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    Clinical Trial Results:
    A Phase III, Multicenter, Randomised, Double-Blind, Placebo-Controlled Study of Atezolizumab (Anti-Pd-L1 Antibody) in Combination With Paclitaxel Compared With Placebo With Paclitaxel for Patients With Previously Untreated Inoperable Locally Advanced or Metastatic Triple Negative Breast Cancer

    Summary
    EudraCT number
    		 2016-004024-29
    Trial protocol
    		 SK   DE   CZ   GB   GR   FR   ES   HR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Feb 2024
    First version publication date
    26 Nov 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Final Results

    Trial information

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    Trial identification
    Sponsor protocol code
    MO39196
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03125902
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Medical Communications, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    15 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Nov 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This Phase 3, multicenter, randomized, double-blind, placebo controlled study is designed to evaluate the efficacy, pharmacokinetics and safety of atezolizumab (MPDL3280A, an anti-programmed death-ligand 1 [PD-L1] antibody) administered in combination with paclitaxel compared with placebo in combination with paclitaxel in subjects with previously untreated, inoperable locally advanced or metastatic, histologically documented TNBC. Subjects are randomized in a 2:1 ratio to receive atezolizumab or placebo plus paclitaxel until disease progression or unacceptable toxicity or end of study, whichever occurs first. In addition, the Sponsor may decide to terminate the study at any time.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with the following: ● Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines ● Applicable ICH Good Clinical Practice (GCP) Guidelines ● Applicable laws and regulations
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 15
    Country: Number of subjects enrolled
    Brazil: 44
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    China: 131
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    France: 63
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    India: 27
    Country: Number of subjects enrolled
    Israel: 26
    Country: Number of subjects enrolled
    Italy: 64
    Country: Number of subjects enrolled
    Japan: 18
    Country: Number of subjects enrolled
    Morocco: 9
    Country: Number of subjects enrolled
    Romania: 11
    Country: Number of subjects enrolled
    Russian Federation: 24
    Country: Number of subjects enrolled
    Slovakia: 9
    Country: Number of subjects enrolled
    Turkey: 31
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Vietnam: 9
    Country: Number of subjects enrolled
    South Africa: 1
    Worldwide total number of subjects
    651
    EEA total number of subjects
    257
    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)
    498
    From 65 to 84 years
    152
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period: 06-Jun-2017 to 11-Sep-2019

    Pre-assignment
    Screening details
    		 The target population included subjects with previously untreated inoperable locally advanced or metastatic TNBC.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Paclitaxel
    Arm description
    		 Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matching to atezolizumab will be administered via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel will be administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle

    Arm title
    		 Atezolizumab + Paclitaxel
    Arm description
    		 Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel will be administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, an engineered anti-PDL1 antibody
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab is administered at a dose of 840 mg via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle.

    Number of subjects in period 1
    		Placebo + Paclitaxel Atezolizumab + Paclitaxel
    Started
    220
    431
    Completed
    0
    0
    Not completed
    220
    431
         Adverse event, serious fatal
    52
    123
         Physician decision
    1
    -
         Consent withdrawn by subject
    13
    25
         Mastectomy
    -
    1
         Study is ongoing
    153
    282
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Reporting group title
    Atezolizumab + Paclitaxel
    Reporting group description
    		 Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Reporting group values
    		 Placebo + Paclitaxel Atezolizumab + Paclitaxel Total
    Number of subjects
    		 220 431 651
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 176 322 498
        >=65 years
    		 44 109 153
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 52.7 ( 12.2 ) 54.8 ( 12.6 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 220 430 650
        Male
    		 0 1 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 66 123 189
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 10 21 31
        White
    		 128 246 374
        More than one race
    		 2 3 5
        Unknown or Not Reported
    		 14 37 51
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 23 44 67
        Not Hispanic or Latino
    		 174 332 506
        Unknown or Not Reported
    		 23 55 78
    Subject analysis sets

    Subject analysis set title
    Placebo and Paclitaxel
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Subject analysis set title
    Atezolizumab and Paclitaxel
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Subject analysis set title
    Placebo and Paclitaxel: PD-L1-Positive Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the ITT population whose PD-L1 status was IC1/2/3 at the time of randomization

    Subject analysis set title
    Atezolizumab and Paclitaxel: PD-L1-Positive Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the ITT population whose PD-L1 status was IC1/2/3 at the time of randomization

