17
    Non-cardiac chest pain
         subjects affected / exposed
    11 / 391 (2.81%)
    5 / 57 (8.77%)
    11 / 395 (2.78%)
    8 / 198 (4.04%)
         occurrences all number
    13
    5
    11
    8
    Malaise
         subjects affected / exposed
    7 / 391 (1.79%)
    3 / 57 (5.26%)
    3 / 395 (0.76%)
    1 / 198 (0.51%)
         occurrences all number
    7
    3
    3
    1
    Localised oedema
         subjects affected / exposed
    0 / 391 (0.00%)
    4 / 57 (7.02%)
    0 / 395 (0.00%)
    1 / 198 (0.51%)
         occurrences all number
    0
    5
    0
    1
    Fatigue
         subjects affected / exposed
    140 / 391 (35.81%)
    24 / 57 (42.11%)
    87 / 395 (22.03%)
    39 / 198 (19.70%)
         occurrences all number
    170
    31
    109
    51
    Chills
         subjects affected / exposed
    16 / 391 (4.09%)
    5 / 57 (8.77%)
    10 / 395 (2.53%)
    2 / 198 (1.01%)
         occurrences all number
    16
    7
    10
    2
    Asthenia
         subjects affected / exposed
    84 / 391 (21.48%)
    4 / 57 (7.02%)
    67 / 395 (16.96%)
    45 / 198 (22.73%)
         occurrences all number
    104
    6
    83
    55
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    31 / 391 (7.93%)
    6 / 57 (10.53%)
    28 / 395 (7.09%)
    13 / 198 (6.57%)
         occurrences all number
    37
    6
    30
    14
    Pneumonitis
         subjects affected / exposed
    31 / 391 (7.93%)
    4 / 57 (7.02%)
    18 / 395 (4.56%)
    4 / 198 (2.02%)
         occurrences all number
    34
    5
    21
    5
    Hypoxia
         subjects affected / exposed
    7 / 391 (1.79%)
    8 / 57 (14.04%)
    10 / 395 (2.53%)
    4 / 198 (2.02%)
         occurrences all number
    10
    8
    11
    4
    Haemoptysis
         subjects affected / exposed
    20 / 391 (5.12%)
    2 / 57 (3.51%)
    21 / 395 (5.32%)
    10 / 198 (5.05%)
         occurrences all number
    24
    2
    24
    11
    Dyspnoea
         subjects affected / exposed
    85 / 391 (21.74%)
    24 / 57 (42.11%)
    85 / 395 (21.52%)
    41 / 198 (20.71%)
         occurrences all number
    97
    29
    93
    44
    Cough
         subjects affected / exposed
    98 / 391 (25.06%)
    13 / 57 (22.81%)
    71 / 395 (17.97%)
    22 / 198 (11.11%)
         occurrences all number
    118
    14
    82
    25
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    7 / 391 (1.79%)
    4 / 57 (7.02%)
    8 / 395 (2.03%)
    5 / 198 (2.53%)
         occurrences all number
    9
    5
    9
    7
    Nasal congestion
         subjects affected / exposed
    8 / 391 (2.05%)
    3 / 57 (5.26%)
    5 / 395 (1.27%)
    1 / 198 (0.51%)
         occurrences all number
    9
    3
    8
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    34 / 391 (8.70%)
    8 / 57 (14.04%)
    17 / 395 (4.30%)
    14 / 198 (7.07%)
         occurrences all number
    38
    8
    17
    14
    Depression
         subjects affected / exposed
    21 / 391 (5.37%)
    8 / 57 (14.04%)
    6 / 395 (1.52%)
    1 / 198 (0.51%)
         occurrences all number
    24
    9
    6
    1
    Anxiety
         subjects affected / exposed
    19 / 391 (4.86%)
    10 / 57 (17.54%)
    11 / 395 (2.78%)
    8 / 198 (4.04%)
         occurrences all number
    21
    13
    11
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    20 / 391 (5.12%)
    6 / 57 (10.53%)
    19 / 395 (4.81%)
    12 / 198 (6.06%)
         occurrences all number
    27
    7
    27
    22
    Amylase increased
         subjects affected / exposed
    27 / 391 (6.91%)
    3 / 57 (5.26%)
    31 / 395 (7.85%)
    19 / 198 (9.60%)
         occurrences all number
    45
    4
    61
    27
    Aspartate aminotransferase increased
