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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Placebo-Controlled Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Nab-Paclitaxel Compared With Placebo With Nab-Paclitaxel for Patients With Previously Untreated Metastatic Triple-Negative Breast Cancer

    Summary
    EudraCT number
    		 2014-005490-37
    Trial protocol
    		 DE   BE   GB   GR   ES   SE   DK   LV   AT   FI   CZ   HU   PL   EE   SI   FR   RO   IT  
    Global end of trial date
    31 Aug 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Jul 2022
    First version publication date
    09 Apr 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    WO29522
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02425891
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IMpassion130: Acronym
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab with nab-paclitaxel compared with placebo with nab-paclitaxelin patients with metastatic or locally advanced triple-negative adenocarcinoma of the breast who have not received prior systemic therapy for metastatic breast cancer (mBC).
    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
    23 Jun 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 19 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Australia: 42
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 1
    Country: Number of subjects enrolled
    Brazil: 59
    Country: Number of subjects enrolled
    Canada: 43
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Chile: 16
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Costa Rica: 15
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    Germany: 88
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 28
    Country: Number of subjects enrolled
    United Kingdom: 44
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Guatemala: 3
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 65
    Country: Number of subjects enrolled
    Korea, Republic of: 56
    Country: Number of subjects enrolled
    Latvia: 5
    Country: Number of subjects enrolled
    Mexico: 25
    Country: Number of subjects enrolled
    Norway: 4
    Country: Number of subjects enrolled
    Panama: 6
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Russian Federation: 34
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Serbia: 2
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Thailand: 5
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Ukraine: 18
    Country: Number of subjects enrolled
    United States: 187
    Worldwide total number of subjects
    902
    EEA total number of subjects
    233
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    683
    From 65 to 84 years
    216
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study included in total 246 centers in 41 countries. The observation of Overall Survival events was complete. Participants still on treatment were handed over to follow-up programs or studies. The study status is "Completed" but some participants discontinued the study because the Sponsor terminated it after it reached the "Completed" state.

    Pre-assignment
    Screening details
    		 This study included participants with metastatic or locally advanced, histologically documented triple-negative breast cancer (TNBC) (absence of human epidermal growth factor 2 [HER2], estrogen receptor [ER], and progesterone receptor [PR] expression) by local laboratory assessment.

    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 Plus Nab-Paclitaxel
    Arm description
    		 Participants assigned to placebo plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered via IV infusion on Days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Nab-Paclitaxel
    Investigational medicinal product code
    Other name
    Abraxane®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nab-Paclitaxel was administered at a starting dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle. Nab-Paclitaxel was administered for a target of at least 6 cycles, with no maximum in the absence of disease progression or unacceptable toxicity.

    Arm title
    		 Atezolizumab Plus Nab-Paclitaxel
    Arm description
    		 Participants assigned to atezolizumab plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nab-Paclitaxel
    Investigational medicinal product code
    Other name
    Abraxane®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nab-Paclitaxel was administered at a starting dose of 100 milligrams per square meter via IV infusion on Days 1, 8, and 15 of each 28-day cycle. Nab-Paclitaxel was administered for a target of at least 6 cycles, with no maximum in the absence of disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq, MPDL3280A
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered at a fixed dose of 840 milligrams via intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until disease progression or unacceptable toxicity.

    Number of subjects in period 1
    		Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Started
    451
    451
    Completed
    0
    0
    Not completed
    451
    451
         Non-Compliance
    1
    1
         Consent withdrawn by subject
    27
    32
         Physician decision
    -
    1
         Accidentally randomized screen failure participant
    -
    1
         Study Terminated By Sponsor
    85
    95
         Death
    333
    314
         Lost to follow-up
    4
    6
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Plus Nab-Paclitaxel
    Reporting group description
    		 Participants assigned to placebo plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.

    Reporting group title
    Atezolizumab Plus Nab-Paclitaxel
    Reporting group description
    		 Participants assigned to atezolizumab plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.

