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    Clinical Trial Results:
    An Open-Label, Randomized, Phase 3 Trial of Nivolumab versus Investigator Choice Chemotherapy as First-Line Therapy for Stage IV or Recurrent PD-L1+ Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2012-004502-93
    Trial protocol
    		 ES   DE   BE   AT   GB   SE   FI   CZ   HU   IT   FR   NL   RO   PL   GR  
    Global end of trial date
    27 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Feb 2023
    First version publication date
    22 Feb 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA209-026
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02041533
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International, Bristol-Myers Squibb International, 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
    25 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the PFS, based on IRRC assessment, of nivolumab monotherapy with investigator choice chemotherapy in subjects with stage IV or recurrent NSCLC with strongly PD-L1+ tumor expression.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. The rights, safety, and well-being of the study subjects were the most important consideration and prevailed over the interests of science and society.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 9
    Country: Number of subjects enrolled
    Australia: 22
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Czechia: 18
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Japan: 36
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 7
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Netherlands: 29
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Switzerland: 16
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 175
    Worldwide total number of subjects
    541
    EEA total number of subjects
    233
    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)
    281
    From 65 to 84 years
    256
    85 years and over
    4

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 541 participants were randomized, 530 participants were treated. Participants in the Investigator Choice Arm who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab.

    Period 1
    Period 1 title
    Pre-Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab
    Arm description
    		 Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity
    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 (3 mg/kg) as an IV infusion, every 2 weeks until disease progression or unacceptable toxicity

    Arm title
    		 Investigator Choice of Chemotherapy
    Arm description
    		 Administered in 3-week cycles for up to 6 cycles: Squamous: -gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or -gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or -paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: -pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or -pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg is administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1250 mg/m2) as a 30-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin (75 mg/m2) as a 30 to 120-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1000 mg/m2) as a 30-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed (500 mg/m2) as a 10-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel (200 mg/m2) as a 180-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin (AUC 6) as a 30 to 60-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin (AUC 5) as a 30 to 60-minute IV infusion for up to 6-cycles

    Number of subjects in period 1
    		Nivolumab Investigator Choice of Chemotherapy
    Started
    271
    270
    Completed
    267
    263
    Not completed
    4
    7
         Participant no Longer Meets Study Criteria
    3
    1
         Participant Withdrew Consent
    -
    5
         Disease Progression
    1
    1
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nivolumab
    Arm description
    		 Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity
    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 (3 mg/kg) as an IV infusion, every 2 weeks until disease progression or unacceptable toxicity

    Arm title
    		 Investigator Choice of Chemotherapy
    Arm description
    		 Administered in 3-week cycles for up to 6 cycles: Squamous: -gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or -gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or -paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: -pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or -pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1000 mg/m2) as a 30-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin (75 mg/m2) as a 30 to 120-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine (1250 mg/m2) as a 30-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin (AUC 6) as a 30 to 60-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel (200 mg/m2) as a 180-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed (500 mg/m2) as a 10-minute IV infusion for up to 6-cycles

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin (AUC 5) as a 30 to 60-minute IV infusion for up to 6-cycles

    Number of subjects in period 2
    		Nivolumab Investigator Choice of Chemotherapy
    Started
    267
    263
    Received optional Nivolumab
    0
    159
    Completed
    0
    28
    Not completed
    267
    235
         Study drug toxicity
    30
    34
         Death
    1
    -
         Not reported
    -
    1
         Maximum clinical benefit
    -
    18
         Adverse event unrelated to study drug
    22
    23
         Poor/Non-compliance
    1
    -
         Other reasons
    9
    2
         Participant Withdrew Consent
    2
    2
         Disease Progression
    189
    146
         Participant request to discontinue study treatment
    12
    9
         Administrative reason by sponsor
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity

    Reporting group title
    Investigator Choice of Chemotherapy
    Reporting group description
    		 Administered in 3-week cycles for up to 6 cycles: Squamous: -gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or -gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or -paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: -pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or -pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg is administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.

