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    Clinical Trial Results:
    A Phase I/III, Randomized, Double-Blind, Placebo-Controlled Study of Carboplatin Plus Etoposide With or Without Atezolizumab (Anti-PD-L1 Antibody) in Patients With Untreated Extensive-Stage Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2015-004861-97
    Trial protocol
    		 DE   PL   HU   CZ   GB   AT   GR   ES   FR   IT  
    Global end of trial date
    07 Jul 2022

    Results information
    Results version number
    		 v3(current)
    This version publication date
    06 Jul 2023
    First version publication date
    05 May 2019
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GO30081
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02763579
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    07 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study was designed to evaluate the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1] antibody) in combination with carboplatin plus (+) etoposide compared with treatment with placebo + carboplatin + etoposide in subjects with chemotherapy-naive extensive-stage small cell lung cancer.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jun 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason
    Long term follow-up duration
    		 32 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    China: 100
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Taiwan: 10
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Czechia: 17
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    United States: 86
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Poland: 45
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Serbia: 15
    Worldwide total number of subjects
    503
    EEA total number of subjects
    168
    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)
    286
    From 65 to 84 years
    215
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 114 centers in 21 countries: United States of America, Poland, Japan, Russia, Spain, Austria, Hungary, Czech Republic, South Korea, Italy, Serbia, Australia, Greece, United Kingdom, Germany, Taiwan, France, Chile, Brazil, Mexico, and China.

    Pre-assignment
    Screening details
    		 Total study population included 503 participants. Global population included 403 participants. An additional 100 participants enrolled during the China Extension. Total China population included 10 Chinese participants from Global population plus 100 participants from the China extension.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo + Carboplatin + Etoposide - Global
    Arm description
    		 Participants in the Global population received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo intravenous infusion was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide intravenous infusion was administered at a dose of 100 mg/m^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).

    Arm title
    		 Atezolizumab + Carboplatin + Etoposide - Global
    Arm description
    		 Participants in the Global population received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, RO5541267, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab intravenous infusion was administered at a dose of 1200 mg on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide intravenous infusion was administered at a dose of 100 mg/m^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).

    Arm title
    		 Placebo + Carboplatin + Etoposide - China
    Arm description
    		 Participants in the China population received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo intravenous infusion was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide intravenous infusion was administered at a dose of 100 mg/m^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).

    Arm title
    		 Atezolizumab + Carboplatin + Etoposide - China
    Arm description
    		 Participants in the China population received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, RO5541267, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab intravenous infusion was administered at a dose of 1200 mg on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide intravenous infusion was administered at a dose of 100 mg/m^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).

    Number of subjects in period 1
    		Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global Placebo + Carboplatin + Etoposide - China Atezolizumab + Carboplatin + Etoposide - China
    Started
    202
    201
    53
    57
    Completed
    0
    0
    0
    0
    Not completed
    202
    201
    53
    57
         Consent withdrawn by subject
    12
    18
    3
    3
         Physician decision
    -
    2
    -
    1
         Study Terminated By Sponsor
    21
    26
    3
    4
         Death
    167
    151
    46
    48
         Lost to follow-up
    2
    4
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 The total study population included 503 participants. The Global population included 403 participants. An additional 100 participants enrolled during the China Extension. The total China population included 10 Chinese participants from the Global population plus 100 participants from the China extension. 10 participants were part of the Global as well as China populations.

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 503 503
    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)
    		 286 286
        From 65-84 years
    		 215 215
        85 years and over
    		 2 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.0 ( 8.9 ) -
    Sex: Female, Male
    As reported from Electronic Case Report Form (eCRF).
    Units: Participants
        Female
    		 164 164
        Male
    		 339 339

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Carboplatin + Etoposide - Global
    Reporting group description
    		 Participants in the Global population received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Atezolizumab + Carboplatin + Etoposide - Global
    Reporting group description
    		 Participants in the Global population received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Placebo + Carboplatin + Etoposide - China
    Reporting group description
    		 Participants in the China population received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Atezolizumab + Carboplatin + Etoposide - China
    Reporting group description
    		 Participants in the China population received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Primary: Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population

