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    Clinical Trial Results:
    A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 Monotherapy and MEDI4736 in Combination with Tremelimumab Versus Standard of Care Therapy in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

    Summary
    EudraCT number
    		 2014-003863-40
    Trial protocol
    		 HU   CZ   BE   DE   ES   FR   PL   RO   HR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Feb 2021
    First version publication date
    06 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4193C00002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02369874
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Forskargatan 18, Sodertalje, Sweden,
    Public contact
    Nassim Morsli, AstraZeneca, +44 7384 520046, nassim.morsli@astrazeneca.com
    Scientific contact
    Nassim Morsli, AstraZeneca, +44 7384 520046, nassim.morsli@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
    Interim
    Date of interim/final analysis
    10 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of durvalumab + tremelimumab combination therapy versus standard of care (SoC) and durvalumab monotherapy versus SoC in terms of overall survival.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation/ Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Sep 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
    Japan: 65
    Country: Number of subjects enrolled
    United States: 40
    Country: Number of subjects enrolled
    Russian Federation: 95
    Country: Number of subjects enrolled
    France: 93
    Country: Number of subjects enrolled
    Spain: 69
    Country: Number of subjects enrolled
    Italy: 56
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Belgium: 43
    Country: Number of subjects enrolled
    Serbia: 27
    Country: Number of subjects enrolled
    Brazil: 18
    Country: Number of subjects enrolled
    Romania: 42
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Ukraine: 36
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Taiwan: 21
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Chile: 1
    Worldwide total number of subjects
    736
    EEA total number of subjects
    372
    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)
    514
    From 65 to 84 years
    222
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of the 1086 participants who enrolled and screened, 77 participants failed screening but were subsequently re-enrolled and re-screened. Of these 77, 56 were randomized and 21 failed re-screening. Overall, 736 patients were randomized to receive treatment with durvalumab + tremelimumab combination therapy, durvalumab monotherapy, or SoC therapy.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Durvalumab + Tremelimumab
    Arm description
    		 Participants received 20 mg/kg durvalumab and 1 mg/kg tremelimumab combination therapy via intravenous (IV) infusion every 4 weeks (q4w) for up to 16 weeks. 4 weeks after completion of combination therapy, participants received dosing with durvalumab 10 mg/kg monotherapy every 2 weeks (q2w) until disease progression (PD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg administered via intravenous (IV) infusion every 4 weeks (q4w) for 4 doses then 10 mg/kg via IV infusion q2w beginning 4 weeks after the last combination dose.

    Investigational medicinal product name
    Tremelimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 mg/kg administered via intravenous (IV) infusion every 4 weeks (q4w) for 4 doses (4 doses total).

    Arm title
    		 Durvalumab
    Arm description
    		 Participants received 10 mg/kg durvalumab via intravenous (IV) infusion every 2 weeks (q2w) until disease progression (PD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg administered via intravenous (IV) infusion every 2 weeks (q2w).

    Arm title
    		 Standard of Care (SoC)
    Arm description
    		 Participants received monotherapy with 1 of the following therapies at the investigator’s discretion until disease progression (PD): cetuximab, a taxane, methotrexate, or a fluoropyrimidine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m^2 administered via intravenous (IV) infusion on Day 0, then 250 mg/m^2 via IV infusion weekly thereafter.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m^2 administered via intravenous (IV) infusion weekly.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m^2 administered via intravenous (IV) infusion weekly.

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2400 mg/m^2 administered via intravenous (IV) infusion over 46 hours every 2 weeks.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m2 administered via intravenous (IV) infusion weekly per the institution’s SoC.

    Investigational medicinal product name
    Tegafur/Gimeracil/Oteracil
    Investigational medicinal product code
    TS-1
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    80 mg/m^2 administered orally once daily for 28 days followed by a 14-day rest.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg/m^2 administered orally twice daily for 7 days followed by a 7-day rest.

    Number of subjects in period 1
    		Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Started
    247
    240
    249
    Received Treatment
    246
    237
    240
    Completed
    203
    183
    188
    Not completed
    44
    57
    61
         Consent withdrawn by subject
    7
    9
    27
         Miscellaneous
    1
    1
    -
         Participant Ongoing
    34
    45
    32
         Lost to follow-up
    2
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Durvalumab + Tremelimumab
    Reporting group description
    		 Participants received 20 mg/kg durvalumab and 1 mg/kg tremelimumab combination therapy via intravenous (IV) infusion every 4 weeks (q4w) for up to 16 weeks. 4 weeks after completion of combination therapy, participants received dosing with durvalumab 10 mg/kg monotherapy every 2 weeks (q2w) until disease progression (PD).