    Reporting group values
    		 Nivolumab Investigator Choice of Chemotherapy Total
    Number of subjects
    		 271 270 541
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 148 133 281
        From 65-84 years
    		 120 136 256
        85 years and over
    		 3 1 4
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.8 ( 10.25 ) 63.4 ( 9.63 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 87 122 209
        Male
    		 184 148 332
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 30 17 47
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 6 10 16
        White
    		 228 242 470
        Other
    		 6 1 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 3 7
        Not Hispanic or Latino
    		 141 139 280
        Unknown or Not Reported
    		 126 128 254

    End points

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    End points reporting groups
    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity

    Reporting group title
    Investigator Choice of Chemotherapy
    Reporting group description
    		 Administered in 3-week cycles for up to 6 cycles: Squamous: -gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or -gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or -paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: -pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or -pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total). Participants who progressed on or after chemotherapy could be eligible to receive optional crossover nivolumab 3 mg/kg is administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.
    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity

    Reporting group title
    Investigator Choice of Chemotherapy
    Reporting group description
    		 Administered in 3-week cycles for up to 6 cycles: Squamous: -gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or -gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or -paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: -pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or -pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total).

    Primary: Progression-Free Survival in participants with PD-L1 expression >= 5%

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    End point title
    		 Progression-Free Survival in participants with PD-L1 expression >= 5%
    End point description
    Progression-Free Survival (PFS) was defined as the time between the date of randomization and the first date of documented tumor progression, as determined by the Independent Radiology Review Committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause, whichever occurs first. Participants who die without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the day they were randomized. Participants who received subsequent anti-cancer therapy prior to documented progression were censored at the last evaluable tumor assessment prior to the initiation of new therapy.
    End point type
    Primary
    End point timeframe
    From date of randomization until date of documented tumor progression (assessed up to August 2016, approximately 28 months)
    End point values
    		 Nivolumab Investigator Choice of Chemotherapy
    Number of subjects analysed
    211
    212
    Units: Months
        median (confidence interval 95%)
    4.21 (2.96 to 5.55)
    5.88 (5.42 to 6.93)
    Statistical analysis title
    		 PFS in participants with PD-L1 expression >= 5%
    Comparison groups
    Nivolumab v Investigator Choice of Chemotherapy
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2511
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.45

    Secondary: Progression-Free Survival in all randomized participants

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    End point title
    		 Progression-Free Survival in all randomized participants
    End point description
    Progression-Free Survival (PFS) was defined as the time between the date of randomization and the first date of documented tumor progression, as determined by the Independent Radiology Review Committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause, whichever occurs first. Participants who die without a reported progression were considered to have progressed on the date of their death. Participants who did not progress or die were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the day they were randomized. Participants who received subsequent anti-cancer therapy prior to documented progression were censored at the last evaluable tumor assessment prior to the initiation of new therapy.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of documented tumor progression (assessed up to August 2016, approximately 28 months)
    End point values
    		 Nivolumab Investigator Choice of Chemotherapy
    Number of subjects analysed
    271
    270
    Units: Months
        median (confidence interval 95%)
    4.21 (3.06 to 5.52)
    5.82 (5.42 to 6.90)
    Statistical analysis title
    		 PFS in all randomized participants
    Comparison groups
    Nivolumab v Investigator Choice of Chemotherapy
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.43

    Secondary: Overall Survival in participants with PD-L1 expression >= 5%

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    End point title
    		 Overall Survival in participants with PD-L1 expression >= 5%
    End point description
    Overall Survival (OS) was defined as the time from randomization to the date of death. A participant who had not died was censored at the last known alive date. OS was censored at the date of randomization for participants who were randomized but had no follow-up.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of death (up to approximately 89 months)
    End point values
    		 Nivolumab Investigator Choice of Chemotherapy
    Number of subjects analysed
    211
    212
    Units: Months
        median (confidence interval 95%)
    14.36 (11.66 to 17.08)
    13.21 (10.81 to 17.28)
    Statistical analysis title
    		 OS in participants with PD-L1 expression >= 5%
    Comparison groups
    Nivolumab v Investigator Choice of Chemotherapy
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.2

    Secondary: Overall Survival in all randomized participants

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    End point title
    		 Overall Survival in all randomized participants
    End point description
    Overall Survival (OS) was defined as the time from randomization to the date of death. A participant who had not died was censored at the last known alive date. OS was censored at the date of randomization for participants who were randomized but had no follow-up.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of death (up to approximately 89 months)
    End point values
    		 Nivolumab Investigator Choice of Chemotherapy
    Number of subjects analysed
    271
    270
    Units: Months
        median (confidence interval 95%)
    13.73 (11.76 to 15.41)
    13.80 (11.01 to 16.99)
    Statistical analysis title
    		 OS in all randomized participants
    Comparison groups
    Nivolumab v Investigator Choice of Chemotherapy
    Number of subjects included in analysis
    541
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.24