         subjects affected / exposed
    14 / 391 (3.58%)
    6 / 57 (10.53%)
    18 / 395 (4.56%)
    11 / 198 (5.56%)
         occurrences all number
    19
    7
    26
    20
    Blood alkaline phosphatase increased
         subjects affected / exposed
    10 / 391 (2.56%)
    6 / 57 (10.53%)
    20 / 395 (5.06%)
    8 / 198 (4.04%)
         occurrences all number
    11
    6
    30
    11
    Blood creatinine increased
         subjects affected / exposed
    18 / 391 (4.60%)
    8 / 57 (14.04%)
    22 / 395 (5.57%)
    11 / 198 (5.56%)
         occurrences all number
    24
    9
    28
    11
    Lipase increased
         subjects affected / exposed
    35 / 391 (8.95%)
    3 / 57 (5.26%)
    31 / 395 (7.85%)
    18 / 198 (9.09%)
         occurrences all number
    51
    5
    62
    21
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 391 (0.77%)
    3 / 57 (5.26%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences all number
    3
    6
    5
    0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 391 (0.77%)
    3 / 57 (5.26%)
    4 / 395 (1.01%)
    1 / 198 (0.51%)
         occurrences all number
    3
    4
    8
    1
    Weight decreased
         subjects affected / exposed
    33 / 391 (8.44%)
    8 / 57 (14.04%)
    23 / 395 (5.82%)
    16 / 198 (8.08%)
         occurrences all number
    35
    9
    23
    17
    Weight increased
         subjects affected / exposed
    4 / 391 (1.02%)
    5 / 57 (8.77%)
    5 / 395 (1.27%)
    2 / 198 (1.01%)
         occurrences all number
    4
    5
    5
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 391 (3.07%)
    8 / 57 (14.04%)
    8 / 395 (2.03%)
    2 / 198 (1.01%)
         occurrences all number
    12
    8
    9
    2
    Infusion related reaction
         subjects affected / exposed
    22 / 391 (5.63%)
    4 / 57 (7.02%)
    11 / 395 (2.78%)
    2 / 198 (1.01%)
         occurrences all number
    26
    5
    12
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    13 / 391 (3.32%)
    3 / 57 (5.26%)
    8 / 395 (2.03%)
    6 / 198 (3.03%)
         occurrences all number
    13
    3
    8
    6
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 391 (0.51%)
    4 / 57 (7.02%)
    2 / 395 (0.51%)
    0 / 198 (0.00%)
         occurrences all number
    2
    6
    2
    0
    Headache
         subjects affected / exposed
    54 / 391 (13.81%)
    10 / 57 (17.54%)
    34 / 395 (8.61%)
    26 / 198 (13.13%)
         occurrences all number
    63
    17
    39
    32
    Dizziness
         subjects affected / exposed
    32 / 391 (8.18%)
    7 / 57 (12.28%)
    24 / 395 (6.08%)
    15 / 198 (7.58%)
         occurrences all number
    39
    7
    24
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    53 / 391 (13.55%)
    13 / 57 (22.81%)
    53 / 395 (13.42%)
    35 / 198 (17.68%)
         occurrences all number
    65
    15
    69
    44
    Eye disorders
    Vision blurred
         subjects affected / exposed
    10 / 391 (2.56%)
    3 / 57 (5.26%)
    5 / 395 (1.27%)
    6 / 198 (3.03%)
         occurrences all number
    11
    3
    5
    6
    Dry eye
         subjects affected / exposed
    7 / 391 (1.79%)
    4 / 57 (7.02%)
    4 / 395 (1.01%)
    1 / 198 (0.51%)
         occurrences all number
    9
    4
    4
    1
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    13 / 391 (3.32%)
    4 / 57 (7.02%)
    3 / 395 (0.76%)
    1 / 198 (0.51%)
         occurrences all number
    15
    6
    3
    1
    Dysphagia
         subjects affected / exposed
    12 / 391 (3.07%)
    3 / 57 (5.26%)
    11 / 395 (2.78%)
    4 / 198 (2.02%)
         occurrences all number
    12
    3
    12
    4
    Dry mouth