    Reporting group title
    Durvalumab
    Reporting group description
    		 Participants received 10 mg/kg durvalumab via intravenous (IV) infusion every 2 weeks (q2w) until disease progression (PD).

    Reporting group title
    Standard of Care (SoC)
    Reporting group description
    		 Participants received monotherapy with 1 of the following therapies at the investigator’s discretion until disease progression (PD): cetuximab, a taxane, methotrexate, or a fluoropyrimidine.

    Reporting group values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC) Total
    Number of subjects
    		 247 240 249 736
    Age, Customized
    Units: Subjects
        < 65 Years
    		 174 169 171 514
        >= 65 - < 75 Years
    		 63 56 64 183
        >= 75 Years
    		 10 15 14 39
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.9 ( 9.14 ) 59.0 ( 10.07 ) 59.5 ( 10.37 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 38 38 42 118
        Male
    		 209 202 207 618
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 33 35 45 113
        Black Or African American
    		 1 0 3 4
        Other
    		 4 5 3 12
        White
    		 204 198 189 591
        Unknown or Not Reported
    		 5 2 9 16
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 16 15 13 44
        Not Hispanic or Latino
    		 226 223 229 678
        Unknown or Not Reported
    		 5 2 7 14

    End points

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    End points reporting groups
    Reporting group title
    Durvalumab + Tremelimumab
    Reporting group description
    		 Participants received 20 mg/kg durvalumab and 1 mg/kg tremelimumab combination therapy via intravenous (IV) infusion every 4 weeks (q4w) for up to 16 weeks. 4 weeks after completion of combination therapy, participants received dosing with durvalumab 10 mg/kg monotherapy every 2 weeks (q2w) until disease progression (PD).

    Reporting group title
    Durvalumab
    Reporting group description
    		 Participants received 10 mg/kg durvalumab via intravenous (IV) infusion every 2 weeks (q2w) until disease progression (PD).

    Reporting group title
    Standard of Care (SoC)
    Reporting group description
    		 Participants received monotherapy with 1 of the following therapies at the investigator’s discretion until disease progression (PD): cetuximab, a taxane, methotrexate, or a fluoropyrimidine.

    Primary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS is defined as the time from the date of randomization until death due to any cause. OS was analyzed for the full analysis set, regardless of programmed death-ligand 1 (PD-L1) status.
    End point type
    Primary
    End point timeframe
    September 2015 to September 2018 (36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    247
    240
    249
    Units: Months
        median (confidence interval 95%)
    6.5 (5.5 to 8.2)
    7.6 (6.1 to 9.8)
    8.3 (7.3 to 9.2)
    Statistical analysis title
    		 Combo therapy vs. SoC
    Comparison groups
    Durvalumab + Tremelimumab v Standard of Care (SoC)
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7624
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.26
    Statistical analysis title
    		 Mono therapy vs. SoC
    Comparison groups
    Durvalumab v Standard of Care (SoC)
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1993
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.08

    Secondary: Overall survival (OS) in PD-L1 negative participants

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    End point title
    		 Overall survival (OS) in PD-L1 negative participants
    End point description
    OS is defined as the time from the date of randomization until death due to any cause. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity.
    End point type
    Secondary
    End point timeframe
    September 2015 to September 2018 (36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    175
    172
    177
    Units: Months
        median (confidence interval 95%)
    7.8 (5.9 to 10.3)
    7.6 (6.2 to 9.5)
    8.0 (6.7 to 8.9)
    Statistical analysis title
    		 Combo therapy vs. SoC
    Comparison groups
    Durvalumab + Tremelimumab v Standard of Care (SoC)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.459
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.17
    Statistical analysis title
    		 Combo therapy vs. mono therapy
    Comparison groups
    Durvalumab + Tremelimumab v Durvalumab
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.36

    Secondary: Overall survival (OS) in PD-L1 positive participants

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    End point title
    		 Overall survival (OS) in PD-L1 positive participants
    End point description
    OS is defined as the time from the date of randomization until death due to any cause. PD-L1 positive was defined as ≥25% of tumor cells with membrane staining for PD-L1 at any intensity.
    End point type
    Secondary
    End point timeframe
    September 2015 to September 2018 (36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    72
    68
    72
    Units: Months
        median (confidence interval 95%)
    4.8 (3.3 to 6.4)
    9.8 (4.3 to 14.1)
    9.0 (6.8 to 9.2)
    Statistical analysis title
    		 Mono therapy vs. SoC
    Comparison groups
    Durvalumab v Standard of Care (SoC)
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.39

