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    Clinical Trial Results:
    A Phase III Multicenter, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Carboplatin+Nab-Paclitaxel for Chemotherapy-Naive Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    2014-003206-32
    Trial protocol
    DE   BE   IT   FR   ES  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Mar 2019
    First version publication date
    29 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GO29537
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02367781
    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, lobal.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
    Interim
    Date of interim/final analysis
    15 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This randomized Phase III, multicenter, open-label study is designed to evaluate the safety and efficacy of atezolizumab (an engineered anti-programmed death-ligand 1 [PD-L1] antibody) in combination with carboplatin+nab-paclitaxel compared with treatment with carboplatin+nab-paclitaxel in chemotherapy-naive subjects with Stage IV non-squamous NSCLC.
    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
    16 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 35
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Germany: 132
    Country: Number of subjects enrolled
    Spain: 71
    Country: Number of subjects enrolled
    France: 45
    Country: Number of subjects enrolled
    Italy: 52
    Country: Number of subjects enrolled
    Canada: 52
    Country: Number of subjects enrolled
    United States: 315
    Worldwide total number of subjects
    723
    EEA total number of subjects
    321
    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)
    362
    From 65 to 84 years
    358
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects in this study included: histologically or cytologically confirmed, Stage IV non-squamous NSCLC; and no prior treatment for Stage IV non-squamous NSCLC.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
    Arm description
    Subjects will receive intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first during induction treatment phase. Subjects will receive IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit.
    Arm type
    Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq, MPDL3280A, RO5541267
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab will be administered as IV infusion at a dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Nab-Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nab-paclitaxel will be administered as IV infusion at a dose of 100 milligrams per square meter (mg/m^2) on Days 1, 8, and 15 of each 21-day cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin will be administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle.

    Arm title
    Arm B (Nab-Paclitaxel+Carboplatin)
    Arm description
    Subjects will receive IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurs first during induction treatment phase. Subjects will receive best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed is also permitted. Subjects who were consented prior to approval of protocol Version 5 will be given the option to cross over to receive atezolizumab as monotherapy until disease progression.
    Arm type
    Active comparator

    Investigational medicinal product name
    Nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nab-paclitaxel will be administered as IV infusion at a dose of 100 milligrams per square meter (mg/m^2) on Days 1, 8, and 15 of each 21-day cycle.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Carboplatin will be administered at area under the concentration curve (AUC) 6 milligrams per milliliter per minute (mg/mL/min) on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Switch maintenance to pemetrexed can be administered within 6 weeks of Day 1 of the last induction cycle.

    Number of subjects in period 1
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Started
    483
    240
    Completed
    0
    0
    Not completed
    483
    240
         On-going in study
    214
    88
         Protocol deviation
    -
    1
         Prolonged Hospitalization
    1
    -
         Physician decision
    1
    -
         Randomized in Error
    5
    4
         Adverse event, serious fatal
    240
    136
         Non-Compliance
    1
    -
         Administrative-Change Facility
    1
    -
         Consent withdrawn by subject
    19
    10
         Death Prior to First Dose
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
    Reporting group description
    Subjects will receive intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first during induction treatment phase. Subjects will receive IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit.

    Reporting group title
    Arm B (Nab-Paclitaxel+Carboplatin)
    Reporting group description
    Subjects will receive IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurs first during induction treatment phase. Subjects will receive best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed is also permitted. Subjects who were consented prior to approval of protocol Version 5 will be given the option to cross over to receive atezolizumab as monotherapy until disease progression.

    Reporting group values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin) Total
    Number of subjects
    483 240 723
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    245 117 362
        From 65-84 years
    236 122 358
        85 years and over
    2 1 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.8 ± 9.5 64.4 ± 8.9 -
    Gender categorical
    Units: Subjects
        Female
    206 102 308
        Male
    277 138 415

    End points

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    End points reporting groups
    Reporting group title
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
    Reporting group description
    Subjects will receive intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first during induction treatment phase. Subjects will receive IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit.

    Reporting group title
    Arm B (Nab-Paclitaxel+Carboplatin)
    Reporting group description
    Subjects will receive IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurs first during induction treatment phase. Subjects will receive best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed is also permitted. Subjects who were consented prior to approval of protocol Version 5 will be given the option to cross over to receive atezolizumab as monotherapy until disease progression.

