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    Clinical Trial Results:
    A Randomized, Multicenter, Double-Blind, Phase 3 Study of Nivolumab, Nivolumab in Combination With Ipilimumab, or Placebo as Maintenance Therapy in Subjects With Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) After Completion of Platinum-based First Line Chemotherapy (CheckMate 451: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 451)

    Summary
    EudraCT number
    		 2015-002441-61
    Trial protocol
    		 BE   AT   GR   SE   DE   ES   GB   IE   FI   PL   NL   RO  
    Global end of trial date
    11 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-451
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02538666
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Bristol-Myers Squibb, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if nivolumab or nivolumab in combination with ipilimumab improve Overall Survival (OS) versus placebo in participants with Extensive-Stage Disease Small Cell Lung Cancer (ED-SCLC) who have completed a first line platinum-based chemotherapy regimen and achieved an ongoing Complete Response (CR), Partial Response (PR) or Stable Disease (SD).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 10
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Brazil: 50
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    China: 77
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Ireland: 16
    Country: Number of subjects enrolled
    Israel: 19
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Japan: 84
    Country: Number of subjects enrolled
    Mexico: 20
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Korea, Republic of: 85
    Country: Number of subjects enrolled
    Romania: 40
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 159
    Worldwide total number of subjects
    909
    EEA total number of subjects
    292
    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)
    463
    From 65 to 84 years
    445
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 907 participants were randomized and 903 were treated. 2 participants were concurrently participating in both the Global and China population. These participants also contributed data to both the Global and China population.

    Pre-assignment
    Screening details
    		 The global study population is defined as all participants enrolled during the global accrual window, including any patient from China enrolled in the window. The China population is defined as all participants from China enrolled in the study, including any subject from China enrolled in the global study as well as the China sub-study.

    Period 1
    Period 1 title
    Pre-Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Global Placebo
    Arm description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Investigational medicinal product name
    Placebo for nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Arm title
    		 Global Nivolumab 240 mg
    Arm description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo for ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg was administered every 2 weeks as a 30-minute IV infusion

    Arm title
    		 Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Arm description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab 3 mg/kg was administered as a 90-minute IV infusion every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 1 mg/kg was administered as a 30-minute IV infusion every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Arm title
    		 China Placebo
    Arm description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Investigational medicinal product name
    Placebo for ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Arm title
    		 China Nivolumab 240 mg
    Arm description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo for ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg was administered every 2 weeks as a 30-minute IV infusion

    Arm title
    		 China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Arm description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab 3 mg/kg was administered as a 90-minute IV infusion every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 1 mg/kg was administered as a 30-minute IV infusion every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Number of subjects in period 1
    		Global Placebo Global Nivolumab 240 mg Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Placebo China Nivolumab 240 mg China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Started
    275
    280
    279
    26
    25
    24
    Completed
    273
    279
    278
    26
    25
    24
    Not completed
    2
    1
    1
    0
    0
    0
         Withdrew Consent
    -
    1
    1
    -
    -
    -
         Disease progression
    1
    -
    -
    -
    -
    -
         no longer meets study criteria
    1
    -
    -
    -
    -
    -
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Global Placebo
    Arm description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Investigational medicinal product name
    Placebo for nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Arm title
    		 Global Nivolumab 240 mg
    Arm description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo for ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg was administered every 2 weeks as a 30-minute IV infusion

    Arm title
    		 Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Arm description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 1 mg/kg was administered as a 30-minute IV infusion every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab 3 mg/kg was administered as a 90-minute IV infusion every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Arm title
    		 China Placebo
    Arm description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Investigational medicinal product name
    Placebo for nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Arm title
    		 China Nivolumab 240 mg
    Arm description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo for ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose was administered as an IV infusion

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    240 mg was administered every 2 weeks as a 30-minute IV infusion

    Arm title
    		 China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Arm description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ipilimumab 3 mg/kg was administered as a 90-minute IV infusion every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Investigational medicinal product name
    Nivolumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nivolumab 1 mg/kg was administered as a 30-minute IV infusion every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Number of subjects in period 2
    		Global Placebo Global Nivolumab 240 mg Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Placebo China Nivolumab 240 mg China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Started
    273
    279
    278
    26
    25
    24
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    273
    279
    278
    26
    25
    24
         Adverse event, serious fatal
    -
    2
    2
    -
    -
    1
         Disease progression
    248
    209
    150
    23
    18
    15
         Participant withdrew consent
    1
    5
    2
    1
    -
    1
         Maximum clinical benefit
    4
    2
    4
    -
    1
    -
         Participant no longer meets study criteria
    -
    2
    -
    -
    -
    -
         Other reasons
    8
    14
    5
    -
    1
    -
         Study drug toxicity
    1
    25
    88
    -
    5
    4
         Not reported
    1
    2
    1
    1
    -
    1
         Adverse event unrelated to study drug
    8
    10
    15
    -
    -
    -
         Lost to follow-up
    -
    1
    1
    -
    -
    -
         Poor/non-compliance
    -
    1
    -
    -
    -
    -
         Participant request to discontinue study treatment
    2
    6
    9
    1
    -
    2
         Administrative reason by sponsor
    -
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Global Placebo
    Reporting group description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion

    Reporting group title
    Global Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion

    Reporting group title
    Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Reporting group title
    China Placebo
    Reporting group description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion

    Reporting group title
    China Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion