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization until the date of objective disease progression or death based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). Objective disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    September 2015 to September 2018 (36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    247
    240
    249
    Units: Months
        median (confidence interval 95%)
    2.0 (1.9 to 2.3)
    2.1 (1.9 to 3.0)
    3.7 (3.1 to 3.7)
    Statistical analysis title
    		 Combo therapy vs. SoC
    Comparison groups
    Durvalumab + Tremelimumab v Standard of Care (SoC)
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 1.33
    Statistical analysis title
    		 Mono therapy vs. SoC
    Comparison groups
    Durvalumab v Standard of Care (SoC)
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.25

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    The percentage of participants who experienced an objective response (complete response [CR] or partial response [PR]), based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Assessed at randomisation and every 8 weeks thereafter
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    247
    240
    249
    Units: Percentage of participants
        number (confidence interval 95%)
    18.2 (13.6 to 23.6)
    17.9 (13.3 to 23.4)
    17.3 (12.8 to 22.5)
    Statistical analysis title
    		 Combo therapy vs. SoC
    Comparison groups
    Durvalumab + Tremelimumab v Standard of Care (SoC)
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.7
    Statistical analysis title
    		 Mono therapy vs. SoC
    Comparison groups
    Durvalumab v Standard of Care (SoC)
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.68

    Secondary: Duration of response (DoR)

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    End point title
    		 Duration of response (DoR)
    End point description
    Median DoR, in months, based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A complete response was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A partial response was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. Values of 99999 represent N/A.
    End point type
    Secondary
    End point timeframe
    September 2015 to September 2018 (36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    45
    43
    43
    Units: Months
        median (inter-quartile range (Q1-Q3))
    7.4 (2.8 to 99999)
    12.9 (5.6 to 99999)
    3.7 (1.9 to 5.5)
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR)
    End point description
    6 Months: The percentage of participants who had a best objective response of complete response (CR) or partial response (PR) in the first 6 months or had demonstrated stable disease (SD) for a minimum interval of 24 weeks following randomization. 12 Months: The percentage of participants who had a best objective response of CR or PR within 12 months or had demonstrated SD for a minimum interval of 48 weeks following randomization. Objective response was based on investigator assessments, according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Baseline up to 6 months; baseline up to 12 months
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    247
    240
    249
    Units: Percentage of participants
    number (not applicable)
        6 Months
    25.1
    24.2
    24.9
        12 Months
    20.6
    18.8
    18.9
    Statistical analysis title
    		 Combo therapy vs. SoC
    Statistical analysis description
    6 Month analysis
    Comparison groups
    Durvalumab + Tremelimumab v Standard of Care (SoC)
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.52
    Statistical analysis title
    		 Mono therapy vs. SoC
    Statistical analysis description
    6 Month analysis
    Comparison groups
    Durvalumab v Standard of Care (SoC)
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.46
    Statistical analysis title
    		 Combo therapy vs. SoC
    Statistical analysis description
    12 Month analysis
    Comparison groups
    Durvalumab + Tremelimumab v Standard of Care (SoC)
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.75
    Statistical analysis title
    		 Mono therapy vs. SoC
    Statistical analysis description
    12 Month analysis
    Comparison groups
    Durvalumab v Standard of Care (SoC)
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.57

    Secondary: Percentage of participants alive and progression free (APF)

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    End point title
    		 Percentage of participants alive and progression free (APF)
    End point description
    APF is defined as the percentage of participants who are alive and progression free at 6 months and 12 months after randomization. Estimates of progression free survival were based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). Objective disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    Baseline up to 6 months; baseline up to 12 months
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    247
    240
    249
    Units: Percentage of participants
    number (confidence interval 95%)
        6 Months
    22.5 (17.4 to 28.0)
    25.1 (19.7 to 30.9)
    23.3 (17.8 to 29.3)
        12 Months
    11.0 (7.4 to 15.5)
    14.4 (10.1 to 19.5)
    5.7 (2.8 to 10.2)
    No statistical analyses for this end point