    Secondary: Objective Response Rate (ORR) in participants with PD-L1 expression >= 5%

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    End point title
    		 Objective Response Rate (ORR) in participants with PD-L1 expression >= 5%
    End point description
    ORR was defined as the proportion of randomized participants who achieved a Best Overall Response (BOR) of CR or PR using the RECIST v1.1 criteria per Independent Radiology Review Committee (IRRC) assessment. BOR was defined as the best response designation recorded between the date of randomization and the date of objectively documented progression or start of subsequent anti-cancer therapy, whichever occurred first. For participants without documented progression or subsequent therapy, all available response designations contributed to the BOR assessment. For participants who continued treatment beyond progression, BOR was determined from response designations recorded up to the time of initial progression. CR= Disappearance of all evidence of disease, confirmed by PET scan; PR= Regression of measureable disease and no new sites; Stable Disease (SD)= Failure to attain CR/PR or PD; Progressive Disease (PD)= Any new lesion or increase by >=50% of previously involved sites from nadir.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of documented tumor progression or subsequent anti-cancer therapy, whichever occurs first (assessed up to August 2016, approximately 28 months)
    End point values
    		 Nivolumab Investigator Choice of Chemotherapy
    Number of subjects analysed
    211
    212
    Units: Percentage of participants
        number (confidence interval 95%)
    26.1 (20.3 to 32.5)
    33.5 (27.2 to 40.3)
    Statistical analysis title
    		 ORR in participants with PD-L1 expression >= 5%
    Comparison groups
    Nivolumab v Investigator Choice of Chemotherapy
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.06

    Secondary: Disease-related symptom improvement rate by Week 12

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    End point title
    		 Disease-related symptom improvement rate by Week 12
    End point description
    The Lung Cancer Symptom Score (LCSS) is a validated instrument designed to assess the impact of treatment on disease-related symptoms. It consists of 6 symptom-specific questions related to dyspnea, cough, fatigue, pain, hemoptysis and anorexia plus 3 summary items: symptom distress, interference with activity, and global HRQoL. The degree of impairment was recorded on a 100 mm visual analogue scale with scores from 0 to 100 with zero representing the best score. Disease-related symptom improvement rate by Week 12 is defined as the proportion of all randomized (all PD-L1+) participants who had 10 points or more decrease from baseline in average symptom burden index score at any time between randomization and Week 12.
    End point type
    Secondary
    End point timeframe
    From date of randomization to week 12
    End point values
    		 Nivolumab Investigator Choice of Chemotherapy
    Number of subjects analysed
    271
    270
    Units: Percentage of participants
        number (confidence interval 95%)
    35.4 (29.7 to 41.4)
    33.7 (28.1 to 39.7)
    No statistical analyses for this end point

    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 89 months). SAEs and NSAEs were assessed from first dose to 100 days following last dose (up to approximately 89 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Nivolumab
    Reporting group description
    		 Nivolumab 3mg/kg IV infusion, every 2 weeks until disease progression or unacceptable toxicity.

    Reporting group title
    Post Chemotherapy Optional Nivolumab
    Reporting group description
    		 Participants in the Investigator Choice Arm who progressed on or after chemotherapy transitioned to nivolumab at 3 mg/kg administered every 2 weeks until disease progression, discontinuation due to unacceptable toxicity, withdrawal of consent or study closure.

    Reporting group title
    Investigator's Choice of Chemotherapy
    Reporting group description
    		 Administered in 3-week cycles for up to 6 cycles: Squamous: -gemcitabine (1250 mg/mg2) with cisplatin (75 mg/m2); or -gemcitabine (1000 mg/m2) with carboplatin (AUC 5); or -paclitaxel (200 mg/m2) with carboplatin (AUC 6) Non-Squamous: -pemetrexed (500 mg/m2) with cisplatin (75 mg/m2); or -pemetrexed (500 mg/m2) with carboplatin (AUC 6) Subjects who discontinued cisplatin could be switched to gemcitabine/carboplatin for the remainder of the platinum doublet cycles (up to 6 cycles in total).