    Reporting group values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel Total
    Number of subjects
    		 451 451 902
    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)
    		 336 347 683
        From 65-84 years
    		 112 104 216
        85 years and over
    		 3 0 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 55.4 ± 12.1 54.3 ± 12.3 -
    Sex: Female, Male
    Units: Participants
        Female
    		 450 449 899
        Male
    		 1 2 3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 23 17 40
        Asian
    		 76 85 161
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 32 26 58
        White
    		 301 308 609
        More than one race
    		 3 2 5
        Unknown or Not Reported
    		 16 12 28
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 83 60 143
        Not Hispanic or Latino
    		 340 368 708
        Unknown or Not Reported
    		 28 23 51

    End points

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    End points reporting groups
    Reporting group title
    Placebo Plus Nab-Paclitaxel
    Reporting group description
    		 Participants assigned to placebo plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.

    Reporting group title
    Atezolizumab Plus Nab-Paclitaxel
    Reporting group description
    		 Participants assigned to atezolizumab plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.

    Subject analysis set title
    Placebo Plus Nab-Paclitaxel Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Placebo Plus Nab-Paclitaxel Safety Population included participants who received any amount of any study drug.

    Subject analysis set title
    Atezolizumab Plus Nab-Paclitaxel Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Atezolizumab Plus Nab-Paclitaxel Safety Population included participants who received any amount of any study drug.

    Primary: Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) in all Randomized Participants

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    End point title
    		 Progression Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) in all Randomized Participants
    End point description
    PFS was defined as the time from randomization to the occurrence of disease progression, as determined by investigators from tumor assessments per RECIST v1.1, or death from any cause, whichever occurred first. The ITT population is defined as all randomized patients, whether or not the assigned study treatment was received.
    End point type
    Primary
    End point timeframe
    Baseline up to approximately 34 months
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    451
    451
    Units: Months
        median (confidence interval 95%)
    5.49 (5.32 to 5.59)
    7.16 (5.59 to 7.46)
    Statistical analysis title
    		 PFS All Randomized Participants
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    902
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.0025
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 0.92
    Notes
    [1] - Stratified Analysis

    Primary: PFS According to RECIST v1.1 in Participants with Detectable Programmed Death-Ligand 1 (PD-L1)

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    End point title
    		 PFS According to RECIST v1.1 in Participants with Detectable Programmed Death-Ligand 1 (PD-L1)
    End point description
    PFS was defined as the time from randomization to the occurrence of disease progression, as determined by investigators from tumor assessments per RECIST v1.1, or death from any cause, whichever occurred first. The PD-L1-selected subpopulation is defined as patients in the ITT population whose PD-L1 status is IC1/2/3 at the time of randomization.
    End point type
    Primary
    End point timeframe
    Baseline up to approximately 34 months
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    184
    185
    Units: Months
        median (confidence interval 95%)
    4.96 (3.81 to 5.55)
    7.46 (6.70 to 9.23)
    Statistical analysis title
    		 PFS PD-L1-Selected Subpopulation
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.78
    Notes
    [2] - Stratified Analysis

    Primary: Overall Survival (OS) in all Randomized Participants

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    End point title
    		 Overall Survival (OS) in all Randomized Participants
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. The ITT population is defined as all randomized patients, whether or not the assigned study treatment was received.
    End point type
    Primary
    End point timeframe
    Baseline until death due to any cause (up to approximately 58 months)
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    451
    451
    Units: Months
        median (confidence interval 95%)
    18.73 (16.85 to 20.76)
    21.03 (19.02 to 23.36)
    Statistical analysis title
    		 OS All Randomized Participants
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    902
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.077
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.02
    Notes
    [3] - Stratified Analysis

    Primary: OS in Participants with Detectable PD-L1

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    End point title
    		 OS in Participants with Detectable PD-L1
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. The PD-L1-selected subpopulation is defined as patients in the ITT population whose PD-L1 status is IC1/2/3 at the time of randomization.
    End point type
    Primary
    End point timeframe
    Baseline until death due to any cause (up to approximately 58 months)
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    184
    185
    Units: Months
        median (confidence interval 95%)
    17.91 (13.63 to 20.30)
    25.43 (19.55 to 30.69)
    Statistical analysis title
    		 OS PD-L1-Selected Subpopulation
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.0016
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.86
    Notes
    [4] - Stratified Analysis

    Secondary: Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST v1.1 in all Randomized Participants