    Subject analysis sets values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel Placebo and Paclitaxel: PD-L1-Positive Population Atezolizumab and Paclitaxel: PD-L1-Positive Population
    Number of subjects
    220
    431
    101
    191
    Age Categorical
    Units: Participants
        <=18 years
    0
    0
        Between 18 and 65 years
    176
    322
        >=65 years
    44
    109
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    52.7 ( 12.2 )
    54.8 ( 12.6 )
    ( )
    ( )
    Sex: Female, Male
    Units: Participants
        Female
    220
    430
        Male
    0
    1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0
    0
        Asian
    66
    123
        Native Hawaiian or Other Pacific Islander
    0
    1
        Black or African American
    10
    21
        White
    128
    246
        More than one race
    2
    3
        Unknown or Not Reported
    14
    37
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    23
    44
        Not Hispanic or Latino
    174
    332
        Unknown or Not Reported
    23
    55

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Reporting group title
    Atezolizumab + Paclitaxel
    Reporting group description
    		 Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Subject analysis set title
    Placebo and Paclitaxel
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Subject analysis set title
    Atezolizumab and Paclitaxel
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Subject analysis set title
    Placebo and Paclitaxel: PD-L1-Positive Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the ITT population whose PD-L1 status was IC1/2/3 at the time of randomization

    Subject analysis set title
    Atezolizumab and Paclitaxel: PD-L1-Positive Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the ITT population whose PD-L1 status was IC1/2/3 at the time of randomization

    Primary: Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Subpopulation with Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status

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    End point title
    		 Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Subpopulation with Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status
    End point description
    PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (>/=) 20 percent (%) relative increase and >/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
    End point type
    Primary
    End point timeframe
    From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    101
    191
    Units: Months
        median (confidence interval 95%)
    5.72 (5.39 to 7.20)
    5.95 (5.62 to 7.43)
    Statistical analysis title
    		 Stratified Analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2032
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.12
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2601
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.14

    Primary: Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population

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    End point title
    		 Progression-Free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in the Intent-to-Treat (ITT) Population
    End point description
    PFS is defined as the time from randomization to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (>/=) 20 percent (%) relative increase and >/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
    End point type
    Primary
    End point timeframe
    From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    220
    431
    Units: Months
        median (confidence interval 95%)
    5.55 (5.36 to 6.51)
    5.68 (5.42 to 7.16)
    Statistical analysis title
    		 Stratified Analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    651
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1343
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.05
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    651
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1285
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.05

    Secondary: Overall Survival (OS) in the PD-L1-Positive Subpopulation

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    End point title
    		 Overall Survival (OS) in the PD-L1-Positive Subpopulation
    End point description
    OS is defined as the time from randomization to death from any cause. 0000 = Data not available 9999= Data not available
    End point type
    Secondary
    End point timeframe
    From Day 1 to death from any cause, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    101
    191
    Units: Months
        median (confidence interval 95%)
    9999 (19.06 to 9999)
    9999 (22.05 to 9999)
    Statistical analysis title
    		 Stratified Analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.142
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 2.8
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1374
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 2.79

    Secondary: Overall Survival (OS) in the ITT Population

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    End point title
    		 Overall Survival (OS) in the ITT Population
    End point description
    OS is defined as the time from randomization to death from any cause. 0000 = Data not available 9999= Data not available
    End point type
    Secondary
    End point timeframe
    From Day 1 to death from any cause, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    220
    431
    Units: Months
        median (confidence interval 95%)
    22.80 (19.06 to 9999)
    18.07 (15.90 to 9999)
    Statistical analysis title
    		 Stratified analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    651
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1097
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.82
    Statistical analysis title
    		 Unstratified analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    651
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1411
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.76

    Secondary: Percentage of Participants Who are Alive at 12 and 18 Months

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    End point title
    		 Percentage of Participants Who are Alive at 12 and 18 Months
    End point description
    End point type
    Secondary
    End point timeframe
    From Day 1 to death from any cause, assessed up to 12 and 18 months
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    220
    431
    Units: Percentage of Participants
    number (confidence interval 95%)
        12 months
    74.86 (67.53 to 82.18)
    68.32 (62.70 to 73.94)
        18 months
    60.95 (50.53 to 71.38)
    51.02 (43.65 to 58.38)
    No statistical analyses for this end point