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    End point title
    		 Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population [1]
    End point description
    Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least 20% increase in the sum of the longest diameter of target lesions compared to baseline, or unequivocal progression in non-target lesion(s), or the appearance of new lesion(s).
    End point type
    Primary
    End point timeframe
    Baseline until PD or death, whichever occurs first (up to approximately 23 months)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    202
    201
    Units: Months
        median (confidence interval 95%)
    4.3 (4.2 to 4.5)
    5.2 (4.4 to 5.6)
    Statistical analysis title
    		 PFS Statistical Analysis
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Logrank
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.96

    Primary: Duration of Overall Survival (OS) in the Global Population

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    End point title
    		 Duration of Overall Survival (OS) in the Global Population [2]
    End point description
    OS is defined as the time from randomization to death from any cause.
    End point type
    Primary
    End point timeframe
    Baseline until death from any cause (up to approximately 23 months)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    202
    201
    Units: Months
        median (confidence interval 95%)
    10.3 (9.3 to 11.3)
    12.3 (10.8 to 15.9)
    Statistical analysis title
    		 OS Statistical Analysis
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0069
    Method
    		 Logrank
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.91

    Secondary: Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population

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    End point title
    		 Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population [3]
    End point description
    Objective response (OR) is defined as complete response (CR) or partial response (PR) as determined by the investigator according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Baseline until partial response (PR) or complete response (CR), whichever occurs first (up to approximately 23 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    202
    201
    Units: Percentage of participants
        number (confidence interval 95%)
    76.7 (70.29 to 82.38)
    74.1 (67.50 to 80.03)
    Statistical analysis title
    		 ORR Statistical Analysis
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.37

    Secondary: Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population

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    End point title
    		 Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population [4]
    End point description
    DOR is defined as the time interval from first occurrence of a documented objective response to the time of disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever comes first.
    End point type
    Secondary
    End point timeframe
    First occurrence of PR or CR until PD or death, whichever occurs first (up to approximately 23 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    155
    149
    Units: Months
        median (confidence interval 95%)
    3.1 (2.9 to 3.9)
    4.1 (3.5 to 4.2)
    Statistical analysis title
    		 DOR Statistical Analysis
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0063
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.715
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.562
         upper limit
    		 0.911

    Secondary: PFS Rate at 6 Months and at 1 year in Global Population

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    End point title
    		 PFS Rate at 6 Months and at 1 year in Global Population [5]
    End point description
    PFS rates at 6 months and at 1 year is defined as the proportion of participants who are alive without disease progression 6 months and 1 year after randomization, respectively.
    End point type
    Secondary
    End point timeframe
    6 months, 1 year
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    202
    201
    Units: Percentage of participants
    number (confidence interval 95%)
        6 Months
    22.39 (16.56 to 28.22)
    30.86 (24.26 to 37.45)
        1 Year
    5.35 (2.14 to 8.56)
    12.62 (7.85 to 17.40)
    Statistical analysis title
    		 PFS Rate 1 Year Statistical Analysis
    Statistical analysis description
    PFS Rate at 1 year
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0133
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    7.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.52
         upper limit
    		 13.02
    Statistical analysis title
    		 PFS Rate 6 Months Statistical Analysis
    Statistical analysis description
    PFS Rate at 6 months
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0593
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    8.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 17.27

    Secondary: OS Rate at 1 Year and 2 Years in the Global Population

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    End point title
    		 OS Rate at 1 Year and 2 Years in the Global Population [6]
    End point description
    OS rates at 1 and 2 years is defined as the proportion of participants who are alive 1 year and 2 years after randomization, respectively. Note: 999999=not estimable.
    End point type
    Secondary
    End point timeframe
    1 year, 2 years
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    202
    201
    Units: Percentage of participants
    number (not applicable)
        1 Year
    38.23
    51.69
        2 Years
    999999
    999999
    Statistical analysis title
    		 OS Rate 1 Year Statistical Analysis
    Statistical analysis description
    OS Rate at 1 year
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0095
    Method
    		 Z-test
    Parameter type
    		 Difference in Event Free Rate
    Point estimate
    13.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.29
         upper limit
    		 23.64

    Secondary: Time to Deterioration (TTD) per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Score in the Global Population