    Reporting group title
    China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Reporting group values
    		 Global Placebo Global Nivolumab 240 mg Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Placebo China Nivolumab 240 mg China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Total
    Number of subjects
    		 275 280 279 26 25 24 909
    Age Categorical
    Units:
        < 65
    		 148 135 140 14 14 12 463
        ≥ 65 and < 75
    		 103 110 103 10 11 12 349
        ≥ 75 and < 85
    		 24 35 35 2 0 0 96
        ≥ 85
    		 0 0 1 0 0 0 1
    Sex: Female, Male
    Units: Participants
        Female
    		 100 103 99 3 3 2 310
        Male
    		 175 177 180 23 22 22 599
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 14 11 15 0 0 0 40
        Not Hispanic or Latino
    		 151 159 164 10 5 7 496
        Unknown or Not Reported
    		 110 110 100 16 20 17 373
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 69 58 58 26 25 24 260
        Black or African American
    		 2 6 1 0 0 0 9
        White
    		 198 213 216 0 0 0 627
        Other
    		 6 3 3 0 0 0 12
        Not Reported
    		 0 0 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Global Placebo
    Reporting group description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion

    Reporting group title
    Global Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion

    Reporting group title
    Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Reporting group title
    China Placebo
    Reporting group description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion

    Reporting group title
    China Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion

    Reporting group title
    China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks
    Reporting group title
    Global Placebo
    Reporting group description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion

    Reporting group title
    Global Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion

    Reporting group title
    Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Reporting group title
    China Placebo
    Reporting group description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion

    Reporting group title
    China Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion

    Reporting group title
    China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Primary: Overall Survival (OS) of Nivolumab + Ipilimumab Versus Placebo In The Global Population

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    End point title
    		 Overall Survival (OS) of Nivolumab + Ipilimumab Versus Placebo In The Global Population [1]
    End point description
    OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug
    End point type
    Primary
    End point timeframe
    From randomization to 400 deaths across the two treatment groups (Nivo+Ipi vs Placebo) (up to approximately 37 months)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Global Placebo Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects analysed
    275
    279
    Units: Months
        median (confidence interval 95%)
    9.56 (8.18 to 11.01)
    9.17 (8.15 to 10.25)
    Statistical analysis title
    		 nivolumab + ipilimumab over placebo
    Statistical analysis description
    nivolumab + ipilimumab over placebo
    Comparison groups
    Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg v Global Placebo
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3693
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.12

    Secondary: Overall Survival (OS) of Nivolumab Versus Placebo

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    End point title
    		 Overall Survival (OS) of Nivolumab Versus Placebo [2]
    End point description
    Overall Survival (OS) comparing nivolumab monotherapy versus placebo. OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death or last known alive date (up to approximately 73 months)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Global Placebo Global Nivolumab 240 mg China Placebo China Nivolumab 240 mg
    Number of subjects analysed
    275
    280
    26
    25
    Units: Months
        median (confidence interval 95%)
    9.56 (8.18 to 11.01)
    10.18 (9.43 to 11.99)
    9.28 (5.59 to 14.26)
    8.18 (7.20 to 14.26)
    Statistical analysis title
    		 Global nivolumab over global placebo
    Statistical analysis description
    Global nivolumab over global placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    555
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.97
    Statistical analysis title
    		 China nivolumab over China Placebo
    Statistical analysis description
    China nivolumab over China Placebo
    Comparison groups
    China Placebo v China Nivolumab 240 mg
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.66

    Secondary: Overall Survival (OS) of Nivolumab + Ipilimumab Versus Nivolumab

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    End point title
    		 Overall Survival (OS) of Nivolumab + Ipilimumab Versus Nivolumab [3]
    End point description
    Overall Survival (OS) comparing Nivolumab + Ipilimumab Versus Nivolumab. OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death or last known alive date (up to approximately 73 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Global Nivolumab 240 mg Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Nivolumab 240 mg China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects analysed
    280
    279
    25
    24
    Units: Months
        median (confidence interval 95%)
    10.18 (9.43 to 11.99)
    9.17 (8.15 to 10.35)
    8.18 (7.20 to 14.26)
    10.48 (7.13 to 13.40)
    Statistical analysis title
    		 Global nivo + ipi over global nivo
    Statistical analysis description
    Global nivolumab + ipilimumab over global nivolumab
    Comparison groups
    Global Nivolumab 240 mg v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.36
    Statistical analysis title
    		 China nivolumab + ipilimumab over China nivolumab
    Statistical analysis description
    China nivolumab + ipilimumab over China nivolumab
    Comparison groups
    China Nivolumab 240 mg v China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.79