    Primary: Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population

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    End point title
    Progression-Free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the ITT-WT Population
    End point description
    PFS is reported for the ITT-WT population. The term "wild type" (WT) refers to randomized subjects who do not have a sensitizing EGFR mutation or ALK translocation.
    End point type
    Primary
    End point timeframe
    Up to approximately 35 months after first patient enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    451
    228
    Units: Months
    median (confidence interval 95%)
        PFS in the ITT-WT Population
    7.0 (6.2 to 7.3)
    5.5 (4.4 to 5.9)
    Statistical analysis title
    Statistical Analysis for PFS in the ITT-WT
    Comparison groups
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects included in analysis
    679
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Stratified Log Rank Test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    0.77

    Primary: Overall Survival (OS) in the ITT-WT Population

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    End point title
    Overall Survival (OS) in the ITT-WT Population
    End point description
    OS is reported for the ITT-WT population. The term "wild type" (WT) refers to randomized subjects who do not have a sensitizing EGFR mutation or ALK translocation.
    End point type
    Primary
    End point timeframe
    Up to approximately 35 months after first patient enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    451
    228
    Units: Months
        median (confidence interval 95%)
    18.6 (16.0 to 21.2)
    13.9 (12.0 to 18.7)
    Statistical analysis title
    Statistical Analysis for OS in the ITT-WT
    Comparison groups
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) v Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects included in analysis
    679
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0331
    Method
    Startified Log-Rank Test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    0.98

    Secondary: PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population

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    End point title
    PFS as Determined by the Investigator Using Recist v1.1 in the ITT Population
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [1] - Data will be analyzed at the time of study completion.
    [2] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: OS as Determined by the Investigator Using Recist v1.1 in the ITT Population

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    End point title
    OS as Determined by the Investigator Using Recist v1.1 in the ITT Population
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        median (standard deviation)
    ±
    ±
    Notes
    [3] - Data will be analyzed at the time of study completion.
    [4] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population

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    End point title
    Percentage of Participants With an Objective Response (OR) (Complete Response [CR] or Partial Response [PR]) as Determined by the Investigator Using RECIST v1.1 in the ITT-WT Population
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [5] - Data will be analyzed at the time of study completion.
    [6] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population

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    End point title
    Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 in ITT-WT Population
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Months
        median (standard deviation)
    ±
    ±
    Notes
    [7] - Data will be analyzed at the time of study completion.
    [8] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who are Alive at Year 1 and 2 in ITT-WT Population

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    End point title
    Percentage of Subjects Who are Alive at Year 1 and 2 in ITT-WT Population
    End point description
    Percentage of subjects who are alive is reported for the ITT-WT population. The term "wild type" (WT) refers to randomized subjects who do not have a sensitizing EGFR mutation or ALK translocation.
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Percentage
        number (not applicable)
    Notes
    [9] - Data will be analyzed at the time of study completion.
    [10] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population

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    End point title
    Time to Deterioration (TTD) in Patient-Reported Lung Cancer Symptoms in the ITT-WT Population
    End point description
    Defined as time from randomization to confirmed deterioration (10-point change) on the combined European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire−Core (EORTC QLQ-C30) and supplemental lung cancer module (EORTC QLQ-LC13) symptom subscales.
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [11] - Data will be analyzed at the time of study completion.
    [12] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale

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    End point title
    Change From Baseline in Patient-Reported Lung Cancer Symptoms Score Using the Symptoms in Lung Cancer (SILC) Scale
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled date
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [13] - Data will be analyzed at the time of study completion.
    [14] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    Percentage of Participants With Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled date
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: Percentage
        number (not applicable)
    Notes
    [15] - Data will be analyzed at the time of study completion.
    [16] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

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    End point title
    Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    Up to approximately 56 months after first subject enrolled
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: Percentage
        number (not applicable)
    Notes
    [17] - Data will be analyzed at the time of study completion.
    [18] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