    Secondary: Time to deterioration (TTD) in Global Health Status/ Health Related Quality of Life (HRQoL) in the PRO Evaluable Population

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    End point title
    		 Time to deterioration (TTD) in Global Health Status/ Health Related Quality of Life (HRQoL) in the PRO Evaluable Population
    End point description
    Deterioration in Global Health Status/HRQoL is defined as a decrease of at least 10 points on the Global Health Status /HRQoL scale (comprised of 2 items: 29 and 30) of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The 2 items use 7-point scale (1 = very poor to 7 = Excellent). Scores are averaged, transformed to 0-100 scale; where higher score=better level of functioning or greater degree of symptoms. 0000 = Data not available 9999= Data not available
    End point type
    Secondary
    End point timeframe
    From Day 1 to deterioration, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    205
    383
    Units: Months
        median (confidence interval 95%)
    17.35 (9.63 to 9999)
    12.45 (9.69 to 9999)
    Statistical analysis title
    		 Stratified analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8435
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.3

    Secondary: Percentage of Participants Who are Alive Without Progression Event at Month 12 Assessed Using RECIST v1.1

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    End point title
    		 Percentage of Participants Who are Alive Without Progression Event at Month 12 Assessed Using RECIST v1.1
    End point description
    PD is defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD or death from any cause, assessed up to 12 months
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    220
    431
    Units: Percentage of Participants
        number (confidence interval 95%)
    16.22 (10.18 to 22.26)
    21.63 (16.74 to 26.51)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1+ Response-evaluable population (Confirmed)

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    End point title
    		 Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the PD-L1+ Response-evaluable population (Confirmed)
    End point description
    Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (<) 10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. Response-evaluable population: subjects in the ITT population with measurable disease at baseline. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    101
    191
    Units: Percentage of Participants
        number (confidence interval 95%)
    40.6 (30.93 to 50.82)
    49.2 (41.92 to 56.53)
    Statistical analysis title
    		 Stratified analysis
    Comparison groups
    Atezolizumab and Paclitaxel v Placebo and Paclitaxel
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1526
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 2.37

    Secondary: Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-evaluable population (Unconfirmed)

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    End point title
    		 Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-evaluable population (Unconfirmed)
    End point description
    Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (<) 10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    101
    191
    Units: Percentage of Participants
        number (confidence interval 95%)
    55.4 (45.22 to 65.34)
    63.4 (56.09 to 70.19)
    Statistical analysis title
    		 Stratified analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1834
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 2.31

    Secondary: Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-evaluable population (Confirmed)

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    End point title
    		 Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-evaluable population (Confirmed)
    End point description
    Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (<) 10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. subjects in the ITT population with measurable disease at baseline. Responses were confirmed after 8 weeks if within first 12 months or after 12 weeks if later.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    219
    431
    Units: Percentage of Participants
        number (confidence interval 95%)
    32.4 (26.27 to 39.05)
    39.9 (35.25 to 44.70)
    Statistical analysis title
    		 Stratified analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    650
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0513
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.02

    Secondary: Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Unconfirmed)

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    End point title
    		 Percentage of Participants With Objective Response Assessed Using RECIST v1.1 in the Response-Evaluable Population (Unconfirmed)
    End point description
    Objective response is defined as complete response (CR) or partial response (PR), as determined by the investigator using RECIST v1.1 criteria. CR is defined as the disappearance of all TLs and SA reduction to less than (<) 10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    219
    431
    Units: Percentage of Participants
        number (confidence interval 95%)
    47.5 (40.72 to 54.33)
    53.6 (48.76 to 58.38)
    Statistical analysis title
    		 Stratified analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    650
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1226
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.81

    Secondary: Duration of Objective Response (DOR) Assessed Using RECIST v1.1 in Response-evaluable population (Unconfirmed)

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    End point title
    		 Duration of Objective Response (DOR) Assessed Using RECIST v1.1 in Response-evaluable population (Unconfirmed)
    End point description
    DOR is defined as the time period from the date of initial CR or PR until the date of PD or death from any cause, whichever occurs first. CR is defined as the disappearance of all TLs and SA reduction to <10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. PD is defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
    End point type
    Secondary
    End point timeframe
    From objective response to PD, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    104
    231
    Units: Months
        median (confidence interval 95%)
    5.45 (4.67 to 6.31)
    6.41 (5.55 to 7.39)
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0641
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.02