    Secondary: Progression Free Survival (PFS) per BICR

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    End point title
    		 Progression Free Survival (PFS) per BICR
    End point description
    PFS was defined as the time between the date of randomization and the first date of documented progression as determined by Blind Independent Central Review (BICR) or death due to any cause, whichever occurred first. Participants who died with no reported progression were considered to have progressed on the date of death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy. Participants who did not have any on study tumor assessments and did not die (or died after initiation of the subsequent anti- cancer therapy) were censored on their date of randomization. Participants who started any subsequent anti- cancer therapy without a prior reported Progressive Disease (PD) per BICR were censored at the last evaluable tumor assessment on or prior to initiation of the subsequent anti-cancer therapy.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 73 months)
    End point values
    		 Global Placebo Global Nivolumab 240 mg Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Placebo China Nivolumab 240 mg China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects analysed
    275
    280
    279
    26
    25
    24
    Units: Months
        median (confidence interval 95%)
    1.41 (1.41 to 1.48)
    1.94 (1.61 to 2.63)
    1.74 (1.48 to 2.63)
    1.38 (1.28 to 2.56)
    1.58 (1.38 to 4.11)
    1.54 (1.28 to 2.73)
    Statistical analysis title
    		 Global nivolumab + ipilimumab over global placebo
    Statistical analysis description
    Global nivolumab + ipilimumab over global placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.88
    Statistical analysis title
    		 Global nivolumab over global placebo
    Statistical analysis description
    Global nivolumab over global placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    555
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.79
    Statistical analysis title
    		 Global nivolumab+ ipilimumab over nivolumab
    Statistical analysis description
    Global nivolumab+ ipilimumab over nivolumab
    Comparison groups
    Global Nivolumab 240 mg v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.35
    Statistical analysis title
    		 China Nivolumab + Ipilimumab over China placebo
    Statistical analysis description
    China Nivolumab + Ipilimumab over China placebo
    Comparison groups
    China Placebo v China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 1.12
    Statistical analysis title
    		 China Nivolumab over China placebo
    Statistical analysis description
    China Nivolumab over China placebo
    Comparison groups
    China Placebo v China Nivolumab 240 mg
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.85
    Statistical analysis title
    		 China Nivolumab + Ipilimumab over China Nivolumab
    Statistical analysis description
    China Nivolumab + Ipilimumab over China Nivolumab
    Comparison groups
    China Nivolumab 240 mg v China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.49

    Secondary: Overall Survival (OS) in Tumor Mutational Burden (TMB) High and Low Subgroups by TMB Cutoff In The Global Population

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    End point title
    		 Overall Survival (OS) in Tumor Mutational Burden (TMB) High and Low Subgroups by TMB Cutoff In The Global Population [4]
    End point description
    Tumor mutational burden (TMB) is measured using FoundationOne CDxTM (F1CDx) assay, a comprehensive genomic profile (CGP) assay based on baseline tumor tissue. TMB is defined as the number of somatic, coding, base substitution, and indel mutations per megabase of genome examined. OS in TMB by the following cutoff points: ≥10 mutations/mb, < 10 mutations/mb, ≥13 mutations/mb, <13 mutations/mb
    End point type
    Secondary
    End point timeframe
    From randomization to the date of death or last known alive date (up to approximately 73 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Global Placebo Global Nivolumab 240 mg Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects analysed
    192
    196
    192
    Units: Months
    median (confidence interval 95%)
        ≥10 mutations/mb
    11.96 (7.49 to 13.67)
    12.81 (9.95 to 18.60)
    10.55 (8.38 to 14.16)
        < 10 mutations/mb
    9.20 (7.46 to 11.04)
    9.76 (8.34 to 11.30)
    8.11 (6.60 to 10.05)
        ≥13 mutations/mb
    9.69 (6.21 to 13.63)
    12.98 (9.95 to 18.60)
    13.47 (9.26 to 21.75)
        <13 mutations/mb
    10.02 (7.66 to 11.47)
    9.89 (8.64 to 11.30)
    7.85 (6.67 to 9.66)
    Statistical analysis title
    		 TMB cutoff ≥10 mutations/mb: Nivo+Ipi over placebo
    Statistical analysis description
    TMB cutoff ≥10 mutations/mb: Nivo+Ipi over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.15
    Statistical analysis title
    		 TMB cutoff ≥10 mutations/mb: Nivo over placebo
    Statistical analysis description
    TMB cutoff ≥10 mutations/mb: Nivo over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.04
    Statistical analysis title
    		 TMB cutoff ≥13 mutations/mb: Nivo+Ipi over placebo
    Statistical analysis description
    TMB cutoff ≥13 mutations/mb: Nivo+Ipi over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.92
    Statistical analysis title
    		 TMB cutoff ≥13 mutations/mb: Nivo over placebo
    Statistical analysis description
    TMB cutoff ≥13 mutations/mb: Nivo over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.93
    Statistical analysis title
    		 TMB cutoff <10 mutations/mb: Nivo+Ipi over placebo
    Statistical analysis description
    TMB cutoff <10 mutations/mb: Nivo+Ipi over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.21
    Statistical analysis title
    		 TMB cutoff <10 mutations/mb: Nivo over placebo
    Statistical analysis description
    TMB cutoff <10 mutations/mb: Nivo over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.18
    Statistical analysis title
    		 TMB cutoff <13 mutations/mb: Nivo+Ipi over placebo
    Statistical analysis description
    TMB cutoff <13 mutations/mb: Nivo+Ipi over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.35
    Statistical analysis title
    		 TMB cutoff <13 mutations/mb: Nivo over placebo
    Statistical analysis description
    TMB cutoff <13 mutations/mb: Nivo over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.2

    Secondary: Progression Free Survival (PFS) per BICR in Tumor Mutational Burden (TMB) High and Low Subgroups by TMB Cutoff In The Global Population