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    End point title
    Maximum Observed Serum Concentration (Cmax) of Atezolizumab in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm [19]
    End point description
    Predose samples will be collected on the same day of treatment administration. The infusion duration of atezolizumab will be of 30-60 minutes.
    End point type
    Secondary
    End point timeframe
    Predose on Day (D) 1 of Cycle (Cy) 1,2,3,4,8,16 and every 8 cycles thereafter up to end of treatment (EOT) (approximately 56 months), 0.5 hours (h) post-infusion on D1 of Cy1,3, at 120 days after EOT (up to approximately 56 months)
    Notes
    [19] - 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: Cmax of Atezolizumab is only relevant for arm with Atezolizumab.
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [20]
    Units: mcg/mL
        geometric mean (standard deviation)
    ±
    Notes
    [20] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm

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    End point title
    Minimum Observed Serum Concentration (Cmin) of Atezolizumab Prior to Infusion in Atezolizumab+Carboplatin+Nab-Paclitaxel Arm [21]
    End point description
    Predose samples will be collected on the same day of treatment administration.
    End point type
    Secondary
    End point timeframe
    Predose on D1 of Cy 1, 2, 3, 4, 8, 16 and every 8 cycles thereafter up to EOT (up to approximately 56 months), at 120 days after EOT (up to approximately 56 months) ]
    Notes
    [21] - 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: Cmin of Atezolizumab is only relevant for arm with Atezolizumab.
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [22]
    Units: mcg/mL
        geometric mean (standard deviation)
    ±
    Notes
    [22] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Carboplatin

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    End point title
    Plasma Concentration of Carboplatin
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (same day of treatment administration), 5-10 minutes before end of carboplatin infusion, 1 h after carboplatin infusion (infusion duration=15 to 30 minutes) on D1 of Cy1,3 (1Cy=21 days)(up to approximately 56 months)
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [23]
    0 [24]
    Units: mcg/mL
        geometric mean (standard deviation)
    ±
    ±
    Notes
    [23] - Data will be analyzed at the time of study completion.
    [24] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel

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    End point title
    Plasma Concentrations of Nab-Paclitaxel Reported as Total Paclitaxel
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (same day of treatment administration), 5-10 minutes before end of nab-paclitaxel infusion, 1 h after nab-paclitaxel infusion (infusion duration=30 minutes) on D1 of Cy1,3 (1Cy=21 days)(up to approximately 56 months)
    End point values
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin) Arm B (Nab-Paclitaxel+Carboplatin)
    Number of subjects analysed
    0 [25]
    0 [26]
    Units: mcg/mL
        geometric mean (standard deviation)
    ±
    ±
    Notes
    [25] - Data will be analyzed at the time of study completion.
    [26] - Data will be analyzed at the time of study completion.
    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: 15 March 2018
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Arm B (Nab-Paclitaxel+Carboplatin)
    Reporting group description
    Subjects will receive IV infusion of carboplatin on Day 1 and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until disease progression whichever occurs first during induction treatment phase. Subjects will receive best supportive care during maintenance treatment phase. Switch maintenance to pemetrexed is also permitted. Subjects who were consented prior to approval of protocol Version 5 will be given the option to cross over to receive atezolizumab as monotherapy until disease progression.

    Reporting group title
    Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
    Reporting group description
    Subjects will receive intravenous (IV) infusion of atezolizumab and carboplatin on Day 1 of each 21-day cycle, and nab-paclitaxel on Days 1, 8, and 15 of each 21-day cycle for 4 or 6 cycles or until loss of clinical benefit whichever occurs first during induction treatment phase. Subjects will receive IV infusion of atezolizumab during maintenance treatment phase until loss of clinical benefit.