    Secondary: Percentage of Participants With Clinical Benefit Assessed Using RECIST v1.1 in Response evaluable population

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    End point title
    		 Percentage of Participants With Clinical Benefit Assessed Using RECIST v1.1 in Response evaluable population
    End point description
    Clinical benefit is defined as the achievement of CR, PR, or stable disease according to RECIST v1.1 that lasts for at least 6 months. CR is defined as the disappearance of all TLs and SA reduction to <10mm for nodal TLs/ non-TLs. PR is defined as >/=30% decrease in SD of TLs, taking as reference the baseline SD. PD is defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference smallest SD since treatment started.
    End point type
    Secondary
    End point timeframe
    From Day 1 to PD, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    219
    431
    Units: Percentage of Participants
        number (confidence interval 95%)
    49.8 (42.96 to 56.59)
    57.1 (52.25 to 61.80)
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab

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    End point title
    		 Minimum Observed Serum Concentration (Cmin) of Atezolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycles 2-4 and at treatment discontinuation (TD), (approximately 9 months).
    End point values
    		 Atezolizumab and Paclitaxel
    Number of subjects analysed
    342
    Units: μg/mL
    arithmetic mean (standard deviation)
        C2D1 predose n=316
    139 ( 53.3 )
        C3D1 predose n=277
    208 ( 78.3 )
        C4D1 predose n=243
    242 ( 84.8 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Atezolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    C1D1 30 min postdose
    End point values
    		 Atezolizumab and Paclitaxel
    Number of subjects analysed
    308
    Units: μg/mL
        arithmetic mean (standard deviation)
    321 ( 90.5 )
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration (Cmin) of Paclitaxel

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    End point title
    		 Minimum Observed Plasma Concentration (Cmin) of Paclitaxel
    End point description
    0000 = Data not available 9999= Data not available
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycle 3 (1 Cycle = 28 days)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    23
    37
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1.51 ( 9999 )
    1.67 ( 9999 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Paclitaxel

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Paclitaxel
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours), 5-10 min before and after paclitaxel infusion, 60 min after paclitaxel infusion on Day 1 of Cycles 1 and 3 (paclitaxel infusion duration= 60 min) (1 Cycle = 28 days)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    23
    37
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        C1D1 Post-Dose (n= 23; n=37)
    518 ( 290.7 )
    301 ( 1501 )
        C3D1 Post-Dose (n=16; n=26)
    666 ( 339 )
    276 ( 1360 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)

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    End point title
    		 Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
    End point description
    Investigator text for AEs is coded using MedDRA version 23.0
    End point type
    Secondary
    End point timeframe
    From Day 1 to 90 days after last dose of study drug, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    218
    431
    Units: Percentage of participants
    number (not applicable)
        Percentage of participants with at least one AE
    97.7
    99.1
        Total number of participants with at least one SAE
    16.1
    22.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Drug Antibodies (ADAs)

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    End point title
    		 Percentage of Participants With Anti-Drug Antibodies (ADAs)
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hours) on Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16, and at every 8 cycles thereafter until TD, at TD, and at 90-150 days after TD (maximum up to 45 months) (1 Cycle = 28 days)
    End point values
    		 Atezolizumab and Paclitaxel
    Number of subjects analysed
    334
    Units: Percentage of Participants
    number (not applicable)
        Positive for ADA at Baseline
    1.5
        Positive for ADA Post-baseline
    14.7
    No statistical analyses for this end point

    Secondary: Overall Survival by PD-L1 Status, Intent to Treat Population

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    End point title
    		 Overall Survival by PD-L1 Status, Intent to Treat Population
    End point description
    ITT population: all randomized participants, whether or not the assigned study treatment was received 9999=Insufficient number of participants with events
    End point type
    Secondary
    End point timeframe
    From Day 1 up to primary analysis (up to approximately 26 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    220
    431
    Units: Months
    median (confidence interval 95%)
        PD-L1 IC0 (n= 119, n= 240)
    20.37 (19.94 to 25.10)
    16.26 (13.50 to 18.99)
        PD-L1 IC1/2/3 (n= 101, n=191)
    9999 (19.06 to 9999)
    9999 (22.05 to 9999)
    No statistical analyses for this end point