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    End point title
    		 Progression Free Survival (PFS) per BICR in Tumor Mutational Burden (TMB) High and Low Subgroups by TMB Cutoff In The Global Population [5]
    End point description
    Tumor mutational burden (TMB) is measured using FoundationOne CDxTM (F1CDx) assay, a comprehensive genomic profile (CGP) assay based on baseline tumor tissue. TMB is defined as the number of somatic, coding, base substitution, and indel mutations per megabase of genome examined. PFS in TMB by the following cutoff points: ≥10 mutations/mb, < 10 mutations/mb, ≥13 mutations/mb, <13 mutations/mb.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of the first documented tumor progression or death due to any cause (up to approximately 73 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Global Placebo Global Nivolumab 240 mg Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects analysed
    192
    196
    192
    Units: Months
    median (confidence interval 95%)
        ≥10 mutations/mb
    1.58 (1.41 to 2.63)
    2.79 (2.04 to 4.17)
    2.33 (1.48 to 2.92)
        < 10 mutations/mb
    1.41 (1.35 to 1.45)
    1.61 (1.45 to 2.53)
    1.48 (1.41 to 2.00)
        ≥13 mutations/mb
    1.58 (1.41 to 2.63)
    2.76 (1.61 to 4.11)
    2.63 (1.48 to 3.81)
        <13 mutations/mb
    1.41 (1.38 to 1.45)
    1.84 (1.48 to 2.66)
    1.48 (1.41 to 2.00)
    Statistical analysis title
    		 TMB cutoff ≥10 mutations/mb: Nivo+Ipi over placebo
    Statistical analysis description
    TMB cutoff ≥10 mutations/mb: Nivo+Ipi over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.09
    Statistical analysis title
    		 TMB cutoff ≥13 mutations/mb: Nivo+Ipi over placebo
    Statistical analysis description
    TMB cutoff ≥13 mutations/mb: Nivo+Ipi over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.07
    Statistical analysis title
    		 TMB cutoff ≥10 mutations/mb: Nivo over placebo
    Statistical analysis description
    TMB cutoff ≥10 mutations/mb: Nivo over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.92
    Statistical analysis title
    		 TMB cutoff ≥13 mutations/mb: Nivo over placebo
    Statistical analysis description
    TMB cutoff ≥13 mutations/mb: Nivo over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.95
    Statistical analysis title
    		 TMB cutoff <10 mutations/mb: Nivo+Ipi over placebo
    Statistical analysis description
    TMB cutoff <10 mutations/mb: Nivo+Ipi over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.96
    Statistical analysis title
    		 TMB cutoff <10 mutations/mb: Nivo over placebo
    Statistical analysis description
    TMB cutoff <10 mutations/mb: Nivo over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.89
    Statistical analysis title
    		 TMB cutoff <13 mutations/mb: Nivo+Ipi over placebo
    Statistical analysis description
    TMB cutoff <13 mutations/mb: Nivo+Ipi over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.01
    Statistical analysis title
    		 TMB cutoff <13 mutations/mb: Nivo over placebo
    Statistical analysis description
    TMB cutoff <13 mutations/mb: Nivo over placebo
    Comparison groups
    Global Placebo v Global Nivolumab 240 mg
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.89

    Post-hoc: Overall Survival (OS) of Nivolumab + Ipilimumab Versus Placebo - Extended Collection

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    End point title
    		 Overall Survival (OS) of Nivolumab + Ipilimumab Versus Placebo - Extended Collection [6]
    End point description
    Overall survival (OS) comparing nivolumab + ipilimumab versus placebo. OS was defined as the time from randomization to the date of death. A participant who had not died was censored at last known alive date. OS was followed up during the blinded study drug treatment and every 3 months via in-person or phone contact after participant discontinued the blinded study drug. Note: This outcome measure represents an updated version of the primary endpoint to include additional data collection that has occurred after the primary completion date. (Assessments were made until 20-Dec-2021).
    End point type
    Post-hoc
    End point timeframe
    From randomization to the date of death or last known alive date (up to approximately 73 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoints are cohort specific and do not report for all arms.
    End point values
    		 Global Placebo Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Placebo China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects analysed
    275
    279
    26
    24
    Units: Months
        median (confidence interval 95%)
    9.56 (8.18 to 11.01)
    9.17 (8.15 to 10.35)
    9.28 (5.59 to 14.26)
    10.48 (7.13 to 13.40)
    Statistical analysis title
    		 China nivolumab + ipilimumab over China placebo
    Statistical analysis description
    China nivolumab + ipilimumab over China placebo
    Comparison groups
    China Placebo v China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    50
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.67
    Statistical analysis title
    		 Global nivolumab + ipilimumab over Global placebo
    Statistical analysis description
    Global nivolumab + ipilimumab over Global placebo
    Comparison groups
    Global Placebo v Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Number of subjects included in analysis
    554
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.09

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Participants were assessed for all-cause mortality from randomization until study completion (up to approximately 73 months). SAEs and Other AEs were assessed from first dose to 100 days after last dose of study therapy (up to approximately 34 months).
    Adverse event reporting additional description
    The total number at risk for all-cause mortality represents all participants who were randomized. The total number at risk by any serious adverse event and other (not including serious) adverse events represents all participants that received at least 1 dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Global Placebo
    Reporting group description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion

    Reporting group title
    Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Reporting group title
    China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
    Reporting group description
    		 Nivolumab 1 mg/kg (30-minute IV infusion) + Ipilimumab 3 mg/kg (90-minute IV infusion) administered every 3 weeks for 4 doses, followed by nivolumab 240 mg every 2 weeks

    Reporting group title
    China Placebo
    Reporting group description
    		 100 mL of 0.9% Sodium Chloride Solution or 5% Dextrose administered as placebo for nivolumab and ipilimumab as an IV infusion