    Secondary: Percentage of participants alive

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    End point title
    		 Percentage of participants alive
    End point description
    Percentage of participants alive at 12, 18 and 24 months using a Kaplan Meier estimate.
    End point type
    Secondary
    End point timeframe
    12, 18 and 24 months
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    247
    240
    249
    Units: Percentage of participants
    number (confidence interval 95%)
        12 Months
    30.4 (24.7 to 36.3)
    37.0 (30.9 to 43.1)
    30.5 (24.7 to 36.4)
        18 Months
    21.0 (15.9 to 26.5)
    25.4 (19.9 to 31.3)
    17.8 (13.1 to 23.2)
        24 Months
    13.3 (8.9 to 18.6)
    18.4 (13.3 to 24.1)
    10.3 (5.7 to 16.5)
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) in PD-L1 negative participants

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    End point title
    		 Progression free survival (PFS) in PD-L1 negative participants
    End point description
    Number of participants with confirmed objective disease progression (PD) at the time of the participant's last evaluable response evaluation criteria in solid tumors 1.1 (RECIST1.1) assessment. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity.
    End point type
    Secondary
    End point timeframe
    September 2015 to September 2018 (36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    175
    172
    177
    Units: Participants
    154
    151
    144
    Statistical analysis title
    		 Combo therapy vs. mono therapy
    Comparison groups
    Durvalumab + Tremelimumab v Durvalumab
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.21

    Secondary: Objective response rate (ORR) in PD-L1 negative participants

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    End point title
    		 Objective response rate (ORR) in PD-L1 negative participants
    End point description
    The percentage of PD-L1 negative participants who experienced an objective response (complete response [CR] or partial response [PR]), based on investigator assessments according to response evaluation criteria in solid tumors 1.1 (RECIST1.1). A CR was defined as the disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 mm. A PR was defined as at least a 30% decrease in the sum of the diameters of TLs, taking as reference the baseline sum of diameters. PD-L1 negative was defined as <25% of tumor cells with membrane staining for PD-L1 at any intensity.
    End point type
    Secondary
    End point timeframe
    Assessed at randomisation and every 8 weeks thereafter
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    175
    172
    177
    Units: Percentage of participants
        number (confidence interval 95%)
    17.7 (12.4 to 24.2)
    14.0 (9.1 to 20.0)
    15.3 (10.3 to 21.4)
    Statistical analysis title
    		 Combo therapy vs. mono therapy
    Comparison groups
    Durvalumab + Tremelimumab v Durvalumab
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 2.39

    Secondary: Time to Deterioration in European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire, version 3 (EORTC QLQ-C30)

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    End point title
    		 Time to Deterioration in European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire, version 3 (EORTC QLQ-C30)
    End point description
    The EORTC QLQ-C30 consists of 30 questions that can be combined to produce functional scales (e.g. physical), symptom scales (e.g. fatigue), and a global measure of health status. Each of the scales are measured from 0 to 100. Deterioration was defined as a 10-point decrease from baseline in a functioning or global health status/ quality of life score or a 10-point increase from baseline in a symptom score.
    End point type
    Secondary
    End point timeframe
    September 2015 to September 2018 (36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    227
    226
    227
    Units: Months
    median (confidence interval 95%)
        Function - Physical
    2.0 (1.9 to 3.2)
    2.2 (1.9 to 3.5)
    3.7 (2.3 to 4.6)
        Function - Role
    1.9 (1.8 to 2.4)
    2.0 (1.8 to 2.7)
    3.7 (2.5 to 4.1)
        Function - Emotional
    2.4 (1.9 to 3.7)
    3.6 (2.5 to 4.9)
    3.8 (3.2 to 4.9)
        Function - Cognitive
    2.1 (1.8 to 2.8)
    2.2 (1.9 to 3.4)
    4.0 (3.2 to 5.5)
        Function - Social
    2.1 (1.9 to 3.4)
    2.0 (1.8 to 3.4)
    3.7 (3.2 to 4.7)
        Symptom - Fatigue
    1.8 (1.3 to 1.9)
    1.4 (1.0 to 1.9)
    1.9 (1.6 to 2.6)
        Symptom - Pain
    1.9 (1.8 to 2.4)
    2.5 (1.9 to 3.7)
    3.7 (2.7 to 4.1)
        Symptom - Nausea/ Vomiting
    2.6 (2.0 to 3.9)
    3.9 (2.8 to 4.9)
    4.0 (3.6 to 5.5)
        Global health status/QoL
    1.9 (1.8 to 2.7)
    2.8 (1.9 to 3.8)
    3.5 (2.9 to 4.0)
    No statistical analyses for this end point

