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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Open-Label Study Comparing Atezolizumab (Anti PD-L1 Antibody) in Combination With Adjuvant Anthracycline/Taxane-Based Chemotherapy Versus Chemotherapy Alone in Patients With Operable Triple Negative Breast Cancer

    Summary
    EudraCT number
    2016-003695-47
    Trial protocol
    IE   DE   GB   PL   CZ   ES   HU   DK   AT   BE   IT   RO  
    Global end of trial date
    14 Aug 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Aug 2024
    First version publication date
    14 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WO39391
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03498716
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4058
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective of this trial was to evaluate the efficacy, safety, and pharmacokinetics of adjuvant atezolizumab in combination with paclitaxel, followed by atezolizumab, dose-dense doxorubicin or epirubicin (investigator’s choice), and cyclophosphamide, compared with paclitaxel followed by dose-dense doxorubicin or epirubicin (investigator’s choice) and cyclophosphamide alone in patients with Stage II-III triple negative breast cancer (TNBC).
    Protection of trial subjects
    All study participants were required to read and sign an informed consent form (ICF).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Aug 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 17
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Brazil: 58
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    China: 268
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Denmark: 22
    Country: Number of subjects enrolled
    Spain: 75
    Country: Number of subjects enrolled
    France: 143
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Hong Kong: 14
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Ireland: 17
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 73
    Country: Number of subjects enrolled
    Japan: 249
    Country: Number of subjects enrolled
    Korea, Republic of: 158
    Country: Number of subjects enrolled
    Mexico: 74
    Country: Number of subjects enrolled
    Peru: 10
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Romania: 21
    Country: Number of subjects enrolled
    Russian Federation: 367
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Thailand: 56
    Country: Number of subjects enrolled
    Türkiye: 6
    Country: Number of subjects enrolled
    Taiwan: 70
    Country: Number of subjects enrolled
    Ukraine: 288
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    2199
    EEA total number of subjects
    472
    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)
    1821
    From 65 to 84 years
    376
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    Participants with newly diagnosed Stage II-III primary invasive Breast cancer (BC) that is of triple negative phenotype and who were to be treated with adjuvant systemic chemotherapy following definitive surgery, were enrolled in 342 centers in 31 countries.

    Pre-assignment
    Screening details
    A total of 2199 participants were enrolled in the study. Participants were randomized in a 1:1 ratio to receive Atezolizumab and Chemotherapy or Chemotherapy alone.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Chemotherapy
    Arm description
    Participants were administered paclitaxel, 80 milligram per square meter (mg/m^2), intravenous (IV) infusion weekly (QW) for maximum of 36 weeks followed by dose-dense doxorubicin, 60 mg/m^2 or dose-dense epirubicin, 90 mg/m^2 IV (investigator’s choice) plus cyclophosphamide, 600 mg/m^2, IV repeated every 2 weeks (Q2W) for a maximum of 20 weeks supported with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment.
    Arm type
    Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80 mg/m^2 QW IV infusion.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide, 600 mg/m^2 Q2W IV infusion.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin 90 mg/m^2 IV infusion.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dxorubicin, 60 mg/m^2 IV infusion.

    Arm title
    Atezolizumab and Chemotherapy
    Arm description
    Participants were administered atezolizumab 840 mg, IV infusion, Q2W in combination with chemotherapy (paclitaxel 80 mg/m^2, IV infusion QW for maximum of 22 weeks followed by dose-dense doxorubicin, 60 mg/m^2 or dose-dense epirubicin, 90 mg/m^2, IV (investigator’s choice) plus cyclophosphamide, 600 mg/m^2, IV repeated Q2W for maximum of 17 weeks supported with G-CSF or GM-CSF treatment followed by atezolizumab, 1200 mg IV infusion every 3 weeks (Q3W) as a maintenance therapy to complete 1 year of atezolizumab treatment from the first dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dxorubicin, 60 mg/m^2 IV infusion.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80 mg/m^2 QW IV infusion.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide, 600 mg/m^2 Q2W IV infusion.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab 840 mg, Q2W and 1200 mg Q3W IV infusion.

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epirubicin 90 mg/m^2 IV infusion.

