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    Clinical Trial Results:
    A Randomized, Multicenter, Double-Blind Phase 3 Trial Comparing the Efficacy of Ipilimumab in Addition to Paclitaxel and Carboplatin versus Placebo in Addition to Paclitaxel and Carboplatin in Subjects with Stage IV/Recurrent Non-Small Cell Lung Cancer (NSCLC)

    Summary
    EudraCT number
    		 2009-017396-19
    Trial protocol
    		 HU   SE   DE   BE   GB   AT   NL   DK   CZ   PT   IE   ES   IT  
    Global end of trial date
    22 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Sep 2018
    First version publication date
    07 Sep 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CA184-104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 Corporation, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare overall survival (OS) of ipilimumab + paclitaxel/carboplatin to placebo + paclitaxel/carboplatin in subjects with stage IV or recurrent non-small cell lung cancer (NSCLC) of squamous histology who received at least one dose of blinded study therapy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 18
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Chile: 29
    Country: Number of subjects enrolled
    China: 72
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Czech Republic: 35
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    France: 43
    Country: Number of subjects enrolled
    Germany: 102
    Country: Number of subjects enrolled
    Hungary: 71
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    Israel: 28
    Country: Number of subjects enrolled
    Italy: 61
    Country: Number of subjects enrolled
    Japan: 84
    Country: Number of subjects enrolled
    Korea, Republic of: 98
    Country: Number of subjects enrolled
    Mexico: 22
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Portugal: 17
    Country: Number of subjects enrolled
    Romania: 66
    Country: Number of subjects enrolled
    Russian Federation: 103
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Taiwan: 47
    Country: Number of subjects enrolled
    Thailand: 35
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 106
    Country: Number of subjects enrolled
    South Africa: 3
    Worldwide total number of subjects
    1289
    EEA total number of subjects
    576
    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)
    670
    From 65 to 84 years
    616
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1289 participants were enrolled and 956 were randomized (479 Ipilimumab, 477 Placebo). 948 were treated (475 Ipilimumab, 473 Placebo). Reasons for non-treatment is 4 no longer met study criteria, 2 adverse events unrelated to study drug, 1 participant request to discontinue, and 1 other .

    Period 1
    Period 1 title
    Randomized
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipilimumab with Paclitaxel/Carboplatin
    Arm description
    		 Ipilimumab + Active Chemotherapy Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection, 200 mg/vial

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection, 50 mg/vial

    Investigational medicinal product name
    Taxol (for IV infusion)
    Investigational medicinal product code
    Other name
    Paclitaxel
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The prescribed dose of TAXOL should be diluted in 500 mL of 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, or 5% dextrose in Ringer’s injection. A concentration of 1.2 mg/mL should not be exceeded.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    These dilutions all produce a carboplatin concentration of 10 mg/mL. PARAPLATIN can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. When prepared as directed, PARAPLATIN solutions are stable for 8 hours at room temperature (25 C).

    Arm title
    		 Placebo with Paclitaxel/Carboplatin
    Arm description
    		 Placebo + Active Chemotherapy Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo of Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection, 200 mg/vial

    Investigational medicinal product name
    Taxol (for IV infusion)
    Investigational medicinal product code
    Other name
    Paclitaxel
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The prescribed dose of TAXOL should be diluted in 500 mL of 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, or 5% dextrose in Ringer’s injection. A concentration of 1.2 mg/mL should not be exceeded.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    These dilutions all produce a carboplatin concentration of 10 mg/mL. PARAPLATIN can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. When prepared as directed, PARAPLATIN solutions are stable for 8 hours at room temperature (25 C).

