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    Clinical Trial Results:
    A Phase III Randomized, Open-label, Multi-center, Global Study of MEDI4736 in Combination with Tremelimumab versus Standard of Care (EXTREME) in the Treatment of First-line Recurrent or Metastatic Squamous Cell Head and Neck Cancer Patients

    Summary
    EudraCT number
    		 2015-003589-10
    Trial protocol
    		 SK   GR   DE   GB   ES   BE   PL   AT   RO   FR   PT   BG   IT  
    Global end of trial date
    06 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Feb 2022
    First version publication date
    05 Feb 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D419LC00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02551159
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca Clinical Study Information Center
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, 1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, 1 8772409479, information.center@astrazeneca.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
    06 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of MEDI4736 monotherapy compared to Standard of Care (SoC) in terms of Overall Survival (OS)
    Protection of trial subjects
    Patients given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 101
    Country: Number of subjects enrolled
    United States: 62
    Country: Number of subjects enrolled
    Ukraine: 61
    Country: Number of subjects enrolled
    France: 58
    Country: Number of subjects enrolled
    Korea, Republic of: 54
    Country: Number of subjects enrolled
    Japan: 52
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    Taiwan: 48
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Canada: 38
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Brazil: 29
    Country: Number of subjects enrolled
    Greece: 26
    Country: Number of subjects enrolled
    India: 23
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Austria: 12
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    Thailand: 12
    Country: Number of subjects enrolled
    Viet Nam: 8
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    Philippines: 2
    Worldwide total number of subjects
    823
    EEA total number of subjects
    301
    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)
    530
    From 65 to 84 years
    290
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients meeting all the eligibility criteria were randomized 2:1:1 to durvalumab plus tremelimumab combination therapy, durvalumab monotherapy or standard of care.

    Pre-assignment
    Screening details
    		 All screening/baseline procedures must be performed within 28 days before the first dose of treatment (Days -28 to -1)

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Durvalumab + tremelimumab
    Arm description
    		 tremelimumab (75 mg) via IV infusion every 4 weeks for a maximum of 4 doses, and durvalumab (1500 mg) via IV infusion every 4 weeks until disease progression
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/mL, solution, IV

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/mL, solution, IV

    Arm title
    		 Durvalumab
    Arm description
    		 durvalumab (1500 mg) via IV infusion every 4 weeks until disease progression
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/mL, solution, IV

    Arm title
    		 Standard of Care (SOC)
    Arm description
    		 either cisplatin (at a dose of 100 mg/m2 of body surface area as an IV infusion) or carboplatin (at an area under the concentration curve of 5 mg/mL/min as an IV infusion) on Day 1 of up to six 3-week cycles, and an infusion of 5-fluorouracil (5FU) (at a dose of 1000 mg/m2/day on Days 1 through 4) every 3 weeks, along with 400 mg/m2 of cetuximab on Cycle 1 Day 1 and 250 mg/m2 weekly for up to 6 cycles and maintenance cetuximab at 250 mg/m2 administered via IV infusion weekly thereafter in patients who achieved stable disease (SD) or better upon completion of chemotherapy until disease progression, toxicity, or withdrawal of consent
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV (as sourced locally)

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV (as sourced locally)

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Intravesical solution/solution for injection, Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV (as sourced locally)

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV (as sourced locally)

    Number of subjects in period 1
    		Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Started
    413
    204
    206
    Full analysis set
    413
    204
    206
    Safety analysis set
    408
    202
    196
    PD-L1 TC/IC high subgroup analysis set
    190
    99
    94
    Completed
    0
    0
    0
    Not completed
    413
    204
    206
         Adverse event, serious fatal
    352
    174
    161
         Consent withdrawn by subject
    8
    5
    16
         Patients alive or lost to follow-up at DCO
    53
    25
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Durvalumab + tremelimumab
    Reporting group description
    		 tremelimumab (75 mg) via IV infusion every 4 weeks for a maximum of 4 doses, and durvalumab (1500 mg) via IV infusion every 4 weeks until disease progression