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    End point title
    		 Time to Deterioration (TTD) per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Score in the Global Population [7]
    End point description
    TTD according to the EORTC QLQ-C30 and EORTC QLQ-LC13 measures were evaluated in each of the following linearly transformed symptom scores: cough, dyspnea (single item), dyspnea (multi-item subscale), chest pain, or arm/shoulder pain. The linear transformation gives each individual symptom subscale a possible score of 0 to 100. For the symptom to be considered “deteriorated,” a score increase of ≥10 points above baseline must be held for at least two consecutive assessments or an initial score increase of ≥10 points is followed by death within 3 weeks from the last assessment. A ≥ 10-point change in the symptoms subscale score is perceived by participants as clinically significant. Note: 999999=not estimable; 000000=not estimable.
    End point type
    Secondary
    End point timeframe
    Baseline until deterioration per symptom subscale (up to approximately 23 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    202
    201
    Units: Month
    median (confidence interval 95%)
        Cough
    999999 (16.6 to 999999)
    20.3 (000000 to 999999)
        Pain in Chest
    999999 (10.9 to 999999)
    999999 (999999 to 999999)
        Pain in Arm or Shoulder
    999999 (8.8 to 999999)
    999999 (9.2 to 999999)
        Dyspnea
    5.6 (3.6 to 8.8)
    999999 (5.5 to 999999)
    Statistical analysis title
    		 TTD Statistical Analysis Cough
    Statistical analysis description
    Cough
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.3604
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.221
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.795
         upper limit
    		 1.874
    Notes
    [8] - Stratified analysis. Stratification factors: Sex (male vs female) and ECOG (0 vs 1).
    Statistical analysis title
    		 TTD Statistical Analysis Pain in Arm or Shoulder
    Statistical analysis description
    Pain in Arm or Shoulder
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.6922
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.077
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.747
         upper limit
    		 1.552
    Notes
    [9] - Stratified analysis. Stratification factors: Sex (male vs female) and ECOG (0 vs 1).
    Statistical analysis title
    		 TTD Statistical Analysis Dyspnea
    Statistical analysis description
    Dyspnea
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.065
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.748
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.549
         upper limit
    		 1.019
    Notes
    [10] - Stratified analysis. Stratification factors: Sex (male vs female) and ECOG (0 vs 1).
    Statistical analysis title
    		 TTD Statistical Analysis Pain in Chest
    Statistical analysis description
    Pain in Chest
    Comparison groups
    Placebo + Carboplatin + Etoposide - Global v Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.7712
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.722
         upper limit
    		 1.553
    Notes
    [11] - Stratified analysis. Stratification factors: Sex (male vs female) and ECOG (0 vs 1).

    Secondary: Percentage of Participants with at Least One Adverse Event in the Global Population

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    End point title
    		 Percentage of Participants with at Least One Adverse Event in the Global Population [12]
    End point description
    The percentage of participants with at least one adverse event in the global population.
    End point type
    Secondary
    End point timeframe
    Baseline until up to 90 days after end of treatment (up to approximately 49 months)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    196
    198
    Units: Percentage of participants
        number (not applicable)
    96.4
    100.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab in the Global Population

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    End point title
    		 Percentage of Participants With Anti-Drug Antibodies (ADA) to Atezolizumab in the Global Population [13]
    End point description
    The baseline prevalence and post-baseline incidence of ADAs against atezolizumab.
    End point type
    Secondary
    End point timeframe
    Predose (0 hours [H]) on Day (D) 1 of Cycles (C) 1, 2, 3, 4, 8, 16, and every 8 cycles (Q8C) thereafter (cycle = 21 days) until treatment discontinuation (up to 23 months) and 120 days after last dose (up to approximately 23 months overall)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    198
    Units: Percentage of participants
    number (not applicable)
        Baseline evaluable participants (n=196)
    2.0
        Post-baseline evaluable participants (n=188)
    18.6
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab in the Global Population

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Atezolizumab in the Global Population [14]
    End point description
    Atezolizumab maximum observed plasma concentration (Cmax; 30 minutes following the end of the atezolizumab infusion) for each respective day.
    End point type
    Secondary
    End point timeframe
    Post-dose Day 1 of Cycle 1 (cycle length = 21 days)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    185
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1
    389 ( 135 )
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population