    Serious adverse events
    		 Nivolumab Post Chemotherapy Optional Nivolumab Investigator's Choice of Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    195 / 267 (73.03%)
    110 / 159 (69.18%)
    203 / 263 (77.19%)
         number of deaths (all causes)
    233
    136
    92
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal metastasis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Follicular lymphoma
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemangioblastoma
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    8 / 267 (3.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 267 (0.00%)
    2 / 159 (1.26%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    69 / 267 (25.84%)
    55 / 159 (34.59%)
    95 / 263 (36.12%)
         occurrences causally related to treatment / all
    0 / 76
    0 / 65
    0 / 105
         deaths causally related to treatment / all
    0 / 48
    0 / 51
    0 / 89
    Metastases to meninges
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesothelioma malignant
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    2 / 267 (0.75%)
    6 / 159 (3.77%)
    8 / 263 (3.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Metastases to liver
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    4 / 267 (1.50%)
    3 / 159 (1.89%)
    5 / 263 (1.90%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    3 / 267 (1.12%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Non-small cell lung cancer
         subjects affected / exposed
    2 / 267 (0.75%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Tumour associated fever
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    4 / 267 (1.50%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    5 / 267 (1.87%)
    0 / 159 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Air embolism
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    3 / 267 (1.12%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    4 / 263 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Extremity necrosis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leriche syndrome
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vein disorder
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular occlusion
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Illness
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 267 (1.50%)
    4 / 159 (2.52%)
    6 / 263 (2.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    3 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    2 / 267 (0.75%)
    3 / 159 (1.89%)
    8 / 263 (3.04%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 267 (2.62%)
    6 / 159 (3.77%)
    9 / 263 (3.42%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 6
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 267 (1.12%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Asthma
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 267 (1.12%)
    1 / 159 (0.63%)
    7 / 263 (2.66%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 267 (2.25%)
    5 / 159 (3.14%)
    9 / 263 (3.42%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Eosinophilic pneumonia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Haemothorax
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal haemorrhage
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mediastinal disorder
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    9 / 267 (3.37%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    10 / 10
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    4 / 267 (1.50%)
    2 / 159 (1.26%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    8 / 267 (3.00%)
    5 / 159 (3.14%)
    11 / 263 (4.18%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
    0 / 12
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    Pleural effusion
         subjects affected / exposed
    8 / 267 (3.00%)
    3 / 159 (1.89%)
    5 / 263 (1.90%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 6
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary microemboli
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 267 (1.50%)
    2 / 159 (1.26%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 267 (1.12%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Organic brain syndrome
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 267 (1.87%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 267 (2.25%)
    2 / 159 (1.26%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kyphosis postoperative
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular procedure complication
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tornwaldt cyst
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 267 (0.37%)
    3 / 159 (1.89%)
    6 / 263 (2.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    3 / 267 (1.12%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 267 (0.00%)
    2 / 159 (1.26%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 267 (0.75%)
    3 / 159 (1.89%)
    4 / 263 (1.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Atrial tachycardia
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 267 (0.00%)
    4 / 159 (2.52%)
    7 / 263 (2.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Cardiovascular disorder
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Aphasia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cubital tunnel syndrome
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant spinal cord compression
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IIIrd nerve paresis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Loss of consciousness
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasticity
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 267 (1.50%)
    0 / 159 (0.00%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIth nerve paresis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 267 (1.50%)