    Reporting group title
    Durvalumab
    Reporting group description
    		 durvalumab (1500 mg) via IV infusion every 4 weeks until disease progression

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 either cisplatin (at a dose of 100 mg/m2 of body surface area as an IV infusion) or carboplatin (at an area under the concentration curve of 5 mg/mL/min as an IV infusion) on Day 1 of up to six 3-week cycles, and an infusion of 5-fluorouracil (5FU) (at a dose of 1000 mg/m2/day on Days 1 through 4) every 3 weeks, along with 400 mg/m2 of cetuximab on Cycle 1 Day 1 and 250 mg/m2 weekly for up to 6 cycles and maintenance cetuximab at 250 mg/m2 administered via IV infusion weekly thereafter in patients who achieved stable disease (SD) or better upon completion of chemotherapy until disease progression, toxicity, or withdrawal of consent

    Reporting group values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC) Total
    Number of subjects
    		 413 204 206 823
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 265 132 133 530
        From 65-84 years
    		 146 71 73 290
        85 years and over
    		 2 1 0 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.5 ( 9.56 ) 60.2 ( 10.41 ) 60.9 ( 9.45 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 73 29 32 134
        Male
    		 340 175 174 689
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 298 145 160 603
        Black or African American
    		 5 3 2 10
        Asian
    		 109 54 42 205
        Other
    		 0 2 2 4
        Missing
    		 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Durvalumab + tremelimumab
    Reporting group description
    		 tremelimumab (75 mg) via IV infusion every 4 weeks for a maximum of 4 doses, and durvalumab (1500 mg) via IV infusion every 4 weeks until disease progression

    Reporting group title
    Durvalumab
    Reporting group description
    		 durvalumab (1500 mg) via IV infusion every 4 weeks until disease progression

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 either cisplatin (at a dose of 100 mg/m2 of body surface area as an IV infusion) or carboplatin (at an area under the concentration curve of 5 mg/mL/min as an IV infusion) on Day 1 of up to six 3-week cycles, and an infusion of 5-fluorouracil (5FU) (at a dose of 1000 mg/m2/day on Days 1 through 4) every 3 weeks, along with 400 mg/m2 of cetuximab on Cycle 1 Day 1 and 250 mg/m2 weekly for up to 6 cycles and maintenance cetuximab at 250 mg/m2 administered via IV infusion weekly thereafter in patients who achieved stable disease (SD) or better upon completion of chemotherapy until disease progression, toxicity, or withdrawal of consent

    Primary: Overall Survival (OS) status in the PD-L1 TC/IC high subgroup - Durvalumab versus Standard of Care (SOC)

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    End point title
    		 Overall Survival (OS) status in the PD-L1 TC/IC high subgroup - Durvalumab versus Standard of Care (SOC)
    End point description
    Number of participants with Overall Survival (OS)
    End point type
    Primary
    End point timeframe
    From date of randomization until time of final analysis, an average of approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    190
    99
    94
    Units: Participants
        Death
    162
    84
    77
        Voluntary Discontinuation by subject
    1
    1
    3
        Alive or lost to follow up
    27
    14
    14
    Statistical analysis title
    		 Overall Survival (OS)
    Statistical analysis description
    Statistical analysis of number of deaths
    Comparison groups
    Durvalumab v Standard of Care (SOC)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.787 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.32
    Notes
    [1] - 2 sided

    Primary: Overall Survival (OS) median duration in the PD-L1 TC/IC high subgroup

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    End point title
    		 Overall Survival (OS) median duration in the PD-L1 TC/IC high subgroup [2]
    End point description
    Time from the date of randomization until death due to any cause (i.e., date of death or censoring – date of randomization + 1)
    End point type
    Primary
    End point timeframe
    From date of randomization until time of final analysis, an average of approximately 4 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The median duration of OS is presented with the associated 95% confidence interval, no further statistical analyses were performed.
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    190
    99
    94
    Units: Months
        median (confidence interval 95%)
    11.2 (9.5 to 13.9)
    10.9 (9.0 to 14.3)
    10.9 (8.3 to 13.4)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) status in the PD-L1 TC/IC high subgroup - Durvalumab + tremelimumab versus Standard of Care (SOC)