    Serious adverse events
    Arm B (Nab-Paclitaxel+Carboplatin) Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    88 / 232 (37.93%)
    240 / 473 (50.74%)
         number of deaths (all causes)
    134
    240
         number of deaths resulting from adverse events
    Vascular disorders
    ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    2 / 232 (0.86%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLISM
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL ARTERY ANEURYSM
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JUGULAR VEIN THROMBOSIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHLEBITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR STENOSIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    ABORTION INDUCED
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR PAIN
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    0 / 232 (0.00%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    4 / 232 (1.72%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 4
    1 / 1
    DRUG INTERACTION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    2 / 232 (0.86%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    2 / 232 (0.86%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERALISED OEDEMA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON−CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERFORMANCE STATUS DECREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    2 / 232 (0.86%)
    8 / 473 (1.69%)
         occurrences causally related to treatment / all
    1 / 2
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISORIENTATION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 232 (0.00%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PUBIS FRACTURE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD GLUCOSE INCREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    6 / 473 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 232 (0.00%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 232 (0.43%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ANEURYSM
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CHRONIC
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC TAMPONADE
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIO−RESPIRATORY ARREST
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 232 (0.43%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    PALPITATIONS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 232 (0.00%)
    6 / 473 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPIRATION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ASTHMA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    3 / 232 (1.29%)
    12 / 473 (2.54%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 17
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COUGH
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    1 / 232 (0.43%)
    11 / 473 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    3 / 232 (1.29%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG DISORDER
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORGANISING PNEUMONIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OROPHARYNGEAL DISCOMFORT
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 232 (0.00%)
    8 / 473 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    3 / 232 (1.29%)
    7 / 473 (1.48%)
         occurrences causally related to treatment / all
    1 / 3
    7 / 7
         deaths causally related to treatment / all
    0 / 1
    2 / 2
    PNEUMOTHORAX
         subjects affected / exposed
    2 / 232 (0.86%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX SPONTANEOUS
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    5 / 232 (2.16%)
    14 / 473 (2.96%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 15
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    PULMONARY HAEMORRHAGE
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 232 (0.86%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    AGRANULOCYTOSIS
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    8 / 232 (3.45%)
    13 / 473 (2.75%)
         occurrences causally related to treatment / all
    6 / 8
    12 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    5 / 232 (2.16%)
    9 / 473 (1.90%)
         occurrences causally related to treatment / all
    5 / 5
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOLYTIC URAEMIC SYNDROME
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    2 / 232 (0.86%)
    14 / 473 (2.96%)
         occurrences causally related to treatment / all
    2 / 2
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 232 (0.00%)
    6 / 473 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    ATAXIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAROTID ARTERY STENOSIS
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    2 / 232 (0.86%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLIC STROKE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEMIPARESIS
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LETHARGY
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAESTHESIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXIC NEUROPATHY
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 232 (0.43%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASOGENIC CEREBRAL OEDEMA
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AUTOIMMUNE COLITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 232 (0.43%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    2 / 232 (0.86%)
    14 / 473 (2.96%)
         occurrences causally related to treatment / all
    1 / 2
    12 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL ULCER
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL VASCULAR MALFORMATION HAEMORRHAGIC
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS PARALYTIC
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINAL STENOSIS
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MELAENA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    4 / 232 (1.72%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    3 / 5
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGEAL FOOD IMPACTION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    2 / 232 (0.86%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    4 / 232 (1.72%)
    6 / 473 (1.27%)