         subjects affected / exposed
    20 / 391 (5.12%)
    3 / 57 (5.26%)
    12 / 395 (3.04%)
    4 / 198 (2.02%)
         occurrences all number
    20
    3
    12
    4
    Diarrhoea
         subjects affected / exposed
    122 / 391 (31.20%)
    23 / 57 (40.35%)
    80 / 395 (20.25%)
    48 / 198 (24.24%)
         occurrences all number
    217
    39
    118
    58
    Constipation
         subjects affected / exposed
    69 / 391 (17.65%)
    11 / 57 (19.30%)
    53 / 395 (13.42%)
    26 / 198 (13.13%)
         occurrences all number
    81
    12
    60
    28
    Colitis
         subjects affected / exposed
    9 / 391 (2.30%)
    4 / 57 (7.02%)
    3 / 395 (0.76%)
    7 / 198 (3.54%)
         occurrences all number
    9
    4
    4
    9
    Abdominal pain
         subjects affected / exposed
    33 / 391 (8.44%)
    7 / 57 (12.28%)
    21 / 395 (5.32%)
    5 / 198 (2.53%)
         occurrences all number
    40
    11
    26
    7
    Nausea
         subjects affected / exposed
    97 / 391 (24.81%)
    25 / 57 (43.86%)
    65 / 395 (16.46%)
    40 / 198 (20.20%)
         occurrences all number
    124
    34
    80
    51
    Vomiting
         subjects affected / exposed
    63 / 391 (16.11%)
    11 / 57 (19.30%)
    52 / 395 (13.16%)
    18 / 198 (9.09%)
         occurrences all number
    94
    16
    61
    25
    Oral pain
         subjects affected / exposed
    1 / 391 (0.26%)
    3 / 57 (5.26%)
    0 / 395 (0.00%)
    0 / 198 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    59 / 391 (15.09%)
    5 / 57 (8.77%)
    52 / 395 (13.16%)
    31 / 198 (15.66%)
         occurrences all number
    81
    9
    73
    45
    Pruritus
         subjects affected / exposed
    82 / 391 (20.97%)
    16 / 57 (28.07%)
    79 / 395 (20.00%)
    32 / 198 (16.16%)
         occurrences all number
    123
    22
    103
    39
    Erythema
         subjects affected / exposed
    10 / 391 (2.56%)
    0 / 57 (0.00%)
    20 / 395 (5.06%)
    6 / 198 (3.03%)
         occurrences all number
    12
    0
    25
    7
    Dry skin
         subjects affected / exposed
    29 / 391 (7.42%)
    2 / 57 (3.51%)
    24 / 395 (6.08%)
    9 / 198 (4.55%)
         occurrences all number
    30
    2
    27
    9
    Rash maculo-papular
         subjects affected / exposed
    30 / 391 (7.67%)
    10 / 57 (17.54%)
    16 / 395 (4.05%)
    6 / 198 (3.03%)
         occurrences all number
    39
    14
    22
    9
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    55 / 391 (14.07%)
    12 / 57 (21.05%)
    45 / 395 (11.39%)
    14 / 198 (7.07%)
         occurrences all number
    60
    13
    50
    17
    Hyperthyroidism
         subjects affected / exposed
    31 / 391 (7.93%)
    5 / 57 (8.77%)
    35 / 395 (8.86%)
    17 / 198 (8.59%)
         occurrences all number
    33
    5
    38
    17
    Adrenal insufficiency
         subjects affected / exposed
    9 / 391 (2.30%)
    4 / 57 (7.02%)
    7 / 395 (1.77%)
    4 / 198 (2.02%)
         occurrences all number
    9
    4
    7
    4
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    30 / 391 (7.67%)
    9 / 57 (15.79%)
    27 / 395 (6.84%)
    7 / 198 (3.54%)
         occurrences all number
    31
    9
    30
    9
    Myalgia
         subjects affected / exposed
    19 / 391 (4.86%)
    4 / 57 (7.02%)
    15 / 395 (3.80%)
    3 / 198 (1.52%)
         occurrences all number
    21
    6
    19
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    12 / 391 (3.07%)
    7 / 57 (12.28%)
    7 / 395 (1.77%)
    1 / 198 (0.51%)
         occurrences all number
    13
    8
    8
    3
    Muscular weakness
         subjects affected / exposed
    14 / 391 (3.58%)
    5 / 57 (8.77%)