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    End point title
    		 Overall Survival (OS) status in the PD-L1 TC/IC high subgroup - Durvalumab + tremelimumab versus Standard of Care (SOC)
    End point description
    Number of participants with Overall Survival (OS)
    End point type
    Secondary
    End point timeframe
    From date of randomization until time of final analysis, an average of approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    190
    99
    94
    Units: Participants
        Died
    162
    84
    77
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    Durvalumab + tremelimumab v Standard of Care (SOC)
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.634 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.39
    Notes
    [3] - 2 sided

    Secondary: Percentage of patients alive at 12, 18 and 24 months in the PD-L1 TC/IC high subgroup

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    End point title
    		 Percentage of patients alive at 12, 18 and 24 months in the PD-L1 TC/IC high subgroup
    End point description
    Percentage of patients alive
    End point type
    Secondary
    End point timeframe
    12, 18 and 24 months after randomization
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    190
    99
    94
    Units: % of participants
    number (confidence interval 95%)
        at 12 months
    49.3 (42.0 to 56.2)
    48.0 (37.8 to 57.4)
    44.0 (33.6 to 53.8)
        at 18 months
    31.8 (25.3 to 38.5)
    34.7 (25.5 to 44.1)
    30.8 (21.6 to 40.4)
        at 24 months
    23.9 (18.0 to 30.1)
    27.6 (19.2 to 36.6)
    26.4 (17.8 to 35.7)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the PD-L1 TC/IC high subgroup

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    End point title
    		 Progression Free Survival (PFS) in the PD-L1 TC/IC high subgroup
    End point description
    Time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined using Response Evaluation Criteria in Solid Tumours criteria (RECIST v1.1), as ≥20% increase in the sum of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
    End point type
    Secondary
    End point timeframe
    Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    190
    99
    94
    Units: Months
        median (confidence interval 95%)
    2.8 (2.6 to 3.3)
    2.8 (1.7 to 4.2)
    5.3 (4.3 to 5.8)
    Statistical analysis title
    		 Progression Free Survival
    Comparison groups
    Durvalumab + tremelimumab v Standard of Care (SOC)
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.028 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.76
    Notes
    [4] - 2 sided
    Statistical analysis title
    		 Progression Free Survival
    Comparison groups
    Durvalumab v Standard of Care (SOC)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.287 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.8
    Notes
    [5] - 2 sided

    Secondary: Objective Response Rate (ORR) in the PD-L1 TC/IC high subgroup

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    End point title
    		 Objective Response Rate (ORR) in the PD-L1 TC/IC high subgroup
    End point description
    Number (%) of patients with at least 1 visit response of complete response (CR) or partial response (PR). Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions (TL) and assessed by MRI or CT: CR: Disappearance of all TLs since baseline; PR: >= 30% decrease in the sum of diameters of TLs; Overall Response (OR = CR + PR)
    End point type
    Secondary
    End point timeframe
    Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    190
    99
    94
    Units: Participants
        Response
    48
    16
    47
        No response
    142
    83
    47
    Statistical analysis title
    		 Objective Response Rate
    Statistical analysis description
    Statistical analysis of number with a response
    Comparison groups
    Durvalumab + tremelimumab v Standard of Care (SOC)
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.57
    Notes
    [6] - 2 sided
    Statistical analysis title
    		 Objective Response Rate
    Statistical analysis description
    Statistical analysis of number with a response
    Comparison groups
    Durvalumab v Standard of Care (SOC)
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.37
    Notes
    [7] - 2 sided