    Reporting group title
    China Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion

    Reporting group title
    Global Nivolumab 240 mg
    Reporting group description
    		 Nivolumab 240 mg administered every 2 weeks as a 30-minute IV infusion

    Serious adverse events
    		 Global Placebo Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Placebo China Nivolumab 240 mg Global Nivolumab 240 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    117 / 273 (42.86%)
    198 / 278 (71.22%)
    19 / 24 (79.17%)
    8 / 26 (30.77%)
    10 / 25 (40.00%)
    131 / 279 (46.95%)
         number of deaths (all causes)
    250
    240
    23
    24
    23
    231
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    50 / 273 (18.32%)
    51 / 278 (18.35%)
    2 / 24 (8.33%)
    4 / 26 (15.38%)
    1 / 25 (4.00%)
    50 / 279 (17.92%)
         occurrences causally related to treatment / all
    0 / 52
    0 / 53
    0 / 2
    0 / 4
    0 / 2
    0 / 52
         deaths causally related to treatment / all
    0 / 43
    0 / 44
    0 / 0
    0 / 4
    0 / 1
    0 / 45
    Metastases to central nervous system
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to spinal cord
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    4 / 279 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 3
    Small cell lung cancer
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Tumour pain
         subjects affected / exposed
    2 / 273 (0.73%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava stenosis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    4 / 279 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 273 (1.10%)
    6 / 278 (2.16%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    3 / 6
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 273 (0.73%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 273 (0.00%)
    3 / 278 (1.08%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Facial pain
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 273 (0.73%)
    7 / 278 (2.52%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 7
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    1 / 273 (0.37%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    5 / 279 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Influenza like illness
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 273 (0.73%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 273 (1.47%)
    8 / 278 (2.88%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    3 / 279 (1.08%)
         occurrences causally related to treatment / all
    1 / 4
    5 / 9
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Autoimmune lung disease
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    5 / 279 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 273 (1.83%)
    4 / 278 (1.44%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    9 / 279 (3.23%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated lung disease
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 273 (0.73%)
    14 / 278 (5.04%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    8 / 279 (2.87%)
         occurrences causally related to treatment / all
    2 / 2
    14 / 14
    1 / 1
    0 / 0
    1 / 1
    8 / 8
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Insomnia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    3 / 273 (1.10%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 1
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 273 (0.73%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 273 (0.73%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cauda equina syndrome
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 273 (0.73%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis autoimmune
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated encephalitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limbic encephalitis
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Occipital neuralgia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    3 / 279 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 273 (2.56%)
    7 / 278 (2.52%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    3 / 279 (1.08%)
         occurrences causally related to treatment / all
    0 / 7
    2 / 7
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Immune thrombocytopenia
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 273 (0.37%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eyelid ptosis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhegmatogenous retinal detachment
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 273 (0.00%)
    19 / 278 (6.83%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    23 / 23
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 273 (0.37%)
    16 / 278 (5.76%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    17 / 19
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 273 (0.37%)
    3 / 278 (1.08%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 273 (0.37%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic mass
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis ulcerative
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 273 (1.10%)
    5 / 278 (1.80%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 5
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 273 (0.00%)
    4 / 278 (1.44%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 273 (0.00%)
    3 / 278 (1.08%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 273 (0.00%)
    3 / 278 (1.08%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder mass
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated cystitis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 273 (0.37%)
    3 / 278 (1.08%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal tubular disorder
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 273 (0.00%)
    4 / 278 (1.44%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cushing's syndrome
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated adrenal insufficiency
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated hyperthyroidism
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 273 (0.37%)
    3 / 278 (1.08%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    3 / 273 (1.10%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal disorder
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 273 (0.37%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus enteritis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 273 (0.00%)