    Secondary: Time to Deterioration for European Organisation for Research and Treatment of Cancer 35-item head and neck quality of life questionnaire (EORTC QLQ-H&N35)

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    End point title
    		 Time to Deterioration for European Organisation for Research and Treatment of Cancer 35-item head and neck quality of life questionnaire (EORTC QLQ-H&N35)
    End point description
    The EORTC QLQ-H&N35 comprises of 35 questions to assess head and neck cancer symptoms (e.g. pain, swallowing). Deterioration was defined as a 10-point increase from baseline in the symptom score.
    End point type
    Secondary
    End point timeframe
    September 2015 to September 2018 (36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    223
    220
    221
    Units: Months
    median (confidence interval 95%)
        Pain (Mouth/ Throat)
    2.9 (2.4 to 3.8)
    2.8 (2.6 to 3.7)
    3.4 (2.7 to 4.0)
        Swallowing
    2.6 (1.9 to 3.6)
    2.8 (1.9 to 3.9)
    3.7 (2.9 to 4.6)
    No statistical analyses for this end point

    Secondary: Number of participants reporting one or more adverse events (AE)

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    End point title
    		 Number of participants reporting one or more adverse events (AE)
    End point description
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. Inclusive of AEs and serious AEs.
    End point type
    Secondary
    End point timeframe
    First dose to last dose + 90 days or data cut off (up to 36 months)
    End point values
    		 Durvalumab + Tremelimumab Durvalumab Standard of Care (SoC)
    Number of subjects analysed
    246
    237
    240
    Units: Participants
    232
    214
    229
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose to last dose + 90 days or data cut off (maximum exposure 32 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Durvalumab + Tremelimumab
    Reporting group description
    		 Participants received 20 mg/kg durvalumab and 1 mg/kg tremelimumab combination therapy via intravenous (IV) infusion every 4 weeks (q4w) for up to 16 weeks. 4 weeks after completion of combination therapy, participants received dosing with durvalumab 10 mg/kg monotherapy every 2 weeks (q2w) until disease progression (PD).

    Reporting group title
    Standard of Care (SoC)
    Reporting group description
    		 Participants received monotherapy with 1 of the following therapies at the investigator’s discretion until disease progression (PD): cetuximab, a taxane, methotrexate, or a fluoropyrimidine.

    Reporting group title
    Durvalumab
    Reporting group description
    		 Participants received 10 mg/kg durvalumab via intravenous (IV) infusion every 2 weeks (q2w) until disease progression (PD).