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    End point title
    		 Minimum Observed Serum Concentration (Cmin) of Atezolizumab in the Global Population [15]
    End point description
    Atezolizumab pre-dose plasma concentration (Cmin) for each respective day. Note: 999999=not estimable.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1 of Cycles 1, 3, 4, 8, 16 and 24 (cycle length = 21 days)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    194
    Units: μg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=194)
    999999 ( 999999 )
        Cycle 3 Day 1 (n=174)
    80.6 ( 32.1 )
        Cycle 4 Day 1 (n=156)
    138 ( 56.4 )
        Cycle 8 Day 1 (n=88)
    186 ( 73.5 )
        Cycle 16 Day 1 (n=22)
    196 ( 63.1 )
        Cycle 24 Day 1 (n=4)
    221 ( 43.4 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Carboplatin in the Global Population

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    End point title
    		 Plasma Concentration of Carboplatin in the Global Population [16]
    End point description
    Plasma concentration of carboplatin in the Global population. Note: 999999=not estimable, D=Day, C=Cycle.
    End point type
    Secondary
    End point timeframe
    Predose, before end of infusion, and after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    13
    13
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-Dose on D1 of C1 (n=12, 11)
    999999 ( 999999 )
    999999 ( 999999 )
        Before End of Infusion on D1 of C1 (n=12, 11)
    13300 ( 4880 )
    11200 ( 5060 )
        Post Infusion on D1 of C1 (n=11, 12)
    7200 ( 1880 )
    6860 ( 1670 )
        Pre-Dose on D1 of C3 (n=12, 13)
    144 ( 58.3 )
    126 ( 48.1 )
        Before End of Infusion on D1 of C3 (n=13, 13)
    13900 ( 3590 )
    11300 ( 5090 )
        Post Infusion on D1 of C3 (n=13, 13)
    7180 ( 1630 )
    6540 ( 2200 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Etoposide in the Global Population