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    End point title
    		 Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST v1.1 in all Randomized Participants
    End point description
    An objective response was defined for participants with measurable disease at baseline as either a partial response (PR) or a complete response (CR) using RECIST v1.1. The ORR-evaluable population is defined as patients in the ITT population with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 34 months
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    449
    450
    Units: Percentage of Participants
        number (not applicable)
    45.9
    56.0
    Statistical analysis title
    		 Objective Response of CR or PR All Randomized
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    899
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.0021
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rates
    Point estimate
    10.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.4
         upper limit
    		 16.84
    Notes
    [5] - Stratified Analysis

    Secondary: Percentage of Participants With an Objective Response of CR or PR According to RECIST v1.1 in Participants with Detectable PD-L1

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    End point title
    		 Percentage of Participants With an Objective Response of CR or PR According to RECIST v1.1 in Participants with Detectable PD-L1
    End point description
    An objective response was defined for participants with measurable disease at baseline as either a partial response (PR) or a complete response (CR) using RECIST v1.1. The PD-L1-ORR-evaluable population is defined as patients in the PD-L1-selected subpopulation with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 34 months
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    183
    185
    Units: Percentage of participants
        number (not applicable)
    42.6
    58.9
    Statistical analysis title
    		 Objective Response of CR or PR in PD-L1-Selected
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.0016
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Overall Response Rates
    Point estimate
    16.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.67
         upper limit
    		 26.92
    Notes
    [6] - Stratified Analysis

    Secondary: Duration of Response (DOR) According to RECIST v1.1 in all Randomized Participants

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    End point title
    		 Duration of Response (DOR) According to RECIST v1.1 in all Randomized Participants
    End point description
    DOR was defined for participants who had an objective response as the time from the first occurrence of a documented unconfirmed response (CR or PR) to the date of disease progression per RECIST v1.1 or death from any cause, whichever occurred first. The duration of response (DOR)-evaluable population is defined as patients with an objective response.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 34 months
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    206
    252
    Units: Months
        number (confidence interval 95%)
    5.62 (5.52 to 6.93)
    7.39 (6.90 to 9.00)
    Statistical analysis title
    		 DOR All Randomized
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.0285
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 0.98
    Notes
    [7] - Unstratified Analysis

    Secondary: DOR Acccording to RECIST v1.1 in Participants with Detectable PD-L1

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    End point title
    		 DOR Acccording to RECIST v1.1 in Participants with Detectable PD-L1
    End point description
    DOR was defined for participants who had an objective response as the time from the first occurrence of a documented unconfirmed response (CR or PR) to the date of disease progression per RECIST v1.1 or death from any cause, whichever occurred first. The duration of response (DOR)-evaluable population is defined as patients with an objective response.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 34 months
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    78
    109
    Units: Months
        number (confidence interval 95%)
    5.49 (3.71 to 7.13)
    8.48 (7.33 to 9.66)
    Statistical analysis title
    		 DOR PD-L1-Selected
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.0047
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.86
    Notes
    [8] - Unstratified Analysis

    Secondary: Time to Deterioration (TTD) in Global Health Status/Health Related Quality of Life According to European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) v3.0 in all Randomized Participants

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    End point title
    		 Time to Deterioration (TTD) in Global Health Status/Health Related Quality of Life According to European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) v3.0 in all Randomized Participants
    End point description
    Deterioration in GHS/HRQoL (Items 29, 30 of the EORTC QLQ C30) was defined by the following two criteria: 1. The time from randomization to the first time the participant’s GHS/HRQoL scale score showed a >=10-point decrease from the baseline scale score. A 10-point change was defined as the minimally important difference (MID). 2. The score decrease of >= 10-points from baseline was held for at least two consecutive cycles, or an initial score decrease of >= 10-points was followed by death or treatment discontinuation within 3 weeks from the last assessment. The patient-reported outcome (PRO)-evaluable population is defined as patients in the ITT population with a baseline and ≥1 post-baseline PRO assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 58 months
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    400
    406
    Units: Months
        median (confidence interval 95%)
    7.98 (5.65 to 11.10)
    8.18 (6.01 to 10.94)
    Statistical analysis title
    		 TTD All Randomized
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    806
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.8078
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.18
    Notes
    [9] - Stratified Analysis

    Secondary: TTD in Global Health Status/Health Related Quality of Life According to EORTC QLQ-C30 v3.0 in Participants with Detectable PD-L1