    Investigational medicinal product name
    Placebo of Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection, 50 mg/vial

    Number of subjects in period 1
    		Ipilimumab with Paclitaxel/Carboplatin Placebo with Paclitaxel/Carboplatin
    Started
    479
    477
    Treated with Chemotherapy (1st dose)
    475
    473
    Completed
    388
    361
    Not completed
    91
    116
         Adverse event, serious fatal
    5
    7
         Consent withdrawn by subject
    8
    11
         Undisclosed Reasons
    1
    -
         Progressive Disease
    41
    61
         Subject No Longer Met Study Criteria
    1
    1
         Adverse Event Unrelated to Study Drug
    18
    18
         Randomized but not Treated
    4
    4
         Study Drug Toxicity
    13
    14
    Period 2
    Period 2 title
    Treated with Blinded Therapy
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipilimumab with Paclitaxel/Carboplatin
    Arm description
    		 Ipilimumab + Active Chemotherapy Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection, 200 mg/vial

    Investigational medicinal product name
    Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection, 50 mg/vial

    Investigational medicinal product name
    Taxol (for IV infusion)
    Investigational medicinal product code
    Other name
    Paclitaxel
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The prescribed dose of TAXOL should be diluted in 500 mL of 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, or 5% dextrose in Ringer’s injection. A concentration of 1.2 mg/mL should not be exceeded.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    These dilutions all produce a carboplatin concentration of 10 mg/mL. PARAPLATIN can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. When prepared as directed, PARAPLATIN solutions are stable for 8 hours at room temperature (25 C).

    Arm title
    		 Placebo with Paclitaxel/Carboplatin
    Arm description
    		 Placebo + Active Chemotherapy Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo of Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection, 200 mg/vial

    Investigational medicinal product name
    Taxol (for IV infusion)
    Investigational medicinal product code
    Other name
    Paclitaxel
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The prescribed dose of TAXOL should be diluted in 500 mL of 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, or 5% dextrose in Ringer’s injection. A concentration of 1.2 mg/mL should not be exceeded.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    PARAPLATIN
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    These dilutions all produce a carboplatin concentration of 10 mg/mL. PARAPLATIN can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. When prepared as directed, PARAPLATIN solutions are stable for 8 hours at room temperature (25 C).

    Investigational medicinal product name
    Placebo of Ipilimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Injection, 50 mg/vial

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The baseline period for this study covers only subjects that have been treated with blinded therapy.
    Number of subjects in period 2 [2]
    		Ipilimumab with Paclitaxel/Carboplatin Placebo with Paclitaxel/Carboplatin
    Started
    388
    361
    Completed
    1
    2
    Not completed
    387
    359
         Adverse event, serious fatal
    11
    3
         Poor/Non-Compliance
    1
    2
         Not Reported
    -
    2
         Physician and subject decision
    1
    3
         Maximum Clinical Benefit
    2
    4
         Subject refused participation
    1
    -
         Subject hospitalized
    1
    -
         Study Drug Toxicity
    87
    14
         Worsening of general condition
    -
    1
         Consent withdrawn by subject
    20
    7
         Progressive Disease
    223
    305
         Subject No Longer Met Study Criteria
    1
    -
         Adverse Event Unrelated to Study Drug
    36
    14
         PI decision to discontinue
    -
    1
         Subject started radiotherapy
    1
    -
         Administrative Reason by Sponsor
    1
    3
         Investigator assessment
    1
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial as out of 1289 subjects who were enrolled only 956 were randomised and 948 were treated. Reasons for no treatment after randomisation include: 4 no longer met study criteria, 2 adverse events unrelated to study drug, 1 participant request to discontinue, and 1 other .

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treated with Blinded Therapy
    Reporting group description
    		 -

    Reporting group values
    		 Treated with Blinded Therapy Total
    Number of subjects
    		 749 749
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 380 380
        From 65-84 years
    		 368 368
        85 years and over
    		 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.7 ± 8.47 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 114 114
        Male
    		 635 635
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1
        Asian
    		 214 214
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 6 6
        White
    		 519 519
        More than one race
    		 0 0
        Unknown or Not Reported
    		 9 9
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG Performance Status is a 6-item scale used to assess disease progression, daily functioning, appropriate treatment, and prognosis. Performance status is scored on a scale ranging from 0-5, with (best score) 0=fully active and able to carry on all pre-disease performance without restriction and (worst score) 5=death.
    Units: Subjects
        baseline ECOG = 0
    		 259 259
        baseline ECOG = 1
    		 485 485
        baseline ECOG = 2
    		 4 4
        baseline ECOG = 3
    		 1 1
    Disease Stage at Study Entry
    Non-Small Cell Lung Cancer is categorized in 4 Stages (I-IV). I: Cancer located only in lungs and has not spread to any lymph nodes. II: Cancer in the lung and nearby lymph nodes. III: Cancer in the lung and lymph nodes in the middle of the chest. Stage III has two subtypes, IIIA (cancer has spread only to lymph nodes on the same side of the chest where the cancer started) and IIIB (cancer has spread to the lymph nodes on the opposite side of the chest, or above the collar bone). IV: Cancer has spread to both lungs, to fluid in the area around the lungs, or to another part of the body.
    Units: Subjects
        Stage IV
    		 700 700
        Recurrent
    		 49 49