    Secondary: Duration of Response (DoR) in the PD-L1 TC/IC high subgroup

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    End point title
    		 Duration of Response (DoR) in the PD-L1 TC/IC high subgroup
    End point description
    Time from the date of first documented response until the first date of documented progression or death in the absence of disease progression
    End point type
    Secondary
    End point timeframe
    Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    48
    16 [8]
    47
    Units: Months
        median (confidence interval 95%)
    6.5 (4.5 to 16.1)
    12.3 (5.6 to 99999999999)
    4.2 (3.0 to 5.7)
    Notes
    [8] - Upper confidence limit was not calculable due to insufficient participants with events.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) status in the all-comers (Full analysis set)

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    End point title
    		 Overall Survival (OS) status in the all-comers (Full analysis set)
    End point description
    Number of participants with Overall Survival (OS)
    End point type
    Secondary
    End point timeframe
    From date of randomization until time of final analysis, an average of approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    413
    204
    206
    Units: Participants
        Death
    356
    176
    171
        Voluntary Discontinuation by subject
    4
    3
    6
        Alive or lost to follow up
    53
    25
    29
    Statistical analysis title
    		 Overall Survival
    Statistical analysis description
    Statistical analysis of number of deaths
    Comparison groups
    Durvalumab v Standard of Care (SOC)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.811 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.27
    Notes
    [9] - 2 sided
    Statistical analysis title
    		 Overall Survival
    Statistical analysis description
    Statistical analysis of number of deaths
    Comparison groups
    Durvalumab + tremelimumab v Standard of Care (SOC)
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.624
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.25

    Secondary: Overall Survival (OS) median duration in the all-comers (Full analysis set)

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    End point title
    		 Overall Survival (OS) median duration in the all-comers (Full analysis set)
    End point description
    Time from the date of randomization until death due to any cause (i.e., date of death or censoring – date of randomization + 1)
    End point type
    Secondary
    End point timeframe
    From date of randomization until time of final analysis, an average of approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    413
    204
    206
    Units: Months
        median (confidence interval 95%)
    10.7 (9.6 to 12.2)
    9.9 (8.9 to 11.9)
    10.3 (9.0 to 12.1)
    No statistical analyses for this end point

    Secondary: Percentage of patients alive at 12, 18 and 24 months in the all-comers (Full analysis set)

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    End point title
    		 Percentage of patients alive at 12, 18 and 24 months in the all-comers (Full analysis set)
    End point description
    Percentage of patients alive
    End point type
    Secondary
    End point timeframe
    12, 18 and 24 months after randomization
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    413
    204
    206
    Units: % of participants
    number (confidence interval 95%)
        at 12 months
    46.5 (41.6 to 51.2)
    42.8 (35.9 to 49.5)
    43.8 (36.8 to 50.5)
        at 18 months
    30.7 (26.3 to 35.2)
    31.2 (24.9 to 37.7)
    29.7 (23.5 to 36.1)
        at 24 months
    22.9 (18.9 to 27.0)
    24.7 (18.9 to 30.8)
    23.2 (17.6 to 29.2)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) in the all-comers (Full analysis set)

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    End point title
    		 Progression Free Survival (PFS) in the all-comers (Full analysis set)
    End point description
    Time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined using Response Evaluation Criteria in Solid Tumours criteria (RECIST v1.1), as ≥20% increase in the sum of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
    End point type
    Secondary
    End point timeframe
    Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    413
    204
    206
    Units: Months
        median (confidence interval 95%)
    2.8 (2.6 to 2.9)
    2.8 (2.0 to 2.8)
    5.4 (4.4 to 5.7)
    Statistical analysis title
    		 Progression Free Survival
    Comparison groups
    Durvalumab v Standard of Care (SOC)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.006 [10]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.68
    Notes
    [10] - 2 sided
    Statistical analysis title
    		 Progression Free Survival
    Comparison groups
    Durvalumab + tremelimumab v Standard of Care (SOC)
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.008 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 1.53
    Notes
    [11] - 2 sided

    Secondary: Objective Response Rate (ORR) in the all-comers (Full analysis set)