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    End point title
    		 TTD in Global Health Status/Health Related Quality of Life According to EORTC QLQ-C30 v3.0 in Participants with Detectable PD-L1
    End point description
    Deterioration in GHS/HRQoL (Items 29, 30 of the EORTC QLQ C30) was defined by the following two criteria: 1. The time from randomization to the first time the participants’s GHS/HRQoL scale score showed a >=10-point decrease from the baseline scale score. A 10-point change was defined as the minimally important difference (MID). 2. The score decrease of >= 10-points from baseline was held for at least two consecutive cycles, or an initial score decrease of >= 10-points was followed by death or treatment discontinuation within 3 weeks from the last assessment. The patient-reported outcome (PRO)-evaluable population is defined as patients in the ITT population with a baseline and ≥1 post-baseline PRO assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 58 months
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    160
    167
    Units: Months
        median (confidence interval 95%)
    6.41 (4.57 to 11.24)
    7.56 (4.99 to 12.12)
    Statistical analysis title
    		 TTD PD-L1 Selected
    Comparison groups
    Placebo Plus Nab-Paclitaxel v Atezolizumab Plus Nab-Paclitaxel
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.8879
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.31
    Notes
    [10] - Stratified Analysis

    Secondary: Percentage of Participants with at Least One Adverse Event

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    End point title
    		 Percentage of Participants with at Least One Adverse Event
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to the data cutoff date: 31 August 2021 (up to approximately 74 months)
    End point values
    		 Placebo Plus Nab-Paclitaxel Safety Population Atezolizumab Plus Nab-Paclitaxel Safety Population
    Number of subjects analysed
    430
    460
    Units: Percentage of participants
        number (not applicable)
    97.9
    99.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab

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    End point title
    		 Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab [11]
    End point description
    Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab. The anti-drug antibodies (ADA)-evaluable population is defined as all patients treated with atezolizumab who have at least one post-baseline ADA result.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 53 months
    Notes
    [11] - 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: There is no statistical analysis for this end point.
    End point values
    		 Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    434
    Units: Percentage of participants
    number (not applicable)
        Baseline Prevalence of ADAs
    1.6
        Incidence of Treatment Emergent ADAs
    13.1
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) for Atezolizumab

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    End point title
    		 Maximum Serum Concentration (Cmax) for Atezolizumab [12]
    End point description
    Maximum serum concentration for atezolizumab. The pharmacokinetic (PK)-evaluable population is defined as all patients who received any dose of study medication and who have at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Cycle = 28 days)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no statistical analysis for this end point.
    End point values
    		 Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    407
    Units: µg/mL
        arithmetic mean (standard deviation)
    329 ± 98.9
    No statistical analyses for this end point

    Secondary: Minimum Serum Concentration (Cmin) for Atezolizumab

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    End point title
    		 Minimum Serum Concentration (Cmin) for Atezolizumab [13]
    End point description
    Minimum serum concentration for atezolizumab. The pharmacokinetic (PK)-evaluable population is defined as all patients who received any dose of study medication and who have at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Day 27 of Cycle 1, 2, 3, and 7 (Cycle = 28 days)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There is no statistical analysis for this end point.
    End point values
    		 Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    420
    Units: µg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 27 (n=420)
    145 ± 52.6
        Cycle 2 Day 27 (n=373)
    215 ± 78.3
        Cycle 3 Day 27 (n=343)
    245 ± 90.3
        Cycle 7 Day 27 (n=188)
    274 ± 111
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Total Paclitaxel

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    End point title
    		 Plasma Concentrations of Total Paclitaxel
    End point description
    Plasma concentrations of total paclitaxel. Note: 999999=non-reportable. The pharmacokinetic (PK)-evaluable population is defined as all patients who received any dose of study medication and who have at least one post-baseline PK sample available.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) on Cycle 1 Day 1, pre-dose (Hour 0), 5-10 minutes before end of nab-paclitaxel infusion, 1 hour after end of nab-paclitaxel infusion (infusion duration = 30 minutes) on Cycle 3 Day 1 (Cycle = 28 days)
    End point values
    		 Placebo Plus Nab-Paclitaxel Atezolizumab Plus Nab-Paclitaxel
    Number of subjects analysed
    321
    436
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1D1/Predose (n=321;n=436)
    999999 ± 999999
    999999 ± 999999
        C3D1/Predose (n=310; n=351)
    999999 ± 999999
    999999 ± 999999
        C3D1/ Before End of Infusion (n=255;n=298)
    2970 ± 2300
    3080 ± 2050
        C3D1/Postdose Paclit (n=221;n=280)
    370 ± 244
    400 ± 275
    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 to the data cutoff date: 31 August 2021 (up to approximately 74 months)
    Adverse event reporting additional description
    The safety-evaluable population is defined as participants who received any amount of any study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Atezolizumab (q2w) + nab-Paclitaxel
    Reporting group description
    		 Participants assigned to atezolizumab plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.