    Serious adverse events
    		 Durvalumab + Tremelimumab Standard of Care (SoC) Durvalumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    79 / 246 (32.11%)
    61 / 240 (25.42%)
    69 / 237 (29.11%)
         number of deaths (all causes)
    206
    199
    186
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Infected neoplasm
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    7 / 246 (2.85%)
    2 / 240 (0.83%)
    4 / 237 (1.69%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Tumour necrosis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial haemorrhage
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Embolism
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Hypertension
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 240 (0.00%)
    0 / 237 (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
    Death
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 240 (0.83%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    1 / 2
    Facial pain
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Fatigue
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    4 / 237 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Hyperthermia
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Pain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 246 (1.63%)
    2 / 240 (0.83%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Drug hypersensitivity
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Respiratory, thoracic and mediastinal disorders
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Apnoea
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Asphyxia
         subjects affected / exposed
    2 / 246 (0.81%)
    3 / 240 (1.25%)
    3 / 237 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    0 / 237 (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
    Dyspnoea
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    3 / 237 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 240 (0.00%)
    0 / 237 (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
    Laryngeal oedema
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    3 / 237 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pharyngeal haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Pleural effusion
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Pneumonia aspiration
         subjects affected / exposed
    3 / 246 (1.22%)
    2 / 240 (0.83%)
    5 / 237 (2.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Pneumonitis
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 240 (0.42%)
    3 / 237 (1.27%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Pulmonary embolism
         subjects affected / exposed
    4 / 246 (1.63%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    0 / 237 (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
    Respiratory failure
         subjects affected / exposed
    0 / 246 (0.00%)
    3 / 240 (1.25%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Stridor
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Confusional state
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Hallucinations, mixed
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    0 / 246 (0.00%)
    2 / 240 (0.83%)
    0 / 237 (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
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    White blood cell count decreased
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Injury, poisoning and procedural complications
    Abdominal wall wound
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Femur fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Fibula fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Gastrostomy tube site complication
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         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
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Nasal injury
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoradionecrosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Periprosthetic fracture
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Petroleum distillate poisoning
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Radius fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Acute coronary syndrome
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Cardiac arrest
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Cardiac failure
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Left ventricular failure
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Nervous system disorders
    Carotid artery disease
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Cerebrovascular accident
         subjects affected / exposed
    3 / 246 (1.22%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Epilepsy
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Horner's syndrome
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Loss of consciousness
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Seizure
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 246 (2.03%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 240 (0.83%)
    0 / 237 (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
    Pancytopenia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Thrombocytopenia
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    0 / 237 (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
    Ear and labyrinth disorders
    Otorrhoea
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 240 (0.00%)
    0 / 237 (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
    Coeliac disease
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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 ischaemic
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Constipation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Diarrhoea
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    4 / 246 (1.63%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric fistula
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Mouth haemorrhage
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 240 (0.00%)
    0 / 237 (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
    Nausea
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Tongue haemorrhage
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Vomiting
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    0 / 237 (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
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Urticaria
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Vasculitic ulcer
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Renal failure
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Trismus
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Abscess oral
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Bacteraemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 246 (1.22%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Escherichia sepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 240 (0.42%)
    0 / 237 (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
    Infection
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 240 (0.83%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Lung infection
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 240 (0.83%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Oesophageal infection