    End points

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    End points reporting groups
    Reporting group title
    Ipilimumab with Paclitaxel/Carboplatin
    Reporting group description
    		 Ipilimumab + Active Chemotherapy Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses

    Reporting group title
    Placebo with Paclitaxel/Carboplatin
    Reporting group description
    		 Placebo + Active Chemotherapy Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses
    Reporting group title
    Ipilimumab with Paclitaxel/Carboplatin
    Reporting group description
    		 Ipilimumab + Active Chemotherapy Backbone The blinded therapy (Ipilimumab) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemo Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses

    Reporting group title
    Placebo with Paclitaxel/Carboplatin
    Reporting group description
    		 Placebo + Active Chemotherapy Backbone The blinded therapy (Placebo) started at the 3rd dose of active chemotherapy backbone (Paclitaxel/Carboplatin). Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Active Chemotherapy Backbone: Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses

    Primary: Overall Survival (OS) in Participants who received at least one dose of blinded study therapy at Primary Endpoint

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    End point title
    		 Overall Survival (OS) in Participants who received at least one dose of blinded study therapy at Primary Endpoint
    End point description
    Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred when the following 2 conditions were both met: (1) 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and (2) 705 deaths were observed in all randomized participants.
    End point type
    Primary
    End point timeframe
    Randomization until 518 deaths, up to June 2015 (approximately 48 months post study start)
    End point values
    		 Ipilimumab with Paclitaxel/Carboplatin Placebo with Paclitaxel/Carboplatin
    Number of subjects analysed
    388
    361
    Units: months
        median (confidence interval 95%)
    13.37 (11.76 to 14.78)
    12.42 (11.60 to 13.63)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Hazard ratio = Ipilimumab with Paclitaxel/Carboplatin over Placebo with Paclitaxel/Carboplatin
    Comparison groups
    Ipilimumab with Paclitaxel/Carboplatin v Placebo with Paclitaxel/Carboplatin
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2517
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.907
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.767
         upper limit
    		 1.072

    Secondary: Overall Survival (OS) in all Randomized Participants at Primary Endpoint

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    End point title
    		 Overall Survival (OS) in all Randomized Participants at Primary Endpoint
    End point description
    Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Interim analysis for the Primary Endpoint occurred when the following 2 conditions were both met: (1) 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and (2) 705 deaths were observed in all randomized participants.
    End point type
    Secondary
    End point timeframe
    Randomization until 705 deaths, up to June 2015 (approximately 48 months post study start)
    End point values
    		 Ipilimumab with Paclitaxel/Carboplatin Placebo with Paclitaxel/Carboplatin
    Number of subjects analysed
    479
    477
    Units: months
        median (confidence interval 95%)
    10.94 (9.56 to 12.02)
    10.74 (9.66 to 11.73)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Hazard ratio = Ipilimumab with Paclitaxel/Carboplatin over Placebo with Paclitaxel/Carboplatin
    Comparison groups
    Ipilimumab with Paclitaxel/Carboplatin v Placebo with Paclitaxel/Carboplatin
    Number of subjects included in analysis
    956
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2421 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.917
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.792
         upper limit
    		 1.061
    Notes
    [1] - p-value based on stratified 2-sided log-rank test

    Secondary: Median Number of Months with Progression Free Survival (PFS) per mWHO in participants who have received at least one dose of blinded study therapy at Primary Endpoint