    3 / 278 (1.08%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Gastric infection
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective thrombosis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 273 (3.30%)
    12 / 278 (4.32%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    6 / 279 (2.15%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 15
    0 / 0
    0 / 1
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    2 / 273 (0.73%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 273 (0.37%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    3 / 273 (1.10%)
    8 / 278 (2.88%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 8
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic shock syndrome
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 273 (0.73%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 273 (0.73%)
    3 / 278 (1.08%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 273 (0.73%)
    6 / 278 (2.16%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 7
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 273 (0.37%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    5 / 273 (1.83%)
    9 / 278 (3.24%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    7 / 279 (2.51%)
         occurrences causally related to treatment / all
    0 / 5
    2 / 10
    1 / 2
    0 / 0
    1 / 1
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Global Placebo Global Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg China Placebo China Nivolumab 240 mg Global Nivolumab 240 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    228 / 273 (83.52%)
    263 / 278 (94.60%)
    24 / 24 (100.00%)
    22 / 26 (84.62%)
    23 / 25 (92.00%)
    244 / 279 (87.46%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 273 (0.73%)
    14 / 278 (5.04%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    7 / 279 (2.51%)
         occurrences all number
    2
    15
    0
    0
    0
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    36 / 273 (13.19%)
    45 / 278 (16.19%)
    0 / 24 (0.00%)
    2 / 26 (7.69%)
    3 / 25 (12.00%)
    39 / 279 (13.98%)
         occurrences all number
    46
    61
    0
    2
    3
    49
    Chest discomfort
         subjects affected / exposed
    2 / 273 (0.73%)
    2 / 278 (0.72%)
    3 / 24 (12.50%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences all number
    2
    2
    4
    0
    0
    2
    Fatigue
         subjects affected / exposed
    66 / 273 (24.18%)
    86 / 278 (30.94%)
    7 / 24 (29.17%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
    88 / 279 (31.54%)
         occurrences all number
    73
    101
    9
    3
    0
    110
    Chest pain
         subjects affected / exposed
    8 / 273 (2.93%)
    9 / 278 (3.24%)
    1 / 24 (4.17%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    10 / 279 (3.58%)
         occurrences all number
    8
    15
    1
    2
    3
    10
    Malaise
         subjects affected / exposed
    7 / 273 (2.56%)
    9 / 278 (3.24%)
    7 / 24 (29.17%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    6 / 279 (2.15%)
         occurrences all number
    7
    11
    7
    1
    1
    7
    Non-cardiac chest pain
         subjects affected / exposed
    17 / 273 (6.23%)
    11 / 278 (3.96%)
    0 / 24 (0.00%)
    3 / 26 (11.54%)
    0 / 25 (0.00%)
    10 / 279 (3.58%)
         occurrences all number
    20
    11
    0
    3
    0
    10
    Oedema peripheral
         subjects affected / exposed
    15 / 273 (5.49%)
    18 / 278 (6.47%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    16 / 279 (5.73%)
         occurrences all number
    19
    18
    1
    0
    1
    16
    Pain
         subjects affected / exposed
    3 / 273 (1.10%)
    5 / 278 (1.80%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    7 / 279 (2.51%)
         occurrences all number
    3
    5
    0
    1
    2
    7
    Pyrexia
         subjects affected / exposed
    11 / 273 (4.03%)
    43 / 278 (15.47%)
    6 / 24 (25.00%)
    4 / 26 (15.38%)
    3 / 25 (12.00%)
    20 / 279 (7.17%)
         occurrences all number
    15
    54
    8
    4
    3
    23
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    1 / 24 (4.17%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    1
    1
    2
    1
    1
    Cough
         subjects affected / exposed
    55 / 273 (20.15%)
    53 / 278 (19.06%)
    11 / 24 (45.83%)
    10 / 26 (38.46%)
    6 / 25 (24.00%)
    55 / 279 (19.71%)
         occurrences all number
    61
    56
    14
    10
    7
    62
    Dyspnoea
         subjects affected / exposed
    40 / 273 (14.65%)
    49 / 278 (17.63%)
    1 / 24 (4.17%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    64 / 279 (22.94%)
         occurrences all number
    43
    53
    1
    3
    1
    66
    Haemoptysis
         subjects affected / exposed
    8 / 273 (2.93%)
    4 / 278 (1.44%)
    2 / 24 (8.33%)
    3 / 26 (11.54%)
    2 / 25 (8.00%)
    7 / 279 (2.51%)
         occurrences all number
    9
    5
    2
    3
    2
    7
    Productive cough
         subjects affected / exposed
    11 / 273 (4.03%)
    13 / 278 (4.68%)
    6 / 24 (25.00%)
    5 / 26 (19.23%)
    0 / 25 (0.00%)
    15 / 279 (5.38%)
         occurrences all number
    11
    15
    7
    6
    0
    18
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 273 (5.86%)
    25 / 278 (8.99%)
    2 / 24 (8.33%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
    19 / 279 (6.81%)
         occurrences all number
    17
    25
    4
    2
    0
    19
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 273 (4.40%)
    43 / 278 (15.47%)
    11 / 24 (45.83%)
    4 / 26 (15.38%)
    6 / 25 (24.00%)
    21 / 279 (7.53%)
         occurrences all number
    16
    50
    15
    7
    6
    23
    Amylase increased
         subjects affected / exposed
    9 / 273 (3.30%)
    19 / 278 (6.83%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    3 / 25 (12.00%)
    9 / 279 (3.23%)
         occurrences all number
    12
    34
    2
    0
    3
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 273 (3.66%)
    39 / 278 (14.03%)
    10 / 24 (41.67%)
    3 / 26 (11.54%)
    7 / 25 (28.00%)
    19 / 279 (6.81%)
         occurrences all number
    10
    55
    14
    5
    7
    22
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    3 / 24 (12.50%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    0
    3
    0
    2