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Peritonitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    9 / 246 (3.66%)
    9 / 240 (3.75%)
    8 / 237 (3.38%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Postoperative wound infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Pulmonary sepsis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Respiratory tract infection
         subjects affected / exposed
    4 / 246 (1.63%)
    1 / 240 (0.42%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 246 (1.22%)
    4 / 240 (1.67%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Staphylococcal infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (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
    Stoma site infection
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Subcutaneous abscess
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 246 (0.41%)
    2 / 240 (0.83%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 246 (0.81%)
    2 / 240 (0.83%)
    4 / 237 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 240 (0.42%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    2 / 237 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 240 (0.00%)
    0 / 237 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 246 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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 Standard of Care (SoC) Durvalumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    203 / 246 (82.52%)
    207 / 240 (86.25%)
    180 / 237 (75.95%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 246 (6.10%)
    17 / 240 (7.08%)
    11 / 237 (4.64%)
         occurrences all number
    20
    28
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    15 / 246 (6.10%)
    14 / 240 (5.83%)
    7 / 237 (2.95%)
         occurrences all number
    17
    23
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    14 / 246 (5.69%)
    8 / 240 (3.33%)
    7 / 237 (2.95%)
         occurrences all number
    20
    9
    11
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    17 / 246 (6.91%)
    12 / 240 (5.00%)
    9 / 237 (3.80%)
         occurrences all number
    18
    19
    11
    Weight decreased
         subjects affected / exposed
    27 / 246 (10.98%)
    20 / 240 (8.33%)
    31 / 237 (13.08%)
         occurrences all number
    27
    22
    33
    Vascular disorders
    Hypertension
         subjects affected / exposed
    17 / 246 (6.91%)
    7 / 240 (2.92%)
    11 / 237 (4.64%)
         occurrences all number
    17
    8
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 246 (4.47%)
    16 / 240 (6.67%)
    13 / 237 (5.49%)
         occurrences all number
    11
    19
    15
    Neuropathy peripheral
         subjects affected / exposed
    4 / 246 (1.63%)
    24 / 240 (10.00%)
    5 / 237 (2.11%)
         occurrences all number
    4
    26
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    55 / 246 (22.36%)
    56 / 240 (23.33%)
    47 / 237 (19.83%)
         occurrences all number
    68
    94
    57
    Leukopenia
         subjects affected / exposed
    10 / 246 (4.07%)
    13 / 240 (5.42%)
    2 / 237 (0.84%)
         occurrences all number
    19
    42
    3
    Neutropenia
         subjects affected / exposed
    11 / 246 (4.47%)
    32 / 240 (13.33%)
    4 / 237 (1.69%)
         occurrences all number
    16
    86
    4
    Thrombocytopenia
         subjects affected / exposed
    11 / 246 (4.47%)
    18 / 240 (7.50%)
    5 / 237 (2.11%)
         occurrences all number
    23
    49
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    51 / 246 (20.73%)
    56 / 240 (23.33%)
    42 / 237 (17.72%)
         occurrences all number
    57
    63
    53
    Fatigue
         subjects affected / exposed
    40 / 246 (16.26%)
    35 / 240 (14.58%)
    31 / 237 (13.08%)
         occurrences all number
    44
    44
    35
    Mucosal inflammation
         subjects affected / exposed
    2 / 246 (0.81%)
    17 / 240 (7.08%)
    3 / 237 (1.27%)
         occurrences all number
    3
    20
    3
    Pyrexia
         subjects affected / exposed
    31 / 246 (12.60%)
    29 / 240 (12.08%)
    19 / 237 (8.02%)
         occurrences all number
    35
    42
    23
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    33 / 246 (13.41%)
    29 / 240 (12.08%)
    33 / 237 (13.92%)
         occurrences all number
    37
    29
    40
    Diarrhoea
         subjects affected / exposed
    38 / 246 (15.45%)
    32 / 240 (13.33%)
    24 / 237 (10.13%)
         occurrences all number
    50
    42
    46
    Dysphagia
         subjects affected / exposed
    20 / 246 (8.13%)
    18 / 240 (7.50%)
    28 / 237 (11.81%)
         occurrences all number
    22
    18
    30
    Nausea
         subjects affected / exposed
    30 / 246 (12.20%)
    41 / 240 (17.08%)
    27 / 237 (11.39%)
         occurrences all number
    36
    47
    29
    Stomatitis
         subjects affected / exposed
    5 / 246 (2.03%)
    27 / 240 (11.25%)
    11 / 237 (4.64%)
         occurrences all number
    7
    34
    12
    Vomiting
         subjects affected / exposed
    15 / 246 (6.10%)
    20 / 240 (8.33%)
    18 / 237 (7.59%)
         occurrences all number
    16
    24
    23
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 246 (10.57%)
    19 / 240 (7.92%)
    25 / 237 (10.55%)
         occurrences all number
    27
    22
    26
    Dyspnoea
         subjects affected / exposed
    27 / 246 (10.98%)
    19 / 240 (7.92%)
    27 / 237 (11.39%)
         occurrences all number
    27
    21
    29
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 246 (0.00%)
    29 / 240 (12.08%)
    0 / 237 (0.00%)
         occurrences all number
    0
    30
    0
    Dermatitis acneiform
         subjects affected / exposed
    2 / 246 (0.81%)
    17 / 240 (7.08%)
    4 / 237 (1.69%)
         occurrences all number
    2
    18
    4
    Pruritus
         subjects affected / exposed
    23 / 246 (9.35%)
    9 / 240 (3.75%)
    10 / 237 (4.22%)
         occurrences all number
    28
    10
    13
    Rash
         subjects affected / exposed
    18 / 246 (7.32%)
    36 / 240 (15.00%)
    19 / 237 (8.02%)
         occurrences all number
    20
    38
    22
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 246 (5.28%)
    8 / 240 (3.33%)
    7 / 237 (2.95%)
         occurrences all number
    13
    8
    7
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    32 / 246 (13.01%)
    5 / 240 (2.08%)
    33 / 237 (13.92%)
         occurrences all number
    33
    5
    44
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    20 / 246 (8.13%)
    23 / 240 (9.58%)
    15 / 237 (6.33%)
         occurrences all number
    20
    24
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    51 / 246 (20.73%)
    48 / 240 (20.00%)
    30 / 237 (12.66%)
         occurrences all number
    51
    56
    33
    Hypercalcaemia
         subjects affected / exposed
    21 / 246 (8.54%)
    7 / 240 (2.92%)
    10 / 237 (4.22%)
         occurrences all number
    21
    8
    12
    Hypomagnesaemia
         subjects affected / exposed
    3 / 246 (1.22%)
    20 / 240 (8.33%)
    8 / 237 (3.38%)
         occurrences all number
    3
    25
    10
    Hyponatraemia
         subjects affected / exposed
    16 / 246 (6.50%)
    8 / 240 (3.33%)
    11 / 237 (4.64%)
         occurrences all number
    16
    8
    15