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    End point title
    		 Plasma Concentration of Etoposide in the Global Population [17]
    End point description
    Plasma concentration of etoposide in the Global Population. Note: 999999=not estimable, C=Cycle, D=Day.
    End point type
    Secondary
    End point timeframe
    Predose, before end of infusion, 1 and 4 hours after end of carboplatin infusion on Day 1 of Cycle 1 and Cycle 3 (cycle = 21 days)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for the endpoint.
    End point values
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - Global
    Number of subjects analysed
    13
    13
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-Dose on D1 of C1 (n=12, 13)
    999999 ( 999999 )
    999999 ( 999999 )
        Before End of Infusion on D1 of C1 (n=10, 10)
    17000 ( 3640 )
    19400 ( 2860 )
        1 Hour Post Infusion on D1 of C1 (n=8, 12)
    11100 ( 2010 )
    12600 ( 1960 )
        4 Hours Post Infusion on D1 of C1 (n=9, 9)
    7640 ( 2360 )
    7300 ( 1230 )
        Pre-Dose on D1 of C3 (n=13, 13)
    999999 ( 999999 )
    999999 ( 999999 )
        Before End of Infusion on D1 of C3 (n=11, 9)
    16600 ( 2180 )
    17700 ( 3600 )
        1 Hour Post Infusion on D1 of C3 (n=10, 13)
    12400 ( 3740 )
    12200 ( 2810 )
        4 Hours Post Infusion on D1 of C3 (n=10, 11)
    6740 ( 1230 )
    7960 ( 2090 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug administration to the data cutoff date: 7 July 2022 (up to 49 months).
    Adverse event reporting additional description
    Adverse events reported based on safety population, which included participants who received any amount of any component of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo + Carboplatin + Etoposide - Global
    Reporting group description
    		 Participants in the Global population received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Atezolizumab + Carboplatin + Etoposide - China
    Reporting group description
    		 Participants in the China population received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Placebo + Carboplatin + Etoposide - China
    Reporting group description
    		 Participants in the China population received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Atezolizumab + Carboplatin + Etoposide - Global
    Reporting group description
    		 Participants in the Global population received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, participants received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Serious adverse events
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - China Placebo + Carboplatin + Etoposide - China Atezolizumab + Carboplatin + Etoposide - Global
    Total subjects affected by serious adverse events
         subjects affected / exposed
    69 / 196 (35.20%)
    22 / 57 (38.60%)
    14 / 52 (26.92%)
    81 / 198 (40.91%)
         number of deaths (all causes)
    164
    48
    46
    155
         number of deaths resulting from adverse events
    3
    2
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 57 (3.51%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 1
    Pain
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    1 / 52 (1.92%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    1 / 52 (1.92%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 57 (0.00%)
    1 / 52 (1.92%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 57 (3.51%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 196 (1.02%)
    4 / 57 (7.02%)
    1 / 52 (1.92%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 57 (3.51%)
    2 / 52 (3.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation oesophagitis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 196 (1.53%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    1 / 52 (1.92%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    1 / 52 (1.92%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord oedema
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    4 / 196 (2.04%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 57 (0.00%)
    1 / 52 (1.92%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 196 (2.04%)
    0 / 57 (0.00%)
    2 / 52 (3.85%)
    5 / 198 (2.53%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    8 / 196 (4.08%)
    1 / 57 (1.75%)
    1 / 52 (1.92%)
    7 / 198 (3.54%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 1
    1 / 1
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Granulocytopenia
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    1 / 52 (1.92%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    9 / 196 (4.59%)
    1 / 57 (1.75%)
    2 / 52 (3.85%)
    5 / 198 (2.53%)
         occurrences causally related to treatment / all
    9 / 9
    1 / 1
    2 / 2
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    1 / 52 (1.92%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip oedema
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 196 (1.53%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 196 (5.10%)