    Reporting group title
    Placebo (q2w) + nab-Paclitaxel
    Reporting group description
    		 Participants assigned to placebo plus nab-paclitaxel received both agents until disease progression or unacceptable toxicity.

    Serious adverse events
    		 Atezolizumab (q2w) + nab-Paclitaxel Placebo (q2w) + nab-Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    110 / 460 (23.91%)
    80 / 430 (18.60%)
         number of deaths (all causes)
    322
    339
         number of deaths resulting from adverse events
    2
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    INFECTED NEOPLASM
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALIGNANT ASCITES
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR HAEMORRHAGE
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (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 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    EMBOLISM
         subjects affected / exposed
    2 / 460 (0.43%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 460 (0.22%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL EMBOLISM
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    CATHETER SITE PAIN
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    2 / 460 (0.43%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILL-DEFINED DISORDER
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         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 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    2 / 460 (0.43%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 460 (0.00%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    5 / 460 (1.09%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    CONTRAST MEDIA ALLERGY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC IMMUNE ACTIVATION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPIRATION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (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
    5 / 460 (1.09%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    4 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    2 / 460 (0.43%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    2 / 460 (0.43%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    5 / 460 (1.09%)
    4 / 430 (0.93%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    STRIDOR
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    AGITATION
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANXIETY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    DEVICE BREAKAGE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOSIS IN DEVICE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROCEDURAL PAIN
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WRIST FRACTURE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ANGINA UNSTABLE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARRHYTHMIA
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 460 (0.22%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 460 (0.00%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYCARDIA
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (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 HAEMORRHAGE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL THROMBOSIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACIAL PARALYSIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLIC STROKE
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC ENCEPHALOPATHY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOAESTHESIA
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IIIRD NERVE PARALYSIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BELL'S PALSY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    5 / 460 (1.09%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOLYSIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOCYTOSIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (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
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    DIPLOPIA
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KERATITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OPTIC NEUROPATHY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (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
    2 / 460 (0.43%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS ULCERATIVE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    2 / 460 (0.43%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 460 (0.22%)
    4 / 430 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL TOXICITY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MECHANICAL ILEUS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    2 / 460 (0.43%)
    3 / 430 (0.70%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         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 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 460 (0.43%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    AUTOIMMUNE HEPATITIS
         subjects affected / exposed
    2 / 460 (0.43%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    AUTOIMMUNE CHOLANGITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BILE DUCT STONE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTOCHOLANGITIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FAILURE
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    HEPATITIS
         subjects affected / exposed
    2 / 460 (0.43%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATOMYOSITIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LICHEN PLANUS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG ERUPTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXIC EPIDERMAL NECROLYSIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (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