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    4 / 24 (16.67%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 273 (1.83%)
    12 / 278 (4.32%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    10 / 279 (3.58%)
         occurrences all number
    6
    12
    1
    0
    2
    11
    Blood bilirubin increased
         subjects affected / exposed
    3 / 273 (1.10%)
    3 / 278 (1.08%)
    5 / 24 (20.83%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    2 / 279 (0.72%)
         occurrences all number
    3
    5
    5
    0
    2
    3
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    9 / 273 (3.30%)
    19 / 278 (6.83%)
    3 / 24 (12.50%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    11 / 279 (3.94%)
         occurrences all number
    10
    28
    8
    1
    5
    17
    Blood sodium decreased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    3 / 24 (12.50%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Blood urea increased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    2 / 24 (8.33%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    0
    5
    1
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 273 (0.73%)
    8 / 278 (2.88%)
    2 / 24 (8.33%)
    2 / 26 (7.69%)
    3 / 25 (12.00%)
    4 / 279 (1.43%)
         occurrences all number
    3
    8
    2
    2
    3
    4
    Lipase increased
         subjects affected / exposed
    11 / 273 (4.03%)
    28 / 278 (10.07%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    12 / 279 (4.30%)
         occurrences all number
    14
    39
    0
    1
    0
    13
    Neutrophil count decreased
         subjects affected / exposed
    15 / 273 (5.49%)
    10 / 278 (3.60%)
    4 / 24 (16.67%)
    8 / 26 (30.77%)
    4 / 25 (16.00%)
    11 / 279 (3.94%)
         occurrences all number
    20
    13
    4
    14
    6
    19
    Platelet count decreased
         subjects affected / exposed
    5 / 273 (1.83%)
    14 / 278 (5.04%)
    1 / 24 (4.17%)
    3 / 26 (11.54%)
    5 / 25 (20.00%)
    12 / 279 (4.30%)
         occurrences all number
    11
    18
    1
    5
    7
    18
    Thyroxine free decreased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    2 / 24 (8.33%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    Weight decreased
         subjects affected / exposed
    12 / 273 (4.40%)
    27 / 278 (9.71%)
    6 / 24 (25.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    16 / 279 (5.73%)
         occurrences all number
    12
    28
    8
    1
    0
    17
    White blood cell count decreased
         subjects affected / exposed
    7 / 273 (2.56%)
    6 / 278 (2.16%)
    3 / 24 (12.50%)
    7 / 26 (26.92%)
    2 / 25 (8.00%)
    8 / 279 (2.87%)
         occurrences all number
    11
    10
    4
    11
    2
    12
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    1
    0
    2
    0
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    24 / 273 (8.79%)
    28 / 278 (10.07%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    29 / 279 (10.39%)
         occurrences all number
    29
    36
    2
    0
    0
    33
    Headache
         subjects affected / exposed
    27 / 273 (9.89%)
    49 / 278 (17.63%)
    2 / 24 (8.33%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    37 / 279 (13.26%)
         occurrences all number
    30
    57
    2
    1
    1
    44
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 273 (11.36%)
    25 / 278 (8.99%)
    12 / 24 (50.00%)
    10 / 26 (38.46%)
    4 / 25 (16.00%)
    30 / 279 (10.75%)
         occurrences all number
    43
    34
    15
    11
    6
    44
    Leukocytosis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    4 / 273 (1.47%)
    2 / 278 (0.72%)
    3 / 24 (12.50%)
    3 / 26 (11.54%)
    2 / 25 (8.00%)
    6 / 279 (2.15%)
         occurrences all number
    6
    2
    3
    3
    5
    10
    Neutropenia
         subjects affected / exposed
    5 / 273 (1.83%)
    6 / 278 (2.16%)
    0 / 24 (0.00%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
    8 / 279 (2.87%)
         occurrences all number
    8
    6
    0
    2
    0
    9
    Thrombocytopenia
         subjects affected / exposed
    7 / 273 (2.56%)
    10 / 278 (3.60%)
    5 / 24 (20.83%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    4 / 279 (1.43%)
         occurrences all number
    8
    11
    7
    1
    0
    5
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 273 (0.73%)
    2 / 278 (0.72%)
    3 / 24 (12.50%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    2 / 279 (0.72%)
         occurrences all number
    2
    2
    3
    1
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    14 / 273 (5.13%)
    11 / 278 (3.96%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    10 / 279 (3.58%)
         occurrences all number
    15
    12
    2
    0
    1
    10
    Abdominal pain
         subjects affected / exposed
    13 / 273 (4.76%)
    22 / 278 (7.91%)
    3 / 24 (12.50%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    16 / 279 (5.73%)
         occurrences all number
    14
    24
    3
    0
    1
    18
    Constipation
         subjects affected / exposed
    37 / 273 (13.55%)
    51 / 278 (18.35%)
    4 / 24 (16.67%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    34 / 279 (12.19%)
         occurrences all number
    44
    60
    4
    1
    0
    35
    Diarrhoea
         subjects affected / exposed
    47 / 273 (17.22%)
    88 / 278 (31.65%)
    4 / 24 (16.67%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
    59 / 279 (21.15%)
         occurrences all number
    56
    126
    7
    2
    0
    93
    Mouth ulceration
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    Nausea
         subjects affected / exposed
    67 / 273 (24.54%)
    78 / 278 (28.06%)
    4 / 24 (16.67%)
    3 / 26 (11.54%)
    3 / 25 (12.00%)
    69 / 279 (24.73%)
         occurrences all number
    75
    110
    4
    3
    3
    84
    Toothache
         subjects affected / exposed
    1 / 273 (0.37%)
    3 / 278 (1.08%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    2 / 279 (0.72%)
         occurrences all number
    1
    3
    2
    0
    3
    2
    Vomiting
         subjects affected / exposed
    21 / 273 (7.69%)
    47 / 278 (16.91%)
    2 / 24 (8.33%)
    3 / 26 (11.54%)
    0 / 25 (0.00%)
    27 / 279 (9.68%)
         occurrences all number
    25
    60
    2
    6
    0
    36
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    3 / 24 (12.50%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    0
    3
    3
    1