    Secondary: Progression Free Survival by PD-L1 Status, Intent to Treat Population

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    End point title
    		 Progression Free Survival by PD-L1 Status, Intent to Treat Population
    End point description
    ITT population: all randomized participants, whether or not the assigned study treatment was received
    End point type
    Secondary
    End point timeframe
    From Day 1 up to primary completion date (approximately 26 months)
    End point values
    		 Placebo + Paclitaxel Atezolizumab + Paclitaxel
    Number of subjects analysed
    220
    431
    Units: Months
    median (confidence interval 95%)
        PD-L1 IC0 (n=119, n=240)
    5.49 (3.84 to 6.51)
    5.45 (4.60 to 6.51)
        PD-L1 IC1/2/3 (n=101, n=191)
    5.72 (5.39 to 7.20)
    5.95 (5.62 to 7.43)
    No statistical analyses for this end point

    Secondary: Duration of Confirmed Response (C-DoR) in C-DoR Evaluable Population

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    End point title
    		 Duration of Confirmed Response (C-DoR) in C-DoR Evaluable Population
    End point description
    C-DoR is defined as the time from the first occurrence of a documented confirmed response (CR or PR) until the date of disease progression per RECIST v1.1 or death from any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    From objective response to PD, assessed up to end of study (up to approximately 40 months)
    End point values
    		 Placebo and Paclitaxel Atezolizumab and Paclitaxel
    Number of subjects analysed
    71
    172
    Units: Months
        median (confidence interval 95%)
    5.75 (5.36 to 7.56)
    7.66 (7.16 to 11.33)
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Placebo and Paclitaxel v Atezolizumab and Paclitaxel
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.01227
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.9

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 to 90 days after last dose of study drug, assessed up to end of study (up to approximately 40 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Participants will receive placebo matching to atezolizumab via IV infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg/m^2 via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Reporting group title
    Atezolizumab + Paclitaxel
    Reporting group description
    		 Participants will receive atezolizumab at a dose of 840 milligrams (mg) via intravenous (IV) infusion on Days 1 and 15 (± 3 days) of every 28-day cycle along with paclitaxel administered at a dose of 90 mg per square meter (mg/m^2) via IV infusion on Days 1, 8, and 15 of every 28-day cycle until disease progression or unacceptable toxicity.