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    End point title
    		 Median Number of Months with Progression Free Survival (PFS) per mWHO in participants who have received at least one dose of blinded study therapy at Primary Endpoint
    End point description
    Progression-free survival (PFS) is defined as the time between the date of randomization and the date of tumor progression per Modified World Health Organization (mWHO) criteria or death, whichever occurs first. A participant who died without reported progression per mWHO criteria were considered to have progressed on the date of death. For participants who remain alive and have not progressed, PFS was censored on the date of last evaluable tumor assessment. For participants who remain alive and have no recorded post-baseline tumor assessment, PFS was censored on the day of randomization.
    End point type
    Secondary
    End point timeframe
    Randomization until 518 deaths, up to June 2015 (approximately 48 months post study start)
    End point values
    		 Ipilimumab with Paclitaxel/Carboplatin Placebo with Paclitaxel/Carboplatin
    Number of subjects analysed
    388
    361
    Units: months
        median (confidence interval 95%)
    5.55 (5.36 to 5.85)
    5.59 (5.52 to 5.72)
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    Hazard ratio = Ipilimumab with Paclitaxel/Carboplatin over Placebo with Paclitaxel/Carboplatin
    Comparison groups
    Ipilimumab with Paclitaxel/Carboplatin v Placebo with Paclitaxel/Carboplatin
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0678
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.869
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.749
         upper limit
    		 1.009

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study therapy and within 90 days of the last dose
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Ipilimumab + Paclitaxel/Carboplatin
    Reporting group description
    		 Subjects received Ipilimumab 10 milligram per kilogram (mg/kg) intravenous (IV) 90 minute infusion once every 3 weeks (q 3 weeks) for up to 4 doses starting at Cycle 3/week 7, then every 12 weeks for a maximum treatment period of 3 years from the first dose; Paclitaxel 175 milligram per meter square (mg/m^2) IV q 3 weeks for up to 6 doses starting at randomization; Carboplatin area under the curve (AUC) equal to (=) 6 IV q 3 weeks for up to 6 doses starting at randomization.

    Reporting group title
    Placebo + Paclitaxel/ Carboplatin
    Reporting group description
    		 Subjects received Placebo IV q 3 weeks for up to 4 doses starting at Cycle 3/week 7 then q 12 weeks for a maximum treatment period of 3 years from the first dose; Paclitaxel 175 mg/m^2 IV q 3 weeks for up to 6 doses starting at randomization; Carboplatin AUC = 6 IV q 3 weeks for up to 6 doses starting at randomization.