         occurrences causally related to treatment / all
    3 / 5
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 232 (0.00%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHRITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROPATHY TOXIC
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTRENAL FAILURE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    2 / 232 (0.86%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBULOINTERSTITIAL NEPHRITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    AUTOIMMUNE HEPATITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BILE DUCT STONE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLESTASIS
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CIRRHOSIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    HEPATITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATOCELLULAR INJURY
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMMUNE−MEDIATED HEPATITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DRUG ERUPTION
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN ULCER
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYALGIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL PAIN
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    ADRENAL INSUFFICIENCY
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTHYROIDISM
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    2 / 232 (0.86%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    2 / 232 (0.86%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC KETOACIDOSIS
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOALBUMINAEMIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    2 / 232 (0.86%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOCALCAEMIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOMAGNESAEMIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 232 (0.00%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TYPE 2 DIABETES MELLITUS
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS PERFORATED
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERIAL COLITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERIAL SEPSIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 232 (0.43%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAMPYLOBACTER INFECTION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CATHETER SITE INFECTION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONJUNCTIVITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    1 / 232 (0.43%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENCEPHALITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE INFECTION
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GANGRENE
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIOUS PLEURAL EFFUSION
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 232 (0.43%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    1 / 232 (0.43%)
    14 / 473 (2.96%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NASOPHARYNGITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC INFECTION
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 473 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    14 / 232 (6.03%)
    28 / 473 (5.92%)
         occurrences causally related to treatment / all
    3 / 16
    6 / 36
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    PULMONARY SEPSIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 232 (0.43%)
    3 / 473 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 232 (0.86%)
    6 / 473 (1.27%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 6
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    SEPTIC SHOCK
         subjects affected / exposed
    2 / 232 (0.86%)
    5 / 473 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    TRACHEOBRONCHITIS
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 473 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 232 (0.43%)
    4 / 473 (0.85%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 473 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm B (Nab-Paclitaxel+Carboplatin) Arm A (Atezolizumab+Nab-Paclitaxel+Carboplatin)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    226 / 232 (97.41%)
    466 / 473 (98.52%)
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    13 / 232 (5.60%)
    32 / 473 (6.77%)
         occurrences all number
    14
    40
    HYPERTENSION
         subjects affected / exposed
    8 / 232 (3.45%)
    24 / 473 (5.07%)
         occurrences all number
    10
    29
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    38 / 232 (16.38%)
    84 / 473 (17.76%)
         occurrences all number
    53
    121
    CHEST PAIN
         subjects affected / exposed
    12 / 232 (5.17%)
    26 / 473 (5.50%)
         occurrences all number
    12
    31
    FATIGUE
         subjects affected / exposed
    109 / 232 (46.98%)
    222 / 473 (46.93%)
         occurrences all number
    133
    276
    OEDEMA PERIPHERAL
         subjects affected / exposed
    25 / 232 (10.78%)
    64 / 473 (13.53%)
         occurrences all number
    28
    71
    PAIN
         subjects affected / exposed
    7 / 232 (3.02%)
    26 / 473 (5.50%)
         occurrences all number
    8
    30
    PYREXIA
         subjects affected / exposed
    21 / 232 (9.05%)
    75 / 473 (15.86%)
         occurrences all number
    29
    96
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    8 / 232 (3.45%)
    28 / 473 (5.92%)
         occurrences all number
    8
    28
    DEPRESSION
         subjects affected / exposed
    5 / 232 (2.16%)
    25 / 473 (5.29%)
         occurrences all number
    5
    25
    INSOMNIA
         subjects affected / exposed
    31 / 232 (13.36%)
    68 / 473 (14.38%)
         occurrences all number
    33
    74
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    14 / 232 (6.03%)
    24 / 473 (5.07%)
         occurrences all number
    18
    34
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    7 / 232 (3.02%)
    25 / 473 (5.29%)
         occurrences all number
    12
    29
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    35 / 232 (15.09%)
    93 / 473 (19.66%)
         occurrences all number
    61
    187
    PLATELET COUNT DECREASED
         subjects affected / exposed
    38 / 232 (16.38%)
    107 / 473 (22.62%)
         occurrences all number
    61
    177
    WEIGHT DECREASED
         subjects affected / exposed