    Serious adverse events
    		 Placebo + Paclitaxel Atezolizumab + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 218 (16.06%)
    98 / 431 (22.74%)
         number of deaths (all causes)
    4
    9
         number of deaths resulting from adverse events
    0
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR PAIN
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         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
    DEATH
         subjects affected / exposed
    0 / 218 (0.00%)
    3 / 431 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PYREXIA
         subjects affected / exposed
    1 / 218 (0.46%)
    3 / 431 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BREAST FIBROSIS
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG DISORDER
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         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 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    6 / 431 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    DEVICE BREAKAGE
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE KINK
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    COMPRESSION FRACTURE
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    2 / 218 (0.92%)
    3 / 431 (0.70%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROCEDURAL PNEUMOTHORAX
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         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
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    PERICARDITIS
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBRAL VENOUS SINUS THROMBOSIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COGNITIVE DISORDER
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYASTHENIA GRAVIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCIATICA
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 218 (0.92%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BICYTOPENIA
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE MARROW FAILURE
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    1 / 218 (0.46%)
    3 / 431 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHADENITIS
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    KERATITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORBITAL MYOSITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         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
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS ULCERATIVE
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 218 (0.46%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL ULCER
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMMUNE-MEDIATED PANCREATITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL HAEMORRHAGE
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    3 / 218 (1.38%)
    3 / 431 (0.70%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GLOMERULONEPHRITIS CHRONIC
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHRITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    HYPOPHYSITIS
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTHYROIDISM
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 218 (0.00%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYMYOSITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA INFECTIOUS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         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 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    2 / 218 (0.92%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYELITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    3 / 218 (1.38%)
    9 / 431 (2.09%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY SEPSIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 218 (0.46%)
    4 / 431 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    SOFT TISSUE INFECTION
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL SKIN INFECTION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOOTH INFECTION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 218 (0.46%)
    3 / 431 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR DEVICE INFECTION
         subjects affected / exposed
    3 / 218 (1.38%)
    2 / 431 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VESTIBULAR NEURONITIS
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERAMYLASAEMIA
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERLIPASAEMIA
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOCALCAEMIA
         subjects affected / exposed
    1 / 218 (0.46%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 218 (0.00%)
    1 / 431 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOPROTEINAEMIA
         subjects affected / exposed
    1 / 218 (0.46%)
    0 / 431 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Paclitaxel Atezolizumab + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    209 / 218 (95.87%)
    418 / 431 (96.98%)
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    11 / 218 (5.05%)
    17 / 431 (3.94%)
         occurrences all number
    12
    19
    HYPERTENSION
         subjects affected / exposed
    11 / 218 (5.05%)
    18 / 431 (4.18%)
         occurrences all number
    11
    32
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    45 / 218 (20.64%)
    99 / 431 (22.97%)
         occurrences all number
    59
    139
    FATIGUE
         subjects affected / exposed
    55 / 218 (25.23%)
    117 / 431 (27.15%)
         occurrences all number
    68
    148
    OEDEMA PERIPHERAL
         subjects affected / exposed
    20 / 218 (9.17%)
    42 / 431 (9.74%)
         occurrences all number
    27
    55
    PYREXIA
         subjects affected / exposed
    25 / 218 (11.47%)
    62 / 431 (14.39%)
         occurrences all number
    33
    83
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    8 / 218 (3.67%)
    26 / 431 (6.03%)
         occurrences all number
    8
    31
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    35 / 218 (16.06%)
    82 / 431 (19.03%)
         occurrences all number
    43
    102
    DYSPNOEA
         subjects affected / exposed
    24 / 218 (11.01%)
    46 / 431 (10.67%)
         occurrences all number
    29
    54
    EPISTAXIS
         subjects affected / exposed
    15 / 218 (6.88%)
    25 / 431 (5.80%)
         occurrences all number
    18
    29
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    21 / 218 (9.63%)
    30 / 431 (6.96%)
         occurrences all number
    21
    36
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    34 / 218 (15.60%)
    79 / 431 (18.33%)
         occurrences all number
    53
    138
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    38 / 218 (17.43%)
    80 / 431 (18.56%)
         occurrences all number
    60
    134
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    33 / 218 (15.14%)
    62 / 431 (14.39%)
         occurrences all number
    169
    226
    WEIGHT DECREASED
         subjects affected / exposed
    6 / 218 (2.75%)
    27 / 431 (6.26%)
         occurrences all number
    6
    28
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    29 / 218 (13.30%)
    60 / 431 (13.92%)
         occurrences all number
    165
    190
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    18 / 218 (8.26%)
    32 / 431 (7.42%)
         occurrences all number
    21
    36
    DYSGEUSIA
         subjects affected / exposed
    16 / 218 (7.34%)
    32 / 431 (7.42%)
         occurrences all number
    18
    34
    HEADACHE
         subjects affected / exposed
    36 / 218 (16.51%)
    51 / 431 (11.83%)
         occurrences all number
    41
    64
    HYPOAESTHESIA
         subjects affected / exposed
    14 / 218 (6.42%)
    23 / 431 (5.34%)
         occurrences all number
    18
    33
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    58 / 218 (26.61%)
    117 / 431 (27.15%)
         occurrences all number
    80
    154
    PARAESTHESIA
         subjects affected / exposed
    22 / 218 (10.09%)
    37 / 431 (8.58%)
         occurrences all number
    30
    46
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    23 / 218 (10.55%)
    41 / 431 (9.51%)
         occurrences all number
    26
    49
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    60 / 218 (27.52%)
    118 / 431 (27.38%)
         occurrences all number
    102
    229
    LEUKOPENIA
         subjects affected / exposed
    15 / 218 (6.88%)
    49 / 431 (11.37%)
         occurrences all number
    32
    148
    NEUTROPENIA
         subjects affected / exposed
    46 / 218 (21.10%)
    91 / 431 (21.11%)
         occurrences all number
    98
    215
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    18 / 218 (8.26%)
    34 / 431 (7.89%)
         occurrences all number
    20
    39
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    14 / 218 (6.42%)
    38 / 431 (8.82%)
         occurrences all number
    20
    43
    CONSTIPATION
         subjects affected / exposed
    31 / 218 (14.22%)
    79 / 431 (18.33%)
         occurrences all number
    51
    95
    DIARRHOEA
         subjects affected / exposed
    48 / 218 (22.02%)
    117 / 431 (27.15%)
         occurrences all number
    75
    184
    DRY MOUTH
         subjects affected / exposed
    7 / 218 (3.21%)
    22 / 431 (5.10%)
         occurrences all number
    8
    30
    DYSPEPSIA
         subjects affected / exposed
    11 / 218 (5.05%)
    16 / 431 (3.71%)
         occurrences all number
    12
    17
    NAUSEA
         subjects affected / exposed
    53 / 218 (24.31%)
    111 / 431 (25.75%)
         occurrences all number
    92
    155
    STOMATITIS
         subjects affected / exposed
    10 / 218 (4.59%)
    23 / 431 (5.34%)
         occurrences all number
    14
    27
    VOMITING
         subjects affected / exposed
    20 / 218 (9.17%)
    66 / 431 (15.31%)
         occurrences all number
    34
    102
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    116 / 218 (53.21%)
    252 / 431 (58.47%)
         occurrences all number
    121
    256
    ERYTHEMA
         subjects affected / exposed
    6 / 218 (2.75%)
    24 / 431 (5.57%)
         occurrences all number
    6
    28
    PRURITUS
         subjects affected / exposed
    18 / 218 (8.26%)
    40 / 431 (9.28%)
         occurrences all number
    20
    64
    RASH
         subjects affected / exposed
    35 / 218 (16.06%)
    73 / 431 (16.94%)
         occurrences all number
    51
    98
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    0 / 218 (0.00%)
    22 / 431 (5.10%)
         occurrences all number
    0
    25
    HYPOTHYROIDISM
         subjects affected / exposed
    5 / 218 (2.29%)
    43 / 431 (9.98%)
         occurrences all number
    5
    49
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    14 / 218 (6.42%)
    50 / 431 (11.60%)
         occurrences all number
    18
    74
    BACK PAIN
         subjects affected / exposed
    18 / 218 (8.26%)
    38 / 431 (8.82%)
         occurrences all number
    21
    42
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    9 / 218 (4.13%)
    24 / 431 (5.57%)
         occurrences all number
    9
    25
    MYALGIA
         subjects affected / exposed
    23 / 218 (10.55%)
    45 / 431 (10.44%)
         occurrences all number
    32
    56
    PAIN IN EXTREMITY
         subjects affected / exposed
    22 / 218 (10.09%)
    45 / 431 (10.44%)
         occurrences all number
    33
    55
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    16 / 218 (7.34%)
    32 / 431 (7.42%)
         occurrences all number
    17
    35
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    12 / 218 (5.50%)
    24 / 431 (5.57%)
         occurrences all number
    14
    33
    URINARY TRACT INFECTION
         subjects affected / exposed
    10 / 218 (4.59%)
    32 / 431 (7.42%)
         occurrences all number
    12
    41
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    18 / 218 (8.26%)
    63 / 431 (14.62%)
         occurrences all number
    27
    100