    4 / 57 (7.02%)
    4 / 52 (7.69%)
    12 / 198 (6.06%)
         occurrences causally related to treatment / all
    3 / 11
    3 / 7
    4 / 5
    5 / 15
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    1 / 1
    Pyopneumothorax
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    1 / 52 (1.92%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 196 (2.04%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Carboplatin + Etoposide - Global Atezolizumab + Carboplatin + Etoposide - China Placebo + Carboplatin + Etoposide - China Atezolizumab + Carboplatin + Etoposide - Global
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    187 / 196 (95.41%)
    56 / 57 (98.25%)
    52 / 52 (100.00%)
    191 / 198 (96.46%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 196 (3.06%)
    0 / 57 (0.00%)
    2 / 52 (3.85%)
    15 / 198 (7.58%)
         occurrences all number
    8
    0
    2
    20
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    5 / 196 (2.55%)
    5 / 57 (8.77%)
    2 / 52 (3.85%)
    2 / 198 (1.01%)
         occurrences all number
    5
    5
    2
    2
    Asthenia
         subjects affected / exposed
    20 / 196 (10.20%)
    4 / 57 (7.02%)
    4 / 52 (7.69%)
    25 / 198 (12.63%)
         occurrences all number
    26
    4
    5
    29
    Chest pain
         subjects affected / exposed
    14 / 196 (7.14%)
    5 / 57 (8.77%)
    4 / 52 (7.69%)
    18 / 198 (9.09%)
         occurrences all number
    14
    5
    4
    22
    Oedema peripheral
         subjects affected / exposed
    7 / 196 (3.57%)
    1 / 57 (1.75%)
    0 / 52 (0.00%)
    13 / 198 (6.57%)
         occurrences all number
    8
    1
    0
    14
    Fatigue
         subjects affected / exposed
    51 / 196 (26.02%)
    6 / 57 (10.53%)
    0 / 52 (0.00%)
    52 / 198 (26.26%)
         occurrences all number
    67
    8
    0
    66
    Pyrexia
         subjects affected / exposed
    16 / 196 (8.16%)
    13 / 57 (22.81%)
    4 / 52 (7.69%)
    20 / 198 (10.10%)
         occurrences all number
    18
    19
    7
    32
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 196 (14.29%)
    14 / 57 (24.56%)
    10 / 52 (19.23%)
    22 / 198 (11.11%)
         occurrences all number
    33
    20
    12
    28
    Haemoptysis
         subjects affected / exposed
    12 / 196 (6.12%)
    4 / 57 (7.02%)
    5 / 52 (9.62%)
    14 / 198 (7.07%)
         occurrences all number
    12
    4
    6
    20
    Oropharyngeal pain
         subjects affected / exposed
    5 / 196 (2.55%)
    2 / 57 (3.51%)
    0 / 52 (0.00%)
    13 / 198 (6.57%)
         occurrences all number
    6
    2
    0
    17
    Productive cough
         subjects affected / exposed
    9 / 196 (4.59%)
    7 / 57 (12.28%)
    5 / 52 (9.62%)
    10 / 198 (5.05%)
         occurrences all number
    14
    7
    5
    10
    Dyspnoea
         subjects affected / exposed
    17 / 196 (8.67%)
    2 / 57 (3.51%)
    2 / 52 (3.85%)
    21 / 198 (10.61%)
         occurrences all number
    18
    2
    2
    24
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 196 (7.14%)
    4 / 57 (7.02%)
    3 / 52 (5.77%)
    16 / 198 (8.08%)
         occurrences all number
    14
    8
    9
    19
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 196 (2.55%)
    11 / 57 (19.30%)
    9 / 52 (17.31%)
    8 / 198 (4.04%)
         occurrences all number
    7
    15
    16
    9
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 196 (1.53%)
    1 / 57 (1.75%)
    3 / 52 (5.77%)
    8 / 198 (4.04%)
         occurrences all number
    3
    2
    4
    8
    Blood triglycerides increased
         subjects affected / exposed
    0 / 196 (0.00%)
    6 / 57 (10.53%)
    4 / 52 (7.69%)
    0 / 198 (0.00%)
         occurrences all number
    0
    18
    5
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 57 (3.51%)
    4 / 52 (7.69%)
    1 / 198 (0.51%)
         occurrences all number
    1
    2
    4
    4
    Neutrophil count decreased
         subjects affected / exposed
    45 / 196 (22.96%)
    41 / 57 (71.93%)
    33 / 52 (63.46%)
    37 / 198 (18.69%)
         occurrences all number
    80
    107
    85
    74
    Blood creatinine increased
         subjects affected / exposed
    3 / 196 (1.53%)
    4 / 57 (7.02%)
    3 / 52 (5.77%)
    7 / 198 (3.54%)
         occurrences all number
    3
    8
    3
    13
    Protein urine present
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    3 / 52 (5.77%)
    0 / 198 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 196 (0.00%)
    3 / 57 (5.26%)
    3 / 52 (5.77%)
    0 / 198 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Platelet count decreased
         subjects affected / exposed
    30 / 196 (15.31%)
    24 / 57 (42.11%)
    14 / 52 (26.92%)
    26 / 198 (13.13%)
         occurrences all number
    41
    40
    26
    38
    Blood cholesterol increased
         subjects affected / exposed
    0 / 196 (0.00%)
    8 / 57 (14.04%)
    4 / 52 (7.69%)