    Serious adverse events
    		 Ipilimumab + Paclitaxel/Carboplatin Placebo + Paclitaxel/ Carboplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    300 / 475 (63.16%)
    235 / 473 (49.68%)
         number of deaths (all causes)
    359
    371
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung cancer metastatic
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colorectal cancer
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    3 / 475 (0.63%)
    8 / 473 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 8
    Malignant neoplasm progression
         subjects affected / exposed
    35 / 475 (7.37%)
    37 / 473 (7.82%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 38
         deaths causally related to treatment / all
    0 / 35
    0 / 36
    Metastases to central nervous system
         subjects affected / exposed
    3 / 475 (0.63%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to liver
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Neoplasm progression
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Small cell lung cancer
         subjects affected / exposed
    2 / 475 (0.42%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Tumour perforation
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tumour compression
         subjects affected / exposed
    0 / 475 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 475 (0.42%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis superficial
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava occlusion
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 475 (1.05%)
    7 / 473 (1.48%)
         occurrences causally related to treatment / all
    5 / 6
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 475 (0.21%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    10 / 475 (2.11%)
    7 / 473 (1.48%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 7
         deaths causally related to treatment / all
    0 / 10
    0 / 7
    Device occlusion
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    4 / 475 (0.84%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Extravasation
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    7 / 475 (1.47%)
    10 / 473 (2.11%)
         occurrences causally related to treatment / all
    2 / 8
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    8 / 475 (1.68%)
    7 / 473 (1.48%)
         occurrences causally related to treatment / all
    4 / 8
    5 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-Organ failure
         subjects affected / exposed
    3 / 475 (0.63%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 3
    1 / 1
    Pain
         subjects affected / exposed
    3 / 475 (0.63%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    3 / 475 (0.63%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Performance status decreased
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    21 / 475 (4.42%)
    14 / 473 (2.96%)
         occurrences causally related to treatment / all
    8 / 24
    2 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 475 (0.63%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    3 / 475 (0.63%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 475 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial disorder
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 475 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 475 (0.84%)
    8 / 473 (1.69%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchostenosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    9 / 475 (1.89%)
    10 / 473 (2.11%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Dyspnoea
         subjects affected / exposed
    17 / 475 (3.58%)
    16 / 473 (3.38%)
         occurrences causally related to treatment / all
    2 / 17
    2 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hiccups
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 475 (0.63%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 475 (0.42%)
    6 / 473 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    4 / 475 (0.84%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 475 (0.84%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery stenosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    11 / 475 (2.32%)
    10 / 473 (2.11%)
         occurrences causally related to treatment / all
    2 / 11
    2 / 11
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Pulmonary haemorrhage
         subjects affected / exposed
    4 / 475 (0.84%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Pulmonary infarction
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 475 (1.26%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Tachypnoea
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 475 (0.63%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    5 / 475 (1.05%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    2 / 475 (0.42%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    C-Reactive protein increased
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    3 / 475 (0.63%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 475 (0.21%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal function test abnormal
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asbestosis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain herniation
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Fall
         subjects affected / exposed
    0 / 475 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart injury
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 475 (0.21%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Toxicity to various agents
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 475 (1.05%)
    8 / 473 (1.69%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 475 (0.42%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    Atrial flutter
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 475 (0.21%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-Respiratory arrest
         subjects affected / exposed
    5 / 475 (1.05%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    1 / 5
    0 / 2
    Cardiogenic shock
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 475 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 475 (0.63%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersomnia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Migraine
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 475 (0.63%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord paralysis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    21 / 475 (4.42%)