    28 / 232 (12.07%)
    53 / 473 (11.21%)
         occurrences all number
    29
    58
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    18 / 232 (7.76%)
    49 / 473 (10.36%)
         occurrences all number
    28
    80
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    116 / 232 (50.00%)
    255 / 473 (53.91%)
         occurrences all number
    132
    346
    NEUTROPENIA
         subjects affected / exposed
    105 / 232 (45.26%)
    212 / 473 (44.82%)
         occurrences all number
    194
    422
    LEUKOPENIA
         subjects affected / exposed
    18 / 232 (7.76%)
    51 / 473 (10.78%)
         occurrences all number
    28
    91
    THROMBOCYTOPENIA
         subjects affected / exposed
    60 / 232 (25.86%)
    130 / 473 (27.48%)
         occurrences all number
    95
    206
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    38 / 232 (16.38%)
    125 / 473 (26.43%)
         occurrences all number
    41
    145
    DYSPNOEA
         subjects affected / exposed
    46 / 232 (19.83%)
    126 / 473 (26.64%)
         occurrences all number
    54
    158
    EPISTAXIS
         subjects affected / exposed
    27 / 232 (11.64%)
    68 / 473 (14.38%)
         occurrences all number
    30
    83
    HAEMOPTYSIS
         subjects affected / exposed
    7 / 232 (3.02%)
    26 / 473 (5.50%)
         occurrences all number
    7
    33
    PRODUCTIVE COUGH
         subjects affected / exposed
    8 / 232 (3.45%)
    33 / 473 (6.98%)
         occurrences all number
    8
    37
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    25 / 232 (10.78%)
    74 / 473 (15.64%)
         occurrences all number
    36
    85
    DYSGEUSIA
         subjects affected / exposed
    14 / 232 (6.03%)
    57 / 473 (12.05%)
         occurrences all number
    14
    60
    HEADACHE
         subjects affected / exposed
    23 / 232 (9.91%)
    77 / 473 (16.28%)
         occurrences all number
    26
    92
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    21 / 232 (9.05%)
    53 / 473 (11.21%)
         occurrences all number
    25
    55
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    23 / 232 (9.91%)
    60 / 473 (12.68%)
         occurrences all number
    29
    69
    PARAESTHESIA
         subjects affected / exposed
    12 / 232 (5.17%)
    40 / 473 (8.46%)
         occurrences all number
    13
    48
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    71 / 232 (30.60%)
    168 / 473 (35.52%)
         occurrences all number
    89
    213
    ABDOMINAL PAIN
         subjects affected / exposed
    17 / 232 (7.33%)
    51 / 473 (10.78%)
         occurrences all number
    20
    62
    DIARRHOEA
         subjects affected / exposed
    71 / 232 (30.60%)
    193 / 473 (40.80%)
         occurrences all number
    100
    300
    DYSPEPSIA
         subjects affected / exposed
    7 / 232 (3.02%)
    30 / 473 (6.34%)
         occurrences all number
    8
    31
    NAUSEA
         subjects affected / exposed
    106 / 232 (45.69%)
    231 / 473 (48.84%)
         occurrences all number
    148
    345
    STOMATITIS
         subjects affected / exposed
    12 / 232 (5.17%)
    37 / 473 (7.82%)
         occurrences all number
    14
    41
    VOMITING
         subjects affected / exposed
    43 / 232 (18.53%)
    125 / 473 (26.43%)
         occurrences all number
    67
    214
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    63 / 232 (27.16%)
    151 / 473 (31.92%)
         occurrences all number
    63
    153
    PRURITUS
         subjects affected / exposed
    12 / 232 (5.17%)
    53 / 473 (11.21%)
         occurrences all number
    12
    63
    DRY SKIN
         subjects affected / exposed
    12 / 232 (5.17%)
    24 / 473 (5.07%)
         occurrences all number
    12
    27
    RASH
         subjects affected / exposed
    16 / 232 (6.90%)
    66 / 473 (13.95%)
         occurrences all number
    18
    77
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    16 / 232 (6.90%)
    79 / 473 (16.70%)
         occurrences all number
    16
    87
    ARTHRALGIA
         subjects affected / exposed
    24 / 232 (10.34%)
    70 / 473 (14.80%)
         occurrences all number
    26
    89
    MUSCULAR WEAKNESS
         subjects affected / exposed
    14 / 232 (6.03%)
    22 / 473 (4.65%)
         occurrences all number
    16
    24
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    10 / 232 (4.31%)
    45 / 473 (9.51%)
         occurrences all number
    10
    53
    MYALGIA
         subjects affected / exposed
    10 / 232 (4.31%)
    41 / 473 (8.67%)
         occurrences all number
    11
    48
    PAIN IN EXTREMITY
         subjects affected / exposed
    14 / 232 (6.03%)
    52 / 473 (10.99%)
         occurrences all number
    14
    58
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    1 / 232 (0.43%)
    50 / 473 (10.57%)
         occurrences all number
    1
    54
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    58 / 232 (25.00%)
    142 / 473 (30.02%)
         occurrences all number
    64
    164
    DEHYDRATION
         subjects affected / exposed
    24 / 232 (10.34%)
    47 / 473 (9.94%)
         occurrences all number
    30
    68
    HYPOKALAEMIA
         subjects affected / exposed
    24 / 232 (10.34%)
    71 / 473 (15.01%)
         occurrences all number
    29
    90
    HYPOMAGNESAEMIA
         subjects affected / exposed
    39 / 232 (16.81%)
    94 / 473 (19.87%)
         occurrences all number
    48
    125
    HYPONATRAEMIA
         subjects affected / exposed
    8 / 232 (3.45%)
    26 / 473 (5.50%)
         occurrences all number
    10
    41
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    9 / 232 (3.88%)
    29 / 473 (6.13%)
         occurrences all number
    9
    39
    BRONCHITIS
         subjects affected / exposed
    6 / 232 (2.59%)
    26 / 473 (5.50%)
         occurrences all number
    7
    27
    PNEUMONIA
         subjects affected / exposed
    5 / 232 (2.16%)
    27 / 473 (5.71%)
         occurrences all number
    5
    28
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    12 / 232 (5.17%)
    33 / 473 (6.98%)
         occurrences all number
    15
    47
    URINARY TRACT INFECTION
         subjects affected / exposed
    19 / 232 (8.19%)
    59 / 473 (12.47%)
         occurrences all number
    20
    79