    0 / 198 (0.00%)
         occurrences all number
    0
    23
    4
    0
    Weight increased
         subjects affected / exposed
    6 / 196 (3.06%)
    1 / 57 (1.75%)
    4 / 52 (7.69%)
    3 / 198 (1.52%)
         occurrences all number
    7
    1
    4
    3
    Weight decreased
         subjects affected / exposed
    10 / 196 (5.10%)
    10 / 57 (17.54%)
    6 / 52 (11.54%)
    21 / 198 (10.61%)
         occurrences all number
    11
    10
    6
    21
    Blood bilirubin increased
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 57 (3.51%)
    5 / 52 (9.62%)
    0 / 198 (0.00%)
         occurrences all number
    0
    2
    6
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 57 (1.75%)
    3 / 52 (5.77%)
    0 / 198 (0.00%)
         occurrences all number
    0
    1
    4
    0
    White blood cell count decreased
         subjects affected / exposed
    24 / 196 (12.24%)
    34 / 57 (59.65%)
    29 / 52 (55.77%)
    18 / 198 (9.09%)
         occurrences all number
    43
    101
    73
    35
    Haemoglobin decreased
         subjects affected / exposed
    3 / 196 (1.53%)
    4 / 57 (7.02%)
    0 / 52 (0.00%)
    1 / 198 (0.51%)
         occurrences all number
    3
    6
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 196 (3.06%)
    13 / 57 (22.81%)
    10 / 52 (19.23%)
    6 / 198 (3.03%)
         occurrences all number
    6
    21
    15
    13
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    8 / 196 (4.08%)
    1 / 57 (1.75%)
    1 / 52 (1.92%)
    10 / 198 (5.05%)
         occurrences all number
    9
    1
    1
    13
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 57 (1.75%)
    4 / 52 (7.69%)
    2 / 198 (1.01%)
         occurrences all number
    2
    1
    4
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 196 (5.61%)
    2 / 57 (3.51%)
    2 / 52 (3.85%)
    20 / 198 (10.10%)
         occurrences all number
    14
    2
    2
    23
    Headache
         subjects affected / exposed
    23 / 196 (11.73%)
    3 / 57 (5.26%)
    3 / 52 (5.77%)
    25 / 198 (12.63%)
         occurrences all number
    26
    3
    3
    30
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    69 / 196 (35.20%)
    46 / 57 (80.70%)
    40 / 52 (76.92%)
    86 / 198 (43.43%)
         occurrences all number
    84
    76
    50
    101
    Thrombocytopenia
         subjects affected / exposed
    29 / 196 (14.80%)
    17 / 57 (29.82%)
    16 / 52 (30.77%)
    31 / 198 (15.66%)
         occurrences all number
    44
    27
    31
    46
    Leukopenia
         subjects affected / exposed
    19 / 196 (9.69%)
    9 / 57 (15.79%)
    14 / 52 (26.92%)
    24 / 198 (12.12%)
         occurrences all number
    32
    24
    22
    44
    Neutropenia
         subjects affected / exposed
    66 / 196 (33.67%)
    11 / 57 (19.30%)
    17 / 52 (32.69%)
    71 / 198 (35.86%)
         occurrences all number
    105
    32
    41
    122
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    58 / 196 (29.59%)
    10 / 57 (17.54%)
    8 / 52 (15.38%)
    52 / 198 (26.26%)
         occurrences all number
    70
    19
    12
    65
    Abdominal distension
         subjects affected / exposed
    2 / 196 (1.02%)
    3 / 57 (5.26%)
    1 / 52 (1.92%)
    5 / 198 (2.53%)
         occurrences all number
    2
    3
    1
    5
    Stomatitis
         subjects affected / exposed
    9 / 196 (4.59%)
    1 / 57 (1.75%)
    1 / 52 (1.92%)
    11 / 198 (5.56%)
         occurrences all number
    9
    1
    1
    11
    Vomiting
         subjects affected / exposed
    34 / 196 (17.35%)
    14 / 57 (24.56%)
    7 / 52 (13.46%)
    40 / 198 (20.20%)
         occurrences all number
    49
    20
    7
    52
    Abdominal pain
         subjects affected / exposed
    11 / 196 (5.61%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    10 / 198 (5.05%)
         occurrences all number
    11
    0
    0
    10
    Diarrhoea
         subjects affected / exposed
    30 / 196 (15.31%)
    4 / 57 (7.02%)
    2 / 52 (3.85%)
    34 / 198 (17.17%)
         occurrences all number
    46
    5
    2
    46
    Nausea
         subjects affected / exposed
    65 / 196 (33.16%)
    21 / 57 (36.84%)
    10 / 52 (19.23%)
    77 / 198 (38.89%)
         occurrences all number
    95
    47
    15
    112
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 196 (0.00%)
    3 / 57 (5.26%)
    3 / 52 (5.77%)
    0 / 198 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    69 / 196 (35.20%)
    25 / 57 (43.86%)
    18 / 52 (34.62%)
    73 / 198 (36.87%)
         occurrences all number
    72
    26
    18
    75
    Rash
         subjects affected / exposed
    13 / 196 (6.63%)
    6 / 57 (10.53%)
    1 / 52 (1.92%)
    15 / 198 (7.58%)
         occurrences all number
    15
    9
    1
    25
    Pruritus
         subjects affected / exposed
    9 / 196 (4.59%)
    2 / 57 (3.51%)
    1 / 52 (1.92%)
    15 / 198 (7.58%)
         occurrences all number
    10
    3
    1
    17
    Rash maculo-papular
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 57 (0.00%)