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2017
    The protocol was amended to address regulatory requests for revisions as part of review through the Voluntary Harmonisation Procedure (VHP).
    05 Dec 2017
    The protocol was amended to include updated safety and efficacy data from the revised Investigator’s Brochure (version 10), align screening assessments for hepatitis in inclusion vs. exclusion criteria across atezolizumab studies, reduce schedule for PK and ADA assessments, update select laboratory assessments in the China population, and to clarify acceptable assessment windows.
    17 Dec 2018
    The major changes to the protocol were prompted by the results of primary analysis of the IMpassion130 (WO29522) study.
    23 May 2019
    Key changes included: • Removal of a planned interim analysis of PFS at 80% information fraction in the PD-L1positive population as a result of feedback from the US Food and Drug Administration (FDA). • Adjustment of target number of primary endpoint events from 158 to 155 with the removal of interim analysis of PFS. • Addition of two new secondary endpoints in keeping with a request from the US FDA: confirmed objective response rate (C-ORR), and duration of confirmed response (C-DoR) • Addition of immune-mediated myositis to the list of identified risks for atezolizumab, along with management guidelines for this newly added risk. Requirements for permanent treatment discontinuation in case of immune-related myositis were clarified.
    11 Feb 2020
    This amendment included updates to risks and management guidelines that aligned with the latest atezolizumab IB (v15.0)

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

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

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