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    End point title
    		 Objective Response Rate (ORR) in the all-comers (Full analysis set)
    End point description
    Number (%) of patients with at least 1 visit response of complete response (CR) or partial response (PR). Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions (TL) and assessed by MRI or CT: CR: Disappearance of all TLs since baseline; PR: >= 30% decrease in the sum of diameters of TLs; Overall Response (OR = CR + PR)
    End point type
    Secondary
    End point timeframe
    Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    413
    204
    206
    Units: Participants
        Response
    90
    35
    101
        No response
    323
    169
    105
    Statistical analysis title
    		 Objective Response Rate
    Comparison groups
    Durvalumab + tremelimumab v Standard of Care (SOC)
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.41
    Notes
    [12] - 2 sided
    Statistical analysis title
    		 Objective Response Rate
    Comparison groups
    Durvalumab v Standard of Care (SOC)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [13]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.33
    Notes
    [13] - 2 sided

    Secondary: Duration of Response (DoR) in the all-comers (Full analysis set)

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    End point title
    		 Duration of Response (DoR) in the all-comers (Full analysis set)
    End point description
    Time from the date of first documented response until the first date of documented progression or death in the absence of disease progression
    End point type
    Secondary
    End point timeframe
    Tumor assessments (per RECIST 1.1) every 6 weeks for the first 24 weeks relative to the date of randomization and then every 8 weeks thereafter, up to approximately 4 years
    End point values
    		 Durvalumab + tremelimumab Durvalumab Standard of Care (SOC)
    Number of subjects analysed
    90
    35
    101
    Units: Months
        median (confidence interval 95%)
    9.2 (6.0 to 19.6)
    11.9 (4.6 to 17.8)
    4.2 (3.7 to 4.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Durvalumab + tremelimumab
    Reporting group description
    		 Durvalumab + tremelimumab

    Reporting group title
    Durvalamab
    Reporting group description
    		 Durvalamab

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 Standard of Care (SOC)