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDRONEPHROSIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    ADDISON'S DISEASE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADRENOCORTICAL INSUFFICIENCY ACUTE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTHYROIDISM
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOPHYSITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    3 / 460 (0.65%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIMB DEFORMITY
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    2 / 460 (0.43%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOPATHY
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NECK PAIN
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYARTHRITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TEMPOROMANDIBULAR JOINT SYNDROME
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRALGIA
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYALGIA
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    5 / 460 (1.09%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    2 / 460 (0.43%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    2 / 460 (0.43%)
    2 / 430 (0.47%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (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
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIOUS PLEURAL EFFUSION
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KLEBSIELLA BACTERAEMIA
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MASTITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (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
    12 / 460 (2.61%)
    5 / 430 (1.16%)
         occurrences causally related to treatment / all
    8 / 14
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA PNEUMOCOCCAL
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION VIRAL
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 460 (0.00%)
    3 / 430 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    SINUSITIS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STREPTOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SOFT TISSUE INFECTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TONSILLITIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOOTH INFECTION
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (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
    2 / 460 (0.43%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    5 / 460 (1.09%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR DEVICE INFECTION
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    2 / 460 (0.43%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC KETOACIDOSIS
         subjects affected / exposed
    1 / 460 (0.22%)
    0 / 430 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 460 (0.22%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    0 / 460 (0.00%)
    1 / 430 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Atezolizumab (q2w) + nab-Paclitaxel Placebo (q2w) + nab-Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    450 / 460 (97.83%)
    414 / 430 (96.28%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    25 / 460 (5.43%)
    21 / 430 (4.88%)
         occurrences all number
    37
    32
    HOT FLUSH
         subjects affected / exposed
    30 / 460 (6.52%)
    32 / 430 (7.44%)
         occurrences all number
    34
    35
    LYMPHOEDEMA
         subjects affected / exposed
    30 / 460 (6.52%)
    30 / 430 (6.98%)
         occurrences all number
    34
    31
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    60 / 460 (13.04%)
    51 / 430 (11.86%)
         occurrences all number
    80
    75
    CHEST PAIN
         subjects affected / exposed
    33 / 460 (7.17%)
    20 / 430 (4.65%)
         occurrences all number
    36
    22
    CHILLS
         subjects affected / exposed
    42 / 460 (9.13%)
    23 / 430 (5.35%)
         occurrences all number
    58
    26
    FATIGUE
         subjects affected / exposed
    216 / 460 (46.96%)
    194 / 430 (45.12%)
         occurrences all number
    264
    238
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    29 / 460 (6.30%)
    11 / 430 (2.56%)
         occurrences all number
    35
    12
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    29 / 460 (6.30%)
    16 / 430 (3.72%)
         occurrences all number
    38
    18
    OEDEMA PERIPHERAL
         subjects affected / exposed
    73 / 460 (15.87%)
    66 / 430 (15.35%)
         occurrences all number
    94
    86
    PYREXIA
         subjects affected / exposed
    89 / 460 (19.35%)
    45 / 430 (10.47%)
         occurrences all number
    145
    72
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    31 / 460 (6.74%)
    21 / 430 (4.88%)
         occurrences all number
    43
    22
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    127 / 460 (27.61%)
    80 / 430 (18.60%)
         occurrences all number
    171
    116
    DYSPNOEA
         subjects affected / exposed
    70 / 460 (15.22%)
    60 / 430 (13.95%)
         occurrences all number
    90
    68
    EPISTAXIS
         subjects affected / exposed
    36 / 460 (7.83%)
    39 / 430 (9.07%)
         occurrences all number
    49
    43
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    30 / 460 (6.52%)
    13 / 430 (3.02%)
         occurrences all number
    37
    16
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    18 / 460 (3.91%)
    22 / 430 (5.12%)
         occurrences all number
    19
    22
    INSOMNIA
         subjects affected / exposed
    54 / 460 (11.74%)
    52 / 430 (12.09%)
         occurrences all number
    59
    54