    10 / 473 (2.11%)
         occurrences causally related to treatment / all
    19 / 23
    8 / 10
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    20 / 475 (4.21%)
    11 / 473 (2.33%)
         occurrences causally related to treatment / all
    23 / 23
    9 / 11
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    2 / 475 (0.42%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 475 (0.63%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    3 / 3
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    16 / 475 (3.37%)
    9 / 473 (1.90%)
         occurrences causally related to treatment / all
    16 / 17
    12 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    7 / 475 (1.47%)
    11 / 473 (2.33%)
         occurrences causally related to treatment / all
    7 / 7
    10 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 475 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Pupils unequal
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 475 (0.63%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    2 / 475 (0.42%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    14 / 475 (2.95%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    17 / 18
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Diarrhoea
         subjects affected / exposed
    37 / 475 (7.79%)
    10 / 473 (2.11%)
         occurrences causally related to treatment / all
    42 / 46
    8 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 475 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematemesis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 475 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    3 / 475 (0.63%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 475 (0.42%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 475 (1.26%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    3 / 6
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-Induced liver injury
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exfoliative rash
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perivascular dermatitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    6 / 475 (1.26%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 475 (0.63%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 475 (0.84%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorder
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothalamo-Pituitary disorder
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 475 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 475 (0.63%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 475 (0.21%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 475 (0.42%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 475 (0.63%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 475 (0.63%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    9 / 475 (1.89%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    1 / 11
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    3 / 475 (0.63%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 475 (0.21%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Necrotising fasciitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pharyngitis
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal infection
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    37 / 475 (7.79%)
    34 / 473 (7.19%)
         occurrences causally related to treatment / all
    11 / 41
    7 / 45
         deaths causally related to treatment / all
    1 / 3
    1 / 6
    Pneumonia bacterial
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sepsis
         subjects affected / exposed
    7 / 475 (1.47%)
    7 / 473 (1.48%)
         occurrences causally related to treatment / all
    2 / 8
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Staphylococcal infection
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 475 (0.63%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viraemia
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 475 (0.21%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cachexia
         subjects affected / exposed
    2 / 475 (0.42%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dehydration
         subjects affected / exposed
    8 / 475 (1.68%)
    7 / 473 (1.48%)
         occurrences causally related to treatment / all
    4 / 9
    3 / 7
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Fulminant type 1 diabetes mellitus
         subjects affected / exposed
    1 / 475 (0.21%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 475 (0.63%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 475 (0.42%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 475 (0.21%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 475 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 475 (0.63%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ipilimumab + Paclitaxel/Carboplatin Placebo + Paclitaxel/ Carboplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    437 / 475 (92.00%)
    428 / 473 (90.49%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    37 / 475 (7.79%)
    26 / 473 (5.50%)
         occurrences all number
    45
    29
    Neutrophil count decreased
         subjects affected / exposed
    31 / 475 (6.53%)
    31 / 473 (6.55%)
         occurrences all number
    55
    66
    Aspartate aminotransferase increased
         subjects affected / exposed
    34 / 475 (7.16%)
    20 / 473 (4.23%)
         occurrences all number
    45
    24
    Platelet count decreased
         subjects affected / exposed
    47 / 475 (9.89%)
    32 / 473 (6.77%)
         occurrences all number
    70
    52
    Haemoglobin decreased
         subjects affected / exposed
    38 / 475 (8.00%)
    30 / 473 (6.34%)
         occurrences all number
    55
    51
    White blood cell count decreased
         subjects affected / exposed
    25 / 475 (5.26%)
    31 / 473 (6.55%)
         occurrences all number
    43
    80
    Weight decreased
         subjects affected / exposed
    44 / 475 (9.26%)
    27 / 473 (5.71%)
         occurrences all number
    45
    29
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    35 / 475 (7.37%)
    58 / 473 (12.26%)
         occurrences all number
    40
    63
    Headache
         subjects affected / exposed
    30 / 475 (6.32%)
    22 / 473 (4.65%)
         occurrences all number
    30
    24
    Neuropathy peripheral
         subjects affected / exposed
    61 / 475 (12.84%)
    57 / 473 (12.05%)