    Serious adverse events
    		 Durvalumab + tremelimumab Durvalamab Standard of Care (SOC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    168 / 408 (41.18%)
    78 / 202 (38.61%)
    94 / 196 (47.96%)
         number of deaths (all causes)
    352
    174
    161
         number of deaths resulting from adverse events
    38
    21
    21
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Infected neoplasm
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    5 / 408 (1.23%)
    7 / 202 (3.47%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 7
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    3 / 408 (0.74%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 408 (0.49%)
    4 / 202 (1.98%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    1 / 4
    0 / 2
    Malaise
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    4 / 196 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    1 / 408 (0.25%)
    3 / 202 (1.49%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 408 (0.74%)
    2 / 202 (0.99%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Oedema
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 408 (1.47%)
    3 / 202 (1.49%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue inflammation
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    3 / 408 (0.74%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    3 / 196 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 408 (0.25%)
    3 / 202 (1.49%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Bronchospasm
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 408 (0.98%)
    3 / 202 (1.49%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 408 (0.49%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    5 / 408 (1.23%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    5 / 408 (1.23%)
    1 / 202 (0.50%)
    4 / 196 (2.04%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    Pneumonitis
         subjects affected / exposed
    7 / 408 (1.72%)
    2 / 202 (0.99%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    9 / 9
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    5 / 196 (2.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper airway obstruction
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    3 / 408 (0.74%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Carbon monoxide poisoning
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Fall
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrostomy failure
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Femoral neck fracture
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    3 / 408 (0.74%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    3 / 408 (0.74%)
    0 / 202 (0.00%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 408 (0.00%)
    2 / 202 (0.99%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 408 (0.25%)
    2 / 202 (0.99%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    3 / 196 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    3 / 196 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    3 / 196 (1.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    5 / 196 (2.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    8 / 196 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    4 / 196 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph node haemorrhage
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    5 / 196 (2.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    4 / 408 (0.98%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    9 / 408 (2.21%)
    2 / 202 (0.99%)
    4 / 196 (2.04%)
         occurrences causally related to treatment / all
    8 / 14
    1 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 408 (0.00%)
    2 / 202 (0.99%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    6 / 408 (1.47%)
    1 / 202 (0.50%)
    5 / 196 (2.55%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Haematemesis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 408 (1.23%)
    0 / 202 (0.00%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue oedema
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    8 / 408 (1.96%)
    1 / 202 (0.50%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    2 / 12
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    3 / 408 (0.74%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal failure
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 408 (0.00%)
    2 / 202 (0.99%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 408 (0.49%)
    1 / 202 (0.50%)
    3 / 196 (1.53%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Renal failure
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    3 / 196 (1.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Autoimmune myositis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Oral infection
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 408 (0.49%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    5 / 408 (1.23%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 408 (0.98%)
    1 / 202 (0.50%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal infection
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    32 / 408 (7.84%)
    14 / 202 (6.93%)
    13 / 196 (6.63%)
         occurrences causally related to treatment / all
    3 / 33
    1 / 14
    1 / 13
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    0 / 4
    Pneumonia staphylococcal
         subjects affected / exposed
    2 / 408 (0.49%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    5 / 408 (1.23%)
    2 / 202 (0.99%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    5 / 408 (1.23%)
    1 / 202 (0.50%)
    4 / 196 (2.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    1 / 1
    Septic shock
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Skin infection
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 408 (0.74%)
    0 / 202 (0.00%)
    3 / 196 (1.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 408 (0.25%)
    1 / 202 (0.50%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 408 (0.00%)
    0 / 202 (0.00%)
    2 / 196 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 408 (0.74%)
    0 / 202 (0.00%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    1 / 196 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    0 / 196 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Durvalumab + tremelimumab Durvalamab Standard of Care (SOC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    317 / 408 (77.70%)
    153 / 202 (75.74%)
    182 / 196 (92.86%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    11 / 408 (2.70%)
    5 / 202 (2.48%)
    11 / 196 (5.61%)
         occurrences all number
    15
    5
    16
    Hypertension
         subjects affected / exposed
    27 / 408 (6.62%)
    9 / 202 (4.46%)
    11 / 196 (5.61%)
         occurrences all number
    36
    10
    19
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    52 / 408 (12.75%)
    18 / 202 (8.91%)
    38 / 196 (19.39%)
         occurrences all number
    60
    23
    61
    Fatigue
         subjects affected / exposed
    66 / 408 (16.18%)
    35 / 202 (17.33%)
    56 / 196 (28.57%)
         occurrences all number
    74
    41
    68
    Mucosal inflammation
         subjects affected / exposed
    15 / 408 (3.68%)