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2015
    Protocol was amended to include change to the name of the test product from MPDL3280A to atezolizumab. The evaluations of progression-free survival at 6 months and at 1 year and overall survival at 3 years have been added as exploratory objectives to further evaluate the clinical benefit of atezolizumab at these time points. The contraception requirements in the inclusion and exclusion criteria and the pregnancy-reporting information have been updated to be consistent with safety information for nab-paclitaxel. The study inclusion criteria have been modified, on the basis of data from an expanding safety database, to allow for patients with treated, asymptomatic cerebellar metastases to be enrolled provided specific criteria are met. The exclusion criteria for history of autoimmune disease has been broadened, on the basis of data from an expanding safety database, to allow for patients with eczema, psoriasis, or lichen simplex chronicus of vitiligo with dermatologic manifestations only to be permitted provided that they meet the specific conditions. The study exclusion criterion regarding treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug (whichever is shorter) prior to randomization has been modified to 4 weeks prior to randomization for consistency with more recent atezolizumab protocols. The exclusion criterion specifying that patients with a history of allergic reaction to intravenous contrast that requires steroid pretreatment should have baseline and subsequent tumor assessments performed via magnetic resonance imaging (MRI) has been removed because this is in conflict with Section 4.5.5. Patients with contraindications to contrast may have assessments done with non-contrast computed tomography or MRI.
    11 Nov 2015
    Protocol was amended to clarify that a wash-out period of at least 4 weeks or five half-lives, whichever is longer, of any systemic immunomodulatory agent is required prior to enrollment.
    15 Jun 2016
    Protocol was amended to add a co-primary endpoint of overall survival (OS) to the progression-free survival (PFS) primary endpoint. For patients consented and randomized to Arm B after Ethics Committee or Institutional Review Board approval of Protocol GO29537, Version 5 at each respective site, the option for crossover to atezolizumab maintenance therapy has been removed to enable the comparative analyses of the two treatment arms. Patients randomized to Arm B who were consented under previous versions of this protocol prior to the approval of Version 5 will continue to have the option for crossover to atezolizumab maintenance therapy. The total number of patients to be randomized in the study has increased from 550 patients to 650 patients to ensure that the study is adequately powered for the comparative analyses. Erlotinib switch maintenance therapy has been removed from the protocol. A secondary efficacy objective and outcome measure has been added to evaluate the efficacy of atezolizumab + carboplatin + nab-paclitaxel compared with carboplatin + nab-paclitaxel as measured by investigator-assessed time to response (TTR) according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for both the intent-to-treat (ITT) and programmed death−ligand 1(PD-L1)−selected populations.
    01 Mar 2017
    Protocol was amended to include change to the primary analysis populations for the co-primary endpoints of progression-free survival (PFS) and overall survival (OS). OS will be analyzed in the intent-to-treat (ITT) population. PFS will be analyzed in the ITT population and a population with a defined level of expression of a PD-L1 and T-effector gene signature in tumor tissue as determined by an RNA-based assay. Patients with known sensitizing EGFR mutations or ALK translocations will be excluded from the primary analysis populations. The analyses of PFS and OS in all randomized patients will be conducted as secondary analyses. Additional censoring rule for the primary endpoint of PFS for U.S. registration purposes has been removed. The statistical testing procedures have been amended to reflect the change in analysis populations. All endpoints (secondary and exploratory) based on the review by an Independent Review Facility (IRF) have been removed.
    24 Oct 2018
    Protocol was amended to correct the end of study definition corrected. This correction ensures that the study continues until last patient, last visit or until the Sponsor terminates the study. The inclusion criterion that addresses female contraception has been modified to specify when women must refrain from donating eggs.
    29 Mar 2019
    Protocol was amended to clarify the inclusion criterion on contraception. In addition, reporting for serious adverse events and adverse events of special interest has been extended to 90 days after last dose of study treatment or until initiation of a new anticancer therapy, whichever occurs first.

    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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