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    53 / 460 (11.52%)
    37 / 430 (8.60%)
         occurrences all number
    100
    38
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    49 / 460 (10.65%)
    42 / 430 (9.77%)
         occurrences all number
    80
    48
    WEIGHT DECREASED
         subjects affected / exposed
    22 / 460 (4.78%)
    26 / 430 (6.05%)
         occurrences all number
    26
    28
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    57 / 460 (12.39%)
    49 / 430 (11.40%)
         occurrences all number
    163
    101
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    39 / 460 (8.48%)
    21 / 430 (4.88%)
         occurrences all number
    89
    37
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    69 / 460 (15.00%)
    43 / 430 (10.00%)
         occurrences all number
    87
    49
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    100 / 460 (21.74%)
    97 / 430 (22.56%)
         occurrences all number
    138
    120
    HEADACHE
         subjects affected / exposed
    116 / 460 (25.22%)
    92 / 430 (21.40%)
         occurrences all number
    172
    125
    DYSGEUSIA
         subjects affected / exposed
    52 / 460 (11.30%)
    44 / 430 (10.23%)
         occurrences all number
    59
    50
    PARAESTHESIA
         subjects affected / exposed
    34 / 460 (7.39%)
    29 / 430 (6.74%)
         occurrences all number
    44
    32
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    74 / 460 (16.09%)
    52 / 430 (12.09%)
         occurrences all number
    90
    62
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    129 / 460 (28.04%)
    115 / 430 (26.74%)
         occurrences all number
    221
    186
    LEUKOPENIA
         subjects affected / exposed
    30 / 460 (6.52%)
    23 / 430 (5.35%)
         occurrences all number
    68
    50
    NEUTROPENIA
         subjects affected / exposed
    101 / 460 (21.96%)
    66 / 430 (15.35%)
         occurrences all number
    238
    176
    Eye disorders
    LACRIMATION INCREASED
         subjects affected / exposed
    28 / 460 (6.09%)
    33 / 430 (7.67%)
         occurrences all number
    28
    33
    DRY EYE
         subjects affected / exposed
    31 / 460 (6.74%)
    15 / 430 (3.49%)
         occurrences all number
    33
    15
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    53 / 460 (11.52%)
    53 / 430 (12.33%)
         occurrences all number
    59
    63
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    29 / 460 (6.30%)
    25 / 430 (5.81%)
         occurrences all number
    35
    26
    CONSTIPATION
         subjects affected / exposed
    115 / 460 (25.00%)
    108 / 430 (25.12%)
         occurrences all number
    140
    132
    DIARRHOEA
         subjects affected / exposed
    151 / 460 (32.83%)
    146 / 430 (33.95%)
         occurrences all number
    307
    212
    DRY MOUTH
         subjects affected / exposed
    39 / 460 (8.48%)
    16 / 430 (3.72%)
         occurrences all number
    39
    17
    DYSPEPSIA
         subjects affected / exposed
    30 / 460 (6.52%)
    31 / 430 (7.21%)
         occurrences all number
    34
    38
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    24 / 460 (5.22%)
    12 / 430 (2.79%)
         occurrences all number
    26
    13
    NAUSEA
         subjects affected / exposed
    213 / 460 (46.30%)
    164 / 430 (38.14%)
         occurrences all number
    338
    244
    STOMATITIS
         subjects affected / exposed
    49 / 460 (10.65%)
    20 / 430 (4.65%)
         occurrences all number
    66
    24
    VOMITING
         subjects affected / exposed
    92 / 460 (20.00%)
    73 / 430 (16.98%)
         occurrences all number
    141
    98
    Skin and subcutaneous tissue disorders
    NAIL DISCOLOURATION
         subjects affected / exposed
    38 / 460 (8.26%)
    30 / 430 (6.98%)
         occurrences all number
    39
    31
    DRY SKIN
         subjects affected / exposed
    42 / 460 (9.13%)
    25 / 430 (5.81%)
         occurrences all number
    45
    27
    ALOPECIA
         subjects affected / exposed
    263 / 460 (57.17%)
    247 / 430 (57.44%)
         occurrences all number
    272
    249
    PRURITUS
         subjects affected / exposed
    73 / 460 (15.87%)
    45 / 430 (10.47%)
         occurrences all number
    93
    53
    RASH
         subjects affected / exposed
    84 / 460 (18.26%)
    71 / 430 (16.51%)
         occurrences all number
    115
    96
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    67 / 460 (14.57%)
    15 / 430 (3.49%)
         occurrences all number
    80
    15
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    104 / 460 (22.61%)
    88 / 430 (20.47%)
         occurrences all number
    174
    120
    BACK PAIN
         subjects affected / exposed
    74 / 460 (16.09%)
    59 / 430 (13.72%)
         occurrences all number
    106
    69
    MUSCLE SPASMS
         subjects affected / exposed
    25 / 460 (5.43%)
    5 / 430 (1.16%)
         occurrences all number
    31
    5
    BONE PAIN
         subjects affected / exposed
    24 / 460 (5.22%)
    11 / 430 (2.56%)
         occurrences all number
    28
    13
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    25 / 460 (5.43%)
    18 / 430 (4.19%)
         occurrences all number
    28
    20
    PAIN IN EXTREMITY
         subjects affected / exposed
    56 / 460 (12.17%)
    41 / 430 (9.53%)
         occurrences all number
    79
    53
    MYALGIA
         subjects affected / exposed
    72 / 460 (15.65%)
    67 / 430 (15.58%)
         occurrences all number
    84
    86
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    52 / 460 (11.30%)
    36 / 430 (8.37%)