    1 / 159 (0.63%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    4 / 263 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 267 (1.12%)
    1 / 159 (0.63%)
    7 / 263 (2.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 267 (0.37%)
    2 / 159 (1.26%)
    16 / 263 (6.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    12 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    6 / 263 (2.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic nerve disorder
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic vein thrombosis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exophthalmos
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    4 / 267 (1.50%)
    3 / 159 (1.89%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    4 / 263 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 267 (2.62%)
    4 / 159 (2.52%)
    6 / 263 (2.28%)
         occurrences causally related to treatment / all
    4 / 7
    1 / 4
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Large intestine perforation
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 267 (1.50%)
    1 / 159 (0.63%)
    5 / 263 (1.90%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 267 (1.50%)
    1 / 159 (0.63%)
    5 / 263 (1.90%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 267 (0.75%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cholelithiasis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 267 (0.75%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal infarct
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 267 (0.00%)
    2 / 159 (1.26%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    4 / 267 (1.50%)
    2 / 159 (1.26%)
    4 / 263 (1.52%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 267 (0.75%)
    1 / 159 (0.63%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pain in extremity
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 267 (0.75%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 267 (0.75%)
    1 / 159 (0.63%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 267 (0.75%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    21 / 267 (7.87%)
    8 / 159 (5.03%)
    26 / 263 (9.89%)
         occurrences causally related to treatment / all
    2 / 25
    0 / 9
    5 / 35
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    0 / 4
    Peritonitis
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Norovirus infection
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    5 / 267 (1.87%)
    3 / 159 (1.89%)
    5 / 263 (1.90%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    1 / 3
    Respiratory tract infection
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Pulmonary sepsis
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Post procedural infection
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 267 (1.12%)
    2 / 159 (1.26%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    4 / 267 (1.50%)
    3 / 159 (1.89%)
    5 / 263 (1.90%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    5 / 267 (1.87%)
    2 / 159 (1.26%)
    4 / 263 (1.52%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    3 / 267 (1.12%)
    3 / 159 (1.89%)
    3 / 263 (1.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 267 (0.75%)
    2 / 159 (1.26%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 267 (0.37%)
    0 / 159 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 267 (0.00%)
    0 / 159 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 267 (0.00%)
    1 / 159 (0.63%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nivolumab Post Chemotherapy Optional Nivolumab Investigator's Choice of Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    245 / 267 (91.76%)
    137 / 159 (86.16%)
    252 / 263 (95.82%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 267 (6.74%)
    8 / 159 (5.03%)
    19 / 263 (7.22%)
         occurrences all number
    19
    12
    30
    Hypotension
         subjects affected / exposed
    9 / 267 (3.37%)
    8 / 159 (5.03%)
    14 / 263 (5.32%)
         occurrences all number
    11
    11
    19
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    9 / 267 (3.37%)
    9 / 159 (5.66%)
    25 / 263 (9.51%)
         occurrences all number
    10
    10
    27
    Asthenia
         subjects affected / exposed
    26 / 267 (9.74%)
    13 / 159 (8.18%)
    41 / 263 (15.59%)
         occurrences all number
    28
    28
    74
    Chills
         subjects affected / exposed
    18 / 267 (6.74%)
    6 / 159 (3.77%)
    18 / 263 (6.84%)
         occurrences all number
    21
    6
    20
    Pyrexia
         subjects affected / exposed
    37 / 267 (13.86%)
    22 / 159 (13.84%)
    55 / 263 (20.91%)
         occurrences all number
    56
    31
    97
    Pain
         subjects affected / exposed
    14 / 267 (5.24%)
    9 / 159 (5.66%)
    12 / 263 (4.56%)
         occurrences all number
    17
    10
    14
    Oedema peripheral
         subjects affected / exposed
    35 / 267 (13.11%)
    21 / 159 (13.21%)
    67 / 263 (25.48%)
         occurrences all number
    39
    22
    78
    Non-cardiac chest pain
         subjects affected / exposed
    25 / 267 (9.36%)
    11 / 159 (6.92%)
    21 / 263 (7.98%)
         occurrences all number
    30
    13
    26
    Mucosal inflammation
         subjects affected / exposed
    7 / 267 (2.62%)
    3 / 159 (1.89%)
    23 / 263 (8.75%)
         occurrences all number
    9
    3
    28
    Malaise
         subjects affected / exposed
    15 / 267 (5.62%)
    5 / 159 (3.14%)
    14 / 263 (5.32%)
         occurrences all number
    20
    7
    28
    Fatigue
         subjects affected / exposed
    108 / 267 (40.45%)
    47 / 159 (29.56%)
    134 / 263 (50.95%)
         occurrences all number
    130
    57
    194
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    17 / 267 (6.37%)
    8 / 159 (5.03%)