    0 / 52 (0.00%)
    11 / 198 (5.56%)
         occurrences all number
    3
    0
    0
    11
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 57 (3.51%)
    7 / 52 (13.46%)
    0 / 198 (0.00%)
         occurrences all number
    1
    3
    10
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 196 (0.51%)
    8 / 57 (14.04%)
    2 / 52 (3.85%)
    20 / 198 (10.10%)
         occurrences all number
    1
    9
    2
    20
    Hyperthyroidism
         subjects affected / exposed
    5 / 196 (2.55%)
    2 / 57 (3.51%)
    0 / 52 (0.00%)
    11 / 198 (5.56%)
         occurrences all number
    5
    2
    0
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    18 / 196 (9.18%)
    3 / 57 (5.26%)
    0 / 52 (0.00%)
    19 / 198 (9.60%)
         occurrences all number
    20
    3
    0
    19
    Pain in extremity
         subjects affected / exposed
    8 / 196 (4.08%)
    2 / 57 (3.51%)
    2 / 52 (3.85%)
    13 / 198 (6.57%)
         occurrences all number
    9
    2
    2
    13
    Arthralgia
         subjects affected / exposed
    22 / 196 (11.22%)
    1 / 57 (1.75%)
    4 / 52 (7.69%)
    25 / 198 (12.63%)
         occurrences all number
    29
    1
    4
    31
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 196 (3.06%)
    2 / 57 (3.51%)
    5 / 52 (9.62%)
    13 / 198 (6.57%)
         occurrences all number
    6
    5
    5
    18
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 196 (8.67%)
    3 / 57 (5.26%)
    2 / 52 (3.85%)
    15 / 198 (7.58%)
         occurrences all number
    20
    3
    2
    19
    Nasopharyngitis
         subjects affected / exposed
    2 / 196 (1.02%)
    3 / 57 (5.26%)
    4 / 52 (7.69%)
    4 / 198 (2.02%)
         occurrences all number
    2
    3
    4
    5
    Metabolism and nutrition disorders
    Hypoproteinaemia
         subjects affected / exposed
    0 / 196 (0.00%)
    4 / 57 (7.02%)
    3 / 52 (5.77%)
    0 / 198 (0.00%)
         occurrences all number
    0
    4
    4
    0
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 196 (1.02%)
    9 / 57 (15.79%)
    5 / 52 (9.62%)
    3 / 198 (1.52%)
         occurrences all number
    2
    14
    5
    5
    Hypochloraemia
         subjects affected / exposed
    2 / 196 (1.02%)
    5 / 57 (8.77%)
    4 / 52 (7.69%)
    0 / 198 (0.00%)
         occurrences all number
    3
    6
    7
    0
    Hypomagnesaemia
         subjects affected / exposed
    10 / 196 (5.10%)
    1 / 57 (1.75%)
    2 / 52 (3.85%)
    13 / 198 (6.57%)
         occurrences all number
    10
    1
    3
    19
    Hyponatraemia
         subjects affected / exposed
    12 / 196 (6.12%)
    10 / 57 (17.54%)
    11 / 52 (21.15%)
    10 / 198 (5.05%)
         occurrences all number
    14
    12
    17
    10
    Hyperglycaemia
         subjects affected / exposed
    5 / 196 (2.55%)
    4 / 57 (7.02%)
    2 / 52 (3.85%)
    9 / 198 (4.55%)
         occurrences all number
    7
    4
    3
    13
    Hypokalaemia
         subjects affected / exposed
    17 / 196 (8.67%)
    5 / 57 (8.77%)
    5 / 52 (9.62%)
    9 / 198 (4.55%)
         occurrences all number
    18
    8
    10
    9
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 196 (0.51%)
    3 / 57 (5.26%)
    0 / 52 (0.00%)
    0 / 198 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 196 (0.00%)
    0 / 57 (0.00%)
    3 / 52 (5.77%)
    1 / 198 (0.51%)
         occurrences all number
    0
    0
    3
    1
    Decreased appetite
         subjects affected / exposed
    41 / 196 (20.92%)
    13 / 57 (22.81%)
    12 / 52 (23.08%)
    55 / 198 (27.78%)
         occurrences all number
    45
    22
    16
    64

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2016
    Protocol was amended to include change of phase from Phase III to Phase I/III. A secondary objective and corresponding outcome measure has been added to evaluate the efficacy of atezolizumab + carboplatin + etoposide compared with placebo + carboplatin + etoposide as measured by investigator-assessed time to response (TTR). TTR will be assessed in the intent-to-treat (ITT) population for patients who had an objective response as determined by the investigator according to RECIST v1.1. Clarifications were made around eligibility criteria and study conduct.
    29 Aug 2017
    Protocol was amended to include modifications to the statistical analysis plan and the timing for the efficacy analyses for progression-free survival (PFS) and overall survival (OS).
    06 Mar 2019
    Protocol was amended to include additional language to the end of study definition to clarify that if the Sponsor decides to terminate the study, subjects who are still receiving study treatment or are in survival follow-up may be enrolled into an extension study or non-interventional study. The timing of the interim and final analysis were modified to be aligned with the statistical analysis plan.

    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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