    6 / 202 (2.97%)
    43 / 196 (21.94%)
         occurrences all number
    16
    8
    58
    Pyrexia
         subjects affected / exposed
    48 / 408 (11.76%)
    12 / 202 (5.94%)
    21 / 196 (10.71%)
         occurrences all number
    54
    13
    33
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    44 / 408 (10.78%)
    14 / 202 (6.93%)
    13 / 196 (6.63%)
         occurrences all number
    47
    14
    15
    Dyspnoea
         subjects affected / exposed
    34 / 408 (8.33%)
    5 / 202 (2.48%)
    18 / 196 (9.18%)
         occurrences all number
    40
    5
    21
    Productive cough
         subjects affected / exposed
    19 / 408 (4.66%)
    12 / 202 (5.94%)
    5 / 196 (2.55%)
         occurrences all number
    22
    12
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 408 (7.11%)
    8 / 202 (3.96%)
    11 / 196 (5.61%)
         occurrences all number
    31
    9
    11
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    27 / 408 (6.62%)
    8 / 202 (3.96%)
    11 / 196 (5.61%)
         occurrences all number
    37
    10
    14
    Neutrophil count decreased
         subjects affected / exposed
    0 / 408 (0.00%)
    1 / 202 (0.50%)
    24 / 196 (12.24%)
         occurrences all number
    0
    1
    36
    Lipase increased
         subjects affected / exposed
    21 / 408 (5.15%)
    5 / 202 (2.48%)
    2 / 196 (1.02%)
         occurrences all number
    27
    8
    2
    Platelet count decreased
         subjects affected / exposed
    5 / 408 (1.23%)
    1 / 202 (0.50%)
    22 / 196 (11.22%)
         occurrences all number
    5
    1
    47
    Weight decreased
         subjects affected / exposed
    39 / 408 (9.56%)
    13 / 202 (6.44%)
    26 / 196 (13.27%)
         occurrences all number
    42
    15
    32
    Alanine aminotransferase increased
         subjects affected / exposed
    23 / 408 (5.64%)
    6 / 202 (2.97%)
    14 / 196 (7.14%)
         occurrences all number
    26
    6
    18
    Blood creatinine increased
         subjects affected / exposed
    15 / 408 (3.68%)
    3 / 202 (1.49%)
    12 / 196 (6.12%)
         occurrences all number
    20
    4
    19
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 408 (3.68%)
    7 / 202 (3.47%)
    14 / 196 (7.14%)
         occurrences all number
    18
    7
    15
    Headache
         subjects affected / exposed
    29 / 408 (7.11%)
    11 / 202 (5.45%)
    13 / 196 (6.63%)
         occurrences all number
    35
    12
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    61 / 408 (14.95%)
    22 / 202 (10.89%)
    65 / 196 (33.16%)
         occurrences all number
    68
    26
    97
    Leukopenia
         subjects affected / exposed
    2 / 408 (0.49%)
    2 / 202 (0.99%)
    26 / 196 (13.27%)
         occurrences all number
    2
    3
    48
    Neutropenia
         subjects affected / exposed
    2 / 408 (0.49%)
    0 / 202 (0.00%)
    63 / 196 (32.14%)
         occurrences all number
    2
    0
    103
    Thrombocytopenia
         subjects affected / exposed
    6 / 408 (1.47%)
    0 / 202 (0.00%)
    39 / 196 (19.90%)
         occurrences all number
    24
    0
    76
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    59 / 408 (14.46%)
    24 / 202 (11.88%)
    54 / 196 (27.55%)
         occurrences all number
    72
    25
    68
    Diarrhoea
         subjects affected / exposed
    70 / 408 (17.16%)
    15 / 202 (7.43%)
    60 / 196 (30.61%)
         occurrences all number
    113
    20
    96
    Nausea
         subjects affected / exposed
    52 / 408 (12.75%)
    13 / 202 (6.44%)
    74 / 196 (37.76%)
         occurrences all number
    65
    14
    120
    Dysphagia
         subjects affected / exposed
    26 / 408 (6.37%)
    8 / 202 (3.96%)
    4 / 196 (2.04%)
         occurrences all number
    28
    9
    4
    Stomatitis
         subjects affected / exposed
    14 / 408 (3.43%)
    6 / 202 (2.97%)
    40 / 196 (20.41%)
         occurrences all number
    16
    6
    54
    Vomiting
         subjects affected / exposed
    34 / 408 (8.33%)
    8 / 202 (3.96%)
    39 / 196 (19.90%)
         occurrences all number
    52
    9
    66
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    2 / 408 (0.49%)
    2 / 202 (0.99%)
    36 / 196 (18.37%)
         occurrences all number
    2
    2
    50
    Alopecia
         subjects affected / exposed
    3 / 408 (0.74%)
    0 / 202 (0.00%)
    11 / 196 (5.61%)
         occurrences all number
    3
    0
    11
    Dry skin
         subjects affected / exposed
    23 / 408 (5.64%)
    4 / 202 (1.98%)
    26 / 196 (13.27%)
         occurrences all number
    24
    4
    34
    Rash
         subjects affected / exposed
    50 / 408 (12.25%)
    17 / 202 (8.42%)
    81 / 196 (41.33%)
         occurrences all number
    62
    17
    114
    Pruritus
         subjects affected / exposed
    45 / 408 (11.03%)
    11 / 202 (5.45%)
    17 / 196 (8.67%)
         occurrences all number
    61
    13
    18
    Skin fissures
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    18 / 196 (9.18%)
         occurrences all number
    1
    0
    23
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    23 / 408 (5.64%)
    6 / 202 (2.97%)
    0 / 196 (0.00%)
         occurrences all number
    30
    6
    0
    Hypothyroidism
         subjects affected / exposed
    68 / 408 (16.67%)
    21 / 202 (10.40%)
    7 / 196 (3.57%)
         occurrences all number
    79
    23
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    23 / 408 (5.64%)
    8 / 202 (3.96%)
    3 / 196 (1.53%)
         occurrences all number
    27
    8
    5
    Pain in extremity
         subjects affected / exposed
    5 / 408 (1.23%)
    5 / 202 (2.48%)
    10 / 196 (5.10%)
         occurrences all number
    6
    5
    10
    Infections and infestations
    Paronychia
         subjects affected / exposed
    1 / 408 (0.25%)
    0 / 202 (0.00%)
    21 / 196 (10.71%)
         occurrences all number
    1
    0
    24
    Pneumonia
         subjects affected / exposed
    19 / 408 (4.66%)
    7 / 202 (3.47%)
    10 / 196 (5.10%)
         occurrences all number
    22
    7
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    52 / 408 (12.75%)
    20 / 202 (9.90%)
    46 / 196 (23.47%)
         occurrences all number
    57
    22
    59
    Hypocalcaemia
         subjects affected / exposed
    7 / 408 (1.72%)
    0 / 202 (0.00%)
    16 / 196 (8.16%)
         occurrences all number
    7
    0
    27
    Hyponatraemia
         subjects affected / exposed
    26 / 408 (6.37%)
    2 / 202 (0.99%)
    11 / 196 (5.61%)
         occurrences all number
    30
    4
    14
    Hypomagnesaemia
         subjects affected / exposed
    11 / 408 (2.70%)
    3 / 202 (1.49%)
    45 / 196 (22.96%)
         occurrences all number
    11
    6
    77
    Dehydration
         subjects affected / exposed
    8 / 408 (1.96%)
    0 / 202 (0.00%)
    10 / 196 (5.10%)
         occurrences all number
    10
    0
    11
    Hyperglycaemia
         subjects affected / exposed
    29 / 408 (7.11%)
    6 / 202 (2.97%)
    8 / 196 (4.08%)
         occurrences all number
    37
    8
    10
    Hypokalaemia
         subjects affected / exposed
    21 / 408 (5.15%)
    6 / 202 (2.97%)
    22 / 196 (11.22%)
         occurrences all number
    26
    8
    42