    20 / 263 (7.60%)
         occurrences all number
    25
    11
    29
    Epistaxis
         subjects affected / exposed
    8 / 267 (3.00%)
    4 / 159 (2.52%)
    22 / 263 (8.37%)
         occurrences all number
    8
    8
    36
    Dyspnoea
         subjects affected / exposed
    69 / 267 (25.84%)
    38 / 159 (23.90%)
    75 / 263 (28.52%)
         occurrences all number
    81
    57
    108
    Dysphonia
         subjects affected / exposed
    12 / 267 (4.49%)
    3 / 159 (1.89%)
    21 / 263 (7.98%)
         occurrences all number
    12
    3
    21
    Cough
         subjects affected / exposed
    77 / 267 (28.84%)
    37 / 159 (23.27%)
    79 / 263 (30.04%)
         occurrences all number
    99
    53
    115
    Oropharyngeal pain
         subjects affected / exposed
    8 / 267 (3.00%)
    5 / 159 (3.14%)
    15 / 263 (5.70%)
         occurrences all number
    11
    7
    17
    Pleural effusion
         subjects affected / exposed
    8 / 267 (3.00%)
    9 / 159 (5.66%)
    16 / 263 (6.08%)
         occurrences all number
    10
    11
    21
    Pneumonitis
         subjects affected / exposed
    12 / 267 (4.49%)
    15 / 159 (9.43%)
    17 / 263 (6.46%)
         occurrences all number
    13
    18
    20
    Productive cough
         subjects affected / exposed
    30 / 267 (11.24%)
    8 / 159 (5.03%)
    25 / 263 (9.51%)
         occurrences all number
    36
    13
    33
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    17 / 267 (6.37%)
    12 / 159 (7.55%)
    18 / 263 (6.84%)
         occurrences all number
    19
    12
    20
    Depression
         subjects affected / exposed
    14 / 267 (5.24%)
    4 / 159 (2.52%)
    13 / 263 (4.94%)
         occurrences all number
    15
    4
    13
    Insomnia
         subjects affected / exposed
    24 / 267 (8.99%)
    18 / 159 (11.32%)
    40 / 263 (15.21%)
         occurrences all number
    27
    18
    46
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    13 / 267 (4.87%)
    17 / 159 (10.69%)
    34 / 263 (12.93%)
         occurrences all number
    28
    20
    54
    Blood alkaline phosphatase increased
         subjects affected / exposed
    22 / 267 (8.24%)
    7 / 159 (4.40%)
    18 / 263 (6.84%)
         occurrences all number
    29
    9
    30
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    10 / 267 (3.75%)
    4 / 159 (2.52%)
    14 / 263 (5.32%)
         occurrences all number
    11
    4
    16
    Alanine aminotransferase increased
         subjects affected / exposed
    31 / 267 (11.61%)
    13 / 159 (8.18%)
    30 / 263 (11.41%)
         occurrences all number
    34
    19
    47
    Aspartate aminotransferase increased
         subjects affected / exposed
    39 / 267 (14.61%)
    10 / 159 (6.29%)
    28 / 263 (10.65%)
         occurrences all number
    53
    19
    48
    Lymphocyte count decreased
         subjects affected / exposed
    18 / 267 (6.74%)
    5 / 159 (3.14%)
    18 / 263 (6.84%)
         occurrences all number
    38
    20
    49
    Neutrophil count decreased
         subjects affected / exposed
    9 / 267 (3.37%)
    4 / 159 (2.52%)
    43 / 263 (16.35%)
         occurrences all number
    21
    5
    70
    Platelet count decreased
         subjects affected / exposed
    12 / 267 (4.49%)
    1 / 159 (0.63%)
    38 / 263 (14.45%)
         occurrences all number
    24
    1
    60
    Weight decreased
         subjects affected / exposed
    42 / 267 (15.73%)
    12 / 159 (7.55%)
    37 / 263 (14.07%)
         occurrences all number
    47
    13
    39
    White blood cell count decreased
         subjects affected / exposed
    7 / 267 (2.62%)
    6 / 159 (3.77%)
    33 / 263 (12.55%)
         occurrences all number
    15
    8
    47
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    15 / 267 (5.62%)
    5 / 159 (3.14%)
    11 / 263 (4.18%)
         occurrences all number
    17
    7
    16
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    14 / 267 (5.24%)
    7 / 159 (4.40%)
    25 / 263 (9.51%)
         occurrences all number
    17
    7
    30
    Dizziness
         subjects affected / exposed
    30 / 267 (11.24%)
    21 / 159 (13.21%)
    41 / 263 (15.59%)
         occurrences all number
    36
    27
    63
    Peripheral sensory neuropathy
         subjects affected / exposed
    7 / 267 (2.62%)
    7 / 159 (4.40%)
    24 / 263 (9.13%)
         occurrences all number
    9
    7
    27
    Neuropathy peripheral
         subjects affected / exposed
    5 / 267 (1.87%)
    8 / 159 (5.03%)
    15 / 263 (5.70%)
         occurrences all number
    5
    8
    15
    Headache
         subjects affected / exposed
    30 / 267 (11.24%)
    19 / 159 (11.95%)
    50 / 263 (19.01%)
         occurrences all number
    37
    31
    70
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 267 (0.37%)
    1 / 159 (0.63%)
    17 / 263 (6.46%)
         occurrences all number
    1
    1
    25
    Anaemia
         subjects affected / exposed
    54 / 267 (20.22%)
    38 / 159 (23.90%)
    142 / 263 (53.99%)
         occurrences all number
    84
    54
    235
    Neutropenia
         subjects affected / exposed
    5 / 267 (1.87%)
    4 / 159 (2.52%)
    54 / 263 (20.53%)
         occurrences all number
    5
    5
    101
    Thrombocytopenia
         subjects affected / exposed
    5 / 267 (1.87%)
    4 / 159 (2.52%)
    40 / 263 (15.21%)
         occurrences all number
    7
    9
    66
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    3 / 267 (1.12%)
    1 / 159 (0.63%)
    21 / 263 (7.98%)
         occurrences all number
    7
    1
    21
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    86 / 267 (32.21%)
    36 / 159 (22.64%)
    149 / 263 (56.65%)
         occurrences all number
    126
    41
    270
    Abdominal pain upper
         subjects affected / exposed
    11 / 267 (4.12%)