    0
    1
    Liver injury
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 278 (0.00%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    15 / 273 (5.49%)
    18 / 278 (6.47%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    11 / 279 (3.94%)
         occurrences all number
    15
    19
    0
    0
    0
    12
    Erythema
         subjects affected / exposed
    2 / 273 (0.73%)
    7 / 278 (2.52%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    6 / 279 (2.15%)
         occurrences all number
    2
    9
    2
    0
    2
    9
    Pruritus
         subjects affected / exposed
    31 / 273 (11.36%)
    80 / 278 (28.78%)
    7 / 24 (29.17%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    43 / 279 (15.41%)
         occurrences all number
    33
    100
    8
    0
    2
    47
    Rash
         subjects affected / exposed
    16 / 273 (5.86%)
    68 / 278 (24.46%)
    4 / 24 (16.67%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    20 / 279 (7.17%)
         occurrences all number
    16
    84
    4
    0
    2
    26
    Rash maculo-papular
         subjects affected / exposed
    9 / 273 (3.30%)
    26 / 278 (9.35%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    10 / 279 (3.58%)
         occurrences all number
    9
    29
    6
    0
    0
    10
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    6 / 273 (2.20%)
    28 / 278 (10.07%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    18 / 279 (6.45%)
         occurrences all number
    7
    30
    2
    0
    0
    21
    Hypothyroidism
         subjects affected / exposed
    3 / 273 (1.10%)
    30 / 278 (10.79%)
    5 / 24 (20.83%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    23 / 279 (8.24%)
         occurrences all number
    3
    34
    5
    2
    6
    24
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    26 / 273 (9.52%)
    31 / 278 (11.15%)
    4 / 24 (16.67%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    35 / 279 (12.54%)
         occurrences all number
    35
    34
    5
    2
    3
    39
    Back pain
         subjects affected / exposed
    22 / 273 (8.06%)
    22 / 278 (7.91%)
    2 / 24 (8.33%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    30 / 279 (10.75%)
         occurrences all number
    23
    27
    2
    1
    1
    36
    Muscular weakness
         subjects affected / exposed
    7 / 273 (2.56%)
    13 / 278 (4.68%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    8 / 279 (2.87%)
         occurrences all number
    8
    14
    2
    0
    0
    8
    Myalgia
         subjects affected / exposed
    16 / 273 (5.86%)
    22 / 278 (7.91%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    26 / 279 (9.32%)
         occurrences all number
    18
    26
    1
    0
    0
    31
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 273 (1.10%)
    5 / 278 (1.80%)
    0 / 24 (0.00%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
    2 / 279 (0.72%)
         occurrences all number
    3
    6
    0
    2
    0
    2
    Pharyngitis
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 279 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    6 / 273 (2.20%)
    14 / 278 (5.04%)
    3 / 24 (12.50%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    15 / 279 (5.38%)
         occurrences all number
    7
    14
    3
    0
    1
    20
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 273 (1.47%)
    14 / 278 (5.04%)
    1 / 24 (4.17%)
    3 / 26 (11.54%)
    0 / 25 (0.00%)
    13 / 279 (4.66%)
         occurrences all number
    6
    16
    1
    3
    0
    14
    Urinary tract infection
         subjects affected / exposed
    8 / 273 (2.93%)
    7 / 278 (2.52%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    7 / 279 (2.51%)
         occurrences all number
    13
    9
    1
    0
    2
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    57 / 273 (20.88%)
    101 / 278 (36.33%)
    9 / 24 (37.50%)
    8 / 26 (30.77%)
    7 / 25 (28.00%)
    71 / 279 (25.45%)
         occurrences all number
    65
    125
    12
    9
    8
    76
    Dehydration
         subjects affected / exposed
    7 / 273 (2.56%)
    17 / 278 (6.12%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    10 / 279 (3.58%)
         occurrences all number
    11
    26
    0
    0
    0
    10
    Hyperglycaemia
         subjects affected / exposed
    13 / 273 (4.76%)
    19 / 278 (6.83%)
    3 / 24 (12.50%)
    1 / 26 (3.85%)
    3 / 25 (12.00%)
    13 / 279 (4.66%)
         occurrences all number
    15
    23
    3
    1
    3
    20
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 273 (0.73%)
    1 / 278 (0.36%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 279 (0.36%)
         occurrences all number
    4
    1
    3
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 273 (0.37%)
    9 / 278 (3.24%)
    1 / 24 (4.17%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    5 / 279 (1.79%)
         occurrences all number
    1
    11
    1
    2
    4
    5
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 273 (0.37%)
    8 / 278 (2.88%)
    3 / 24 (12.50%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    5 / 279 (1.79%)
         occurrences all number
    1
    8
    3
    0
    2
    8
    Hypokalaemia
         subjects affected / exposed
    7 / 273 (2.56%)
    20 / 278 (7.19%)
    4 / 24 (16.67%)
    2 / 26 (7.69%)
    2 / 25 (8.00%)
    11 / 279 (3.94%)
         occurrences all number
    7
    30
    4
    3
    4
    13
    Hypomagnesaemia
         subjects affected / exposed
    9 / 273 (3.30%)
    15 / 278 (5.40%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    11 / 279 (3.94%)
         occurrences all number
    9
    21
    1
    0
    0
    14
    Hyponatraemia
         subjects affected / exposed
    15 / 273 (5.49%)
    35 / 278 (12.59%)
    5 / 24 (20.83%)
    2 / 26 (7.69%)
    4 / 25 (16.00%)
    22 / 279 (7.89%)
         occurrences all number
    25
    41
    9
    3
    4
    26

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 May 2017
    The protocol was amended to allow enrollment of patients from China.
    14 Jul 2018
    BICR-assessed PFS was changed as a primary objective to secondary objective. Tumor mutational burden (TMB) added as a potential predictive biomarker secondary objective.
    20 Sep 2018
    Moved OS of nivolumab vs placebo to secondary objectives.

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

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