    15 / 395 (3.80%)
    5 / 198 (2.53%)
         occurrences all number
    16
    5
    15
    5
    Back pain
         subjects affected / exposed
    51 / 391 (13.04%)
    9 / 57 (15.79%)
    47 / 395 (11.90%)
    15 / 198 (7.58%)
         occurrences all number
    57
    10
    52
    15
    Arthritis
         subjects affected / exposed
    6 / 391 (1.53%)
    3 / 57 (5.26%)
    3 / 395 (0.76%)
    7 / 198 (3.54%)
         occurrences all number
    6
    3
    6
    7
    Arthralgia
         subjects affected / exposed
    63 / 391 (16.11%)
    9 / 57 (15.79%)
    44 / 395 (11.14%)
    25 / 198 (12.63%)
         occurrences all number
    76
    11
    50
    27
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    24 / 391 (6.14%)
    4 / 57 (7.02%)
    11 / 395 (2.78%)
    7 / 198 (3.54%)
         occurrences all number
    30
    4
    15
    8
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 391 (5.88%)
    6 / 57 (10.53%)
    23 / 395 (5.82%)
    6 / 198 (3.03%)
         occurrences all number
    33
    7
    25
    8
    Pneumonia
         subjects affected / exposed
    23 / 391 (5.88%)
    4 / 57 (7.02%)
    17 / 395 (4.30%)
    15 / 198 (7.58%)
         occurrences all number
    25
    6
    17
    15
    Nasopharyngitis
         subjects affected / exposed
    29 / 391 (7.42%)
    0 / 57 (0.00%)
    14 / 395 (3.54%)
    10 / 198 (5.05%)
         occurrences all number
    36
    0
    20
    11
    Bronchitis
         subjects affected / exposed
    18 / 391 (4.60%)
    4 / 57 (7.02%)
    23 / 395 (5.82%)
    8 / 198 (4.04%)
         occurrences all number
    21
    4
    25
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    96 / 391 (24.55%)
    22 / 57 (38.60%)
    83 / 395 (21.01%)
    38 / 198 (19.19%)
         occurrences all number
    115
    27
    94
    46
    Dehydration
         subjects affected / exposed
    26 / 391 (6.65%)
    12 / 57 (21.05%)
    12 / 395 (3.04%)
    6 / 198 (3.03%)
         occurrences all number
    31
    12
    13
    8
    Hyperglycaemia
         subjects affected / exposed
    12 / 391 (3.07%)
    8 / 57 (14.04%)
    21 / 395 (5.32%)
    11 / 198 (5.56%)
         occurrences all number
    15
    9
    24
    11
    Hypoalbuminaemia
         subjects affected / exposed
    8 / 391 (2.05%)
    8 / 57 (14.04%)
    8 / 395 (2.03%)
    4 / 198 (2.02%)
         occurrences all number
    12
    10
    10
    6
    Hypocalcaemia
         subjects affected / exposed
    11 / 391 (2.81%)
    3 / 57 (5.26%)
    9 / 395 (2.28%)
    7 / 198 (3.54%)
         occurrences all number
    17
    3
    10
    7
    Hypokalaemia
         subjects affected / exposed
    31 / 391 (7.93%)
    18 / 57 (31.58%)
    24 / 395 (6.08%)
    12 / 198 (6.06%)
         occurrences all number
    56
    25
    28
    15
    Hypomagnesaemia
         subjects affected / exposed
    12 / 391 (3.07%)
    6 / 57 (10.53%)
    4 / 395 (1.01%)
    4 / 198 (2.02%)
         occurrences all number
    16
    6
    4
    5
    Hyponatraemia
         subjects affected / exposed
    18 / 391 (4.60%)
    12 / 57 (21.05%)
    29 / 395 (7.34%)
    13 / 198 (6.57%)
         occurrences all number
    24
    17
    34
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2016
    Management Algorithms updated
    09 Nov 2016
    Study design and exclusion criteria updated
    27 Jul 2017
    Study design and new study personnel updated
    25 Oct 2017
    Study design updated
    04 Jun 2018
    Endpoints for Cohort C updated
    02 Jul 2019
    Updated FACT-L collection during survival follow-up

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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