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2016
    The text has been updated to reflect that BICR assessments according to RECIST 1.1 will be used instead of Investigator assessments to measure the co-primary objective of PFS and the secondary objectives of PFS, ORR, DoR, and APF12
    13 Feb 2018
    Change of Progression Free Survival from primary objective to secondary objective
    03 Oct 2018
    Change of Overall Survival in the all-comer population from primary objective to secondary objective
    25 Jan 2019
    Change of primary objective from MEDI4736 + tremelimumab combination therapy versus SoC in a biomarker-selected subgroup (PD-L1 TC/IC), to MEDI4736 monotherapy versus SoC in all randomized patients (all-comers) in terms of OS
    04 Oct 2019
    Change of primary objective from MEDI4736 monotherapy versus SoC in all randomized patients (all-comers) in terms of OS to MEDI4736 monotherapy versus SoC in patients who are at low risk of early mortality based on baseline characteristics in terms of OS
    29 Jun 2020
    Change of primary objective from MEDI4736 monotherapy versus Standard of Care (SoC) in patients who are at low risk of early mortality based on baseline laboratory values according to a model developed by AstraZeneca in terms of SoC,to MEDI4736 versus SoC in a biomarker-selected population (PD-L1 TC/IC high subgroup) in terms of overall survival (OS)

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

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