    9 / 159 (5.66%)
    23 / 263 (8.75%)
         occurrences all number
    11
    11
    27
    Constipation
         subjects affected / exposed
    65 / 267 (24.34%)
    24 / 159 (15.09%)
    84 / 263 (31.94%)
         occurrences all number
    73
    30
    123
    Diarrhoea
         subjects affected / exposed
    84 / 267 (31.46%)
    29 / 159 (18.24%)
    82 / 263 (31.18%)
         occurrences all number
    124
    42
    119
    Dry mouth
         subjects affected / exposed
    13 / 267 (4.87%)
    8 / 159 (5.03%)
    12 / 263 (4.56%)
         occurrences all number
    13
    8
    13
    Dyspepsia
         subjects affected / exposed
    19 / 267 (7.12%)
    2 / 159 (1.26%)
    13 / 263 (4.94%)
         occurrences all number
    20
    3
    15
    Abdominal pain
         subjects affected / exposed
    35 / 267 (13.11%)
    12 / 159 (7.55%)
    32 / 263 (12.17%)
         occurrences all number
    41
    14
    38
    Vomiting
         subjects affected / exposed
    59 / 267 (22.10%)
    16 / 159 (10.06%)
    77 / 263 (29.28%)
         occurrences all number
    87
    18
    126
    Stomatitis
         subjects affected / exposed
    13 / 267 (4.87%)
    5 / 159 (3.14%)
    20 / 263 (7.60%)
         occurrences all number
    14
    5
    29
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    39 / 267 (14.61%)
    20 / 159 (12.58%)
    37 / 263 (14.07%)
         occurrences all number
    58
    24
    46
    Pruritus
         subjects affected / exposed
    39 / 267 (14.61%)
    17 / 159 (10.69%)
    31 / 263 (11.79%)
         occurrences all number
    59
    26
    42
    Dry skin
         subjects affected / exposed
    22 / 267 (8.24%)
    14 / 159 (8.81%)
    26 / 263 (9.89%)
         occurrences all number
    28
    15
    29
    Alopecia
         subjects affected / exposed
    9 / 267 (3.37%)
    3 / 159 (1.89%)
    26 / 263 (9.89%)
         occurrences all number
    9
    3
    26
    Rash maculo-papular
         subjects affected / exposed
    18 / 267 (6.74%)
    6 / 159 (3.77%)
    12 / 263 (4.56%)
         occurrences all number
    24
    8
    16
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    23 / 267 (8.61%)
    14 / 159 (8.81%)
    23 / 263 (8.75%)
         occurrences all number
    28
    14
    24
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    53 / 267 (19.85%)
    29 / 159 (18.24%)
    47 / 263 (17.87%)
         occurrences all number
    63
    43
    67
    Back pain
         subjects affected / exposed
    42 / 267 (15.73%)
    23 / 159 (14.47%)
    62 / 263 (23.57%)
         occurrences all number
    51
    24
    67
    Muscular weakness
         subjects affected / exposed
    17 / 267 (6.37%)
    9 / 159 (5.66%)
    26 / 263 (9.89%)
         occurrences all number
    18
    17
    38
    Musculoskeletal chest pain
         subjects affected / exposed
    18 / 267 (6.74%)
    5 / 159 (3.14%)
    13 / 263 (4.94%)
         occurrences all number
    19
    5
    14
    Myalgia
         subjects affected / exposed
    28 / 267 (10.49%)
    10 / 159 (6.29%)
    28 / 263 (10.65%)
         occurrences all number
    31
    12
    31
    Pain in extremity
         subjects affected / exposed
    23 / 267 (8.61%)
    11 / 159 (6.92%)
    31 / 263 (11.79%)
         occurrences all number
    27
    12
    32
    Muscle spasms
         subjects affected / exposed
    9 / 267 (3.37%)
    10 / 159 (6.29%)
    14 / 263 (5.32%)
         occurrences all number
    10
    12
    17
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    13 / 267 (4.87%)
    10 / 159 (6.29%)
    19 / 263 (7.22%)
         occurrences all number
    16
    11
    24
    Nasopharyngitis
         subjects affected / exposed
    19 / 267 (7.12%)
    10 / 159 (6.29%)
    20 / 263 (7.60%)
         occurrences all number
    42
    18
    39
    Pneumonia
         subjects affected / exposed
    25 / 267 (9.36%)
    9 / 159 (5.66%)
    23 / 263 (8.75%)
         occurrences all number
    29
    10
    27
    Urinary tract infection
         subjects affected / exposed
    14 / 267 (5.24%)
    4 / 159 (2.52%)
    13 / 263 (4.94%)
         occurrences all number
    16
    6
    19
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 267 (8.99%)
    9 / 159 (5.66%)
    24 / 263 (9.13%)
         occurrences all number
    34
    9
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    91 / 267 (34.08%)
    37 / 159 (23.27%)
    102 / 263 (38.78%)
         occurrences all number
    112
    40
    171
    Dehydration
         subjects affected / exposed
    10 / 267 (3.75%)
    7 / 159 (4.40%)
    19 / 263 (7.22%)
         occurrences all number
    12
    7
    23
    Hyperglycaemia
         subjects affected / exposed
    19 / 267 (7.12%)
    10 / 159 (6.29%)
    18 / 263 (6.84%)
         occurrences all number
    35
    19
    37
    Hyperkalaemia
         subjects affected / exposed
    15 / 267 (5.62%)
    11 / 159 (6.92%)
    19 / 263 (7.22%)
         occurrences all number
    25
    32
    53
    Hypoalbuminaemia
         subjects affected / exposed
    28 / 267 (10.49%)
    11 / 159 (6.92%)
    27 / 263 (10.27%)
         occurrences all number
    35
    14
    37
    Hypokalaemia
         subjects affected / exposed
    24 / 267 (8.99%)
    13 / 159 (8.18%)
    31 / 263 (11.79%)
         occurrences all number
    27
    18
    47
    Hypophosphataemia
         subjects affected / exposed
    6 / 267 (2.25%)
    6 / 159 (3.77%)
    17 / 263 (6.46%)
         occurrences all number
    7
    16
    43
    Hyponatraemia
         subjects affected / exposed
    28 / 267 (10.49%)
    13 / 159 (8.18%)
    37 / 263 (14.07%)
         occurrences all number
    57
    23
    65
    Hypomagnesaemia
         subjects affected / exposed
    16 / 267 (5.99%)
    19 / 159 (11.95%)
    49 / 263 (18.63%)
         occurrences all number
    21
    33
    78