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jan 2015
    Updates to the following: - Management of non-immune-related toxicity using dose modifications. - Stratification factors changed to include PD-L1 status. - ‘Deep sustained response’ (DSR) endpoint removed. - Change to pre-specify stratified log-rank test as primary method of analysis for OS and PFS in all-comers population, while retaining the weighted HR approach as a supportive analysis. - PD-L1 status added as a pre-specified subgroup analysis.
    03 Apr 2015
    Updates to the following: - Change to doses of durvalumab and tremelimumab in the combination arm. - Clarification of procedures regarding discontinuation or retreatment in cases of confirmed PD. - Modifications to eligibility criteria. - Changes to endpoints and assessments.
    01 Jun 2015
    Updates to the following: - Eligibility criteria modified. - Clarification that no further enrolment into the durvalumab monotherapy arm applies to patients with PD-L1-negative tumors, should external data suggest lack of benefit of durvalumab monotherapy in the PD-L1 negative population.
    18 Feb 2016
    Updates to the following: - Co-primary endpoint of PFS removed, leaving only a primary endpoint of OS (accordingly, the multiple testing procedure was simplified). - Primary objective clarified as assessment of durvalumab + tremelimumab vs SoC in PD-L1-positive and -negative patients (ie, regardless of PD-L1 status). (throughout the document). - Previous primary comparison included monotherapy vs SoC in PD-L1-positive patients. - Clarification of key secondary objectives. - PFS, ORR, DoR, DCR, APF6, APF12 to be based on Investigator assessment rather than BICR. - PRO measures reduced and prioritised for formal analysis. - PRO for CTCAE reduced from collection of 30 PRO-CTCAE symptoms to 11. - Eligibility criteria modified. - Removal of text referring to possibility of halting enrolment of PD-L1- negative patients into the durvalumab monotherapy arm. - Definition of disease progression now to include clinical disease progression as well as confirmed objective disease progression. - Removal of the requirement to confirm response (amended to objective response). - Addition of one interim analysis for OS at 80% maturity, when 314 death events have occurred across the combination and SoC arms. - Update sample size estimate calculation and statistical assumptions. - Added analysis of patients with subsequent anticancer therapy. - HPV testing and analysis of OS by HPV status in patients with oropharyngeal cancer only. - Addition of subgroup analysis by race. - Management of study drug-related toxicities modified. - The timing and procedures for scheduled assessments and/or study design were modified and clarified.
    07 Sep 2016
    Updates to the following: - Change from single primary objective of durvalumab + tremelimumab vs SoC in terms of OS to co-primary objectives of durvalumab + tremelimumab vs SoC in terms of OS and durvalumab monotherapy vs SoC in terms of OS. - Treatment in all arms to continue until progression. - Retreatment sections updated to only allow retreatment for patients on the combination arm, provided that progression occurs during the monotherapy portion of dosing. - The hypothesis testing is expected to be performed after ~11 months of follow-up instead of 10 months, and after ~375 death events have occurred instead of 392. The number of events that triggers the interim analysis was reduced from 314 to 300. - The requirement for a min of 300 patients with PD-L1-positive disease was removed and enrolment was to be based on the natural prevalence of PD-L1-positive and -negative patients. - Updated to clarify that the specified PD-L1 expression cut-off level will be used for the purpose of stratification, however the cut-off level to be used for the subgroup analyses by PD-L1 status and for determining the PD-L1- negative subgroup in the MTP may be different and will be determined from emerging data outside of this trial. - Updated to include text to allow the study to stop for superiority based on interim OS analysis. - DoR will be analysed by descriptive statistical and Kaplan Meier plots. - Primary tumor status, prior radiation therapy, use of chewing tobacco, oral snuff, and sublingual nicotine, smoking history, ECOG PS, prior lines of systemic therapy for treatment of HNSCC, and extent of disease added as subgroups for analysis. - Weighted estimate of the overall HR removed. - The sensitivity analyses and information on the ascertainment bias, subgroup analysis and its display on forest plot, and adjustment of significance level of testing were removed.
    23 Jan 2018
    Updates to the following: - Updates to various sections to align with the most current safety information per the update to the Investigator’s Brochure. - New section added for survival status for withdrawn consent and lost to follow-up patients. - Clarification to collection of variables for SAEs. - New section added to describe treatment with durvalumab after the final data cut-off. - Updates to allow sites more flexibility in timing of survival calls after data cut-off.
    10 Sep 2018
    Updates to the following (12-Dec-2018): - New section added to the CSP (Safety data to be collected following the final data cut-off of the study) to describe how safety data would be recorded for patients continuing to receive study drug after final data cut-off and database closure. - Treatment regimens text amended to clarify that patients currently receiving treatment with durvalumab may be transitioned to a roll-over or safety extension study after the analysis is finalized.

    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.
    Multiple testing was performed for OS analysis in the intent-to-treat (ITT) population and OS analysis in the PD-L1 negative population for durvalumab + tremelimumab versus SoC only.
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