         occurrences all number
    80
    42
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    55 / 460 (11.96%)
    38 / 430 (8.84%)
         occurrences all number
    84
    49
    URINARY TRACT INFECTION
         subjects affected / exposed
    57 / 460 (12.39%)
    42 / 430 (9.77%)
         occurrences all number
    86
    60
    Metabolism and nutrition disorders
    HYPOKALAEMIA
         subjects affected / exposed
    29 / 460 (6.30%)
    9 / 430 (2.09%)
         occurrences all number
    45
    10
    HYPOCALCAEMIA
         subjects affected / exposed
    25 / 460 (5.43%)
    10 / 430 (2.33%)
         occurrences all number
    33
    11
    DECREASED APPETITE
         subjects affected / exposed
    92 / 460 (20.00%)
    80 / 430 (18.60%)
         occurrences all number
    117
    86
    HYPOMAGNESAEMIA
         subjects affected / exposed
    26 / 460 (5.65%)
    11 / 430 (2.56%)
         occurrences all number
    62
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2015
    Protocol was amended to include modification to the following eligibility criteria: Expansion of the target population to include male participants with TNBC. Contraceptive requirements were updated accordingly. Exclusion of participants with CNS metastasis was clarified. Participants with known PD-L1 expression status from other clinical trials were excluded. In addition, guidelines for the management of nab-paclitaxel-related toxicities were updated and clarified. Also, aspects of standard safety reporting requirements have been updated and clarified, including those related to pregnancies in female partners of male participants.
    20 Nov 2015
    Protocol was amendment to include the increase in the number of participants in the study from 350 to up to 900 to support the promotion of overall survival from secondary to co-primary outcome measure. The statistical methods were modified accordingly. Management guidelines for atezolizumab-specific AEs were deleted from the protocol and instead, reference was made to the current IB. Systemic immune activation (SIA) was identified as a potential risk of atezolizumab when given in combination with other immunomodulating agents. The inclusion criterion regarding representative tumor specimens was modified. If no paraffin block was available, at least 20 unstained slides (previously 15 slides) had to be submitted. Additionally, further details were included regarding participant eligibility per archival and fresh tumor tissue quantity and histology. The study inclusion criterion regarding treated, asymptomatic CNS metastases was modified to clarify that cerebellar metastases were permitted. The exclusion criterion regarding history of autoimmune disease was broadened, on the basis of an expanding safety database, to allow for participants with eczema, psoriasis, or lichen simplex chronicus or vitiligo with dermatologic manifestations only to be permitted provided that they met specific conditions. The contraception requirements in the inclusion and exclusion criteria and the pregnancy reporting information were updated to be consistent with the current safety information for nab-paclitaxel. The cap on the percentage of participants with liver metastases was removed in light of results from recently completed randomized studies with atezolizumab.
    07 Sep 2016
    Protocol was amended to include removal of the option to treat participants beyond initial radiographic progression and related rationale and procedures were removed. Evaluation criteria of tumor response per immune modified RECIST were removed to reflect the change that participants directly entered survival follow-up after disease progression. For women of childbearing potential, the duration to remain abstinent or use contraceptive methods that result in a failure rate of <1% per year during the treatment period was increased from at least 90 days to at least 5 months after the last dose of atezolizumab. Whole brain radiation within 14 days prior to randomization was added to cancer-specific exclusion criteria. Exclusion of participants with negative PD-L1 status based on screening for entry into another trial was removed from the eligibility criteria. The period that participants must agree not to receive live, attenuated vaccine following the last dose of atezolizumab/placebo was extended from 90 days to 5 months based on a revision of the known half-life of atezolizumab. Traditional herbal medicines were removed from prohibited therapies. Methods of evaluation of PFS were revised.
    02 Mar 2018
    Protocol was amended to include the length of time atezolizumab or placebo could be withheld before discontinuing treatment was lengthened from 42 days to 12 weeks.
    28 Sep 2018
    Protocol was amended to include allowing for crossover of participants who were originally randomized to receive placebo and who have not experienced disease progression and who have not started any other systemic non-protocol-specified anticancer agents to the atezolizumab arm provided that they still meet the safety-related eligibility criteria for the study. Guidelines for managing participants who experience atezolizumab-associated adverse events have been revised to include nephritis.
    31 Jan 2020
    Protocol was amended to include update to the list of atezolizumab risks to include myositis. Systemic immune activation has been replaced by hemophagocytic lymphohistiocytosis and macrophage activation syndrome in the list of potential risks for atezolizumab.

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

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

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