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2014
    Updated guidelines for use of palliative local therapy, Best Overall Response was added to the Efficacy Assessments section, and the Inclusion Criteria were updated.
    08 Sep 2014
    The requirements for submission of tumor tissue slides during the Screening Phase of the study were modified. Additional updates to the eligibility criteria were also made.
    12 Feb 2015
    Clarifications as to the sample size and timing of the primary analysis were added. The order of the first two secondary objectives were also changed. Additional changes included a clarification of the tumor assessment submission duration, an update of tissue requirements for PDL1 testing, and that survival data collection may be requested outside the protocol defined 3-month window.
    09 Dec 2015
    The timing of the final analysis of PFS based on external data was updated. In addition, an interim analysis of PFS was included. OS was moved ahead of ORR in the hierarchical testing of secondary efficacy endpoints.
    31 May 2016
    The interim analysis for superiority was removed. An additional secondary objective of comparing overall survival associated with nivolumab monotherapy and investigator’s choice chemotherapy in subjects with any PD-L1+ tumor expression was specified.
    24 Aug 2016
    Study-related procedures were updated after the final analysis data base lock on 02-Aug-2016 demonstrated that the study did not meet its primary endpoint of PFS as assessed by the IRRC among subjects with strongly PD-L1+ tumor expression. Changes from the updated nivolumab IB Version 15 and Erratum 01, including those related to the use of contraceptives were also incorporated.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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