         occurrences all number
    73
    65
    Peripheral sensory neuropathy
         subjects affected / exposed
    71 / 475 (14.95%)
    98 / 473 (20.72%)
         occurrences all number
    79
    111
    Paraesthesia
         subjects affected / exposed
    20 / 475 (4.21%)
    28 / 473 (5.92%)
         occurrences all number
    23
    31
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    171 / 475 (36.00%)
    157 / 473 (33.19%)
         occurrences all number
    232
    205
    Neutropenia
         subjects affected / exposed
    107 / 475 (22.53%)
    102 / 473 (21.56%)
         occurrences all number
    207
    214
    Leukopenia
         subjects affected / exposed
    44 / 475 (9.26%)
    54 / 473 (11.42%)
         occurrences all number
    106
    122
    Thrombocytopenia
         subjects affected / exposed
    77 / 475 (16.21%)
    70 / 473 (14.80%)
         occurrences all number
    123
    102
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    80 / 475 (16.84%)
    55 / 473 (11.63%)
         occurrences all number
    112
    70
    Chest pain
         subjects affected / exposed
    26 / 475 (5.47%)
    45 / 473 (9.51%)
         occurrences all number
    30
    49
    Oedema peripheral
         subjects affected / exposed
    25 / 475 (5.26%)
    31 / 473 (6.55%)
         occurrences all number
    28
    35
    Fatigue
         subjects affected / exposed
    142 / 475 (29.89%)
    140 / 473 (29.60%)
         occurrences all number
    185
    190
    Mucosal inflammation
         subjects affected / exposed
    10 / 475 (2.11%)
    27 / 473 (5.71%)
         occurrences all number
    12
    32
    Pyrexia
         subjects affected / exposed
    91 / 475 (19.16%)
    70 / 473 (14.80%)
         occurrences all number
    144
    94
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    25 / 475 (5.26%)
    26 / 473 (5.50%)
         occurrences all number
    30
    29
    Constipation
         subjects affected / exposed
    117 / 475 (24.63%)
    103 / 473 (21.78%)
         occurrences all number
    147
    137
    Abdominal pain upper
         subjects affected / exposed
    24 / 475 (5.05%)
    23 / 473 (4.86%)
         occurrences all number
    26
    26
    Diarrhoea
         subjects affected / exposed
    145 / 475 (30.53%)
    89 / 473 (18.82%)
         occurrences all number
    235
    124
    Nausea
         subjects affected / exposed
    152 / 475 (32.00%)
    151 / 473 (31.92%)
         occurrences all number
    254
    238
    Vomiting
         subjects affected / exposed
    89 / 475 (18.74%)
    68 / 473 (14.38%)
         occurrences all number
    134
    91
    Stomatitis
         subjects affected / exposed
    27 / 475 (5.68%)
    24 / 473 (5.07%)
         occurrences all number
    33
    29
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    94 / 475 (19.79%)
    97 / 473 (20.51%)
         occurrences all number
    111
    114
    Haemoptysis
         subjects affected / exposed
    34 / 475 (7.16%)
    41 / 473 (8.67%)
         occurrences all number
    38
    46
    Cough
         subjects affected / exposed
    82 / 475 (17.26%)
    85 / 473 (17.97%)
         occurrences all number
    92
    104
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    181 / 475 (38.11%)
    175 / 473 (37.00%)
         occurrences all number
    188
    177
    Pruritus
         subjects affected / exposed
    78 / 475 (16.42%)
    27 / 473 (5.71%)
         occurrences all number
    92
    33
    Rash
         subjects affected / exposed
    87 / 475 (18.32%)
    45 / 473 (9.51%)
         occurrences all number
    115
    55
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    61 / 475 (12.84%)
    49 / 473 (10.36%)
         occurrences all number
    65
    51
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    77 / 475 (16.21%)
    58 / 473 (12.26%)
         occurrences all number
    107
    95
    Musculoskeletal pain
         subjects affected / exposed
    20 / 475 (4.21%)
    24 / 473 (5.07%)
         occurrences all number
    24
    28
    Bone pain
         subjects affected / exposed
    32 / 475 (6.74%)
    26 / 473 (5.50%)
         occurrences all number
    49
    43
    Back pain
         subjects affected / exposed
    34 / 475 (7.16%)
    38 / 473 (8.03%)
         occurrences all number
    39
    42
    Myalgia
         subjects affected / exposed
    66 / 475 (13.89%)
    61 / 473 (12.90%)
         occurrences all number
    107
    105
    Pain in extremity
         subjects affected / exposed
    43 / 475 (9.05%)
    43 / 473 (9.09%)
         occurrences all number
    56
    54
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    145 / 475 (30.53%)
    116 / 473 (24.52%)
         occurrences all number
    189
    154
    Dehydration
         subjects affected / exposed
    24 / 475 (5.05%)
    7 / 473 (1.48%)
         occurrences all number
    27
    8
    Hypomagnesaemia
         subjects affected / exposed
    27 / 475 (5.68%)
    15 / 473 (3.17%)
         occurrences all number
    33
    15
    Hypokalaemia
         subjects affected / exposed
    51 / 475 (10.74%)
    31 / 473 (6.55%)
         occurrences all number
    68
    36
    Hyponatraemia
         subjects affected / exposed
    37 / 475 (7.79%)
    11 / 473 (2.33%)
         occurrences all number
    46
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2010
    Grammatical and typographical errors corrected. Deleted optional re-induction sections, changed patient population to squamous only changed irRC to exploratory and patient management using mWHO criteria.
    25 Apr 2011
    Adds pre-dose TSH testing to the protocol in order to ensure consistency with the FDA approved label for ipilimumab.
    15 Jul 2011
    Moves randomization to Day 1 and removes the Lead-in Phase. Sample size changed to 920 randomized. CA184041 efficacy results updated. Added in secondary objective for OS in all blinded therapy treated subjects and moved outcomes objective to exploratory.
    21 Aug 2011
    Changes placebo to IMP.
    04 Oct 2012
    Updates to WOCBP language, informed consent and follow up after study treatment discontinuation, imAR and irAE language, inclusion and exclusion criteria modifications.
    25 Apr 2014
    Updates study endpoints, adds 3-year dosing limit, updates the Global Medical Monitor, and makes other miscellaneous clarifications and corrections.

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

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