    Number of subjects in period 1
    Chemotherapy Atezolizumab and Chemotherapy
    Started
    1098
    1101
    Safety Evaluable Population
    1084
    1093
    Completed
    0
    0
    Not completed
    1098
    1101
         Adverse event, serious fatal
    58
    72
         Consent withdrawn by subject
    88
    73
         Physician decision
    4
    2
         Disease Relapse
    -
    1
         Study Terminated By Sponsor
    933
    927
         Lost to follow-up
    15
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants were administered paclitaxel, 80 milligram per square meter (mg/m^2), intravenous (IV) infusion weekly (QW) for maximum of 36 weeks followed by dose-dense doxorubicin, 60 mg/m^2 or dose-dense epirubicin, 90 mg/m^2 IV (investigator’s choice) plus cyclophosphamide, 600 mg/m^2, IV repeated every 2 weeks (Q2W) for a maximum of 20 weeks supported with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment.

    Reporting group title
    Atezolizumab and Chemotherapy
    Reporting group description
    Participants were administered atezolizumab 840 mg, IV infusion, Q2W in combination with chemotherapy (paclitaxel 80 mg/m^2, IV infusion QW for maximum of 22 weeks followed by dose-dense doxorubicin, 60 mg/m^2 or dose-dense epirubicin, 90 mg/m^2, IV (investigator’s choice) plus cyclophosphamide, 600 mg/m^2, IV repeated Q2W for maximum of 17 weeks supported with G-CSF or GM-CSF treatment followed by atezolizumab, 1200 mg IV infusion every 3 weeks (Q3W) as a maintenance therapy to complete 1 year of atezolizumab treatment from the first dose.

    Reporting group values
    Chemotherapy Atezolizumab and Chemotherapy Total
    Number of subjects
    1098 1101 2199
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    52.8 ( 11.4 ) 52.3 ( 11.9 ) -
    Sex: Female, Male
    Units: participants
        Female
    1094 1101 2195
        Male
    4 0 4
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    28 29 57
        Asian
    401 423 824
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Black or African American
    2 8 10
        White
    567 554 1121
        More than one race
    0 1 1
        Unknown or Not Reported
    99 86 185
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    100 75 175
        Not Hispanic or Latino
    906 950 1856
        Unknown or Not Reported
    92 76 168

    End points

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    End points reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants were administered paclitaxel, 80 milligram per square meter (mg/m^2), intravenous (IV) infusion weekly (QW) for maximum of 36 weeks followed by dose-dense doxorubicin, 60 mg/m^2 or dose-dense epirubicin, 90 mg/m^2 IV (investigator’s choice) plus cyclophosphamide, 600 mg/m^2, IV repeated every 2 weeks (Q2W) for a maximum of 20 weeks supported with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment.

    Reporting group title
    Atezolizumab and Chemotherapy
    Reporting group description
    Participants were administered atezolizumab 840 mg, IV infusion, Q2W in combination with chemotherapy (paclitaxel 80 mg/m^2, IV infusion QW for maximum of 22 weeks followed by dose-dense doxorubicin, 60 mg/m^2 or dose-dense epirubicin, 90 mg/m^2, IV (investigator’s choice) plus cyclophosphamide, 600 mg/m^2, IV repeated Q2W for maximum of 17 weeks supported with G-CSF or GM-CSF treatment followed by atezolizumab, 1200 mg IV infusion every 3 weeks (Q3W) as a maintenance therapy to complete 1 year of atezolizumab treatment from the first dose.

    Primary: Invasive Disease-Free Survival (iDFS)

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    End point title
    Invasive Disease-Free Survival (iDFS)
    End point description
    iDFS=time from randomization until date of first occurrence of 1 of the events: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer involving same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (an invasive breast cancer in axilla, regional lymph nodes, chest wall, &/or skin of ipsilateral breast); Ipsilateral second primary invasive breast cancer; Contralateral invasive breast cancer; Distant recurrence (evidence of breast cancer in any anatomic site) that is histologically confirmed &/or clinically/radiographically diagnosed as recurrent invasive breast cancer; & Death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. Analysis using Kaplan-Meier estimates where participants with no events at time of analysis/no post-baseline data were censored. ITT population. 9999=Median & 95% CI were not estimable due to too few events having occurred.
    End point type
    Primary
    End point timeframe
    From randomization until the occurrence of an iDFS event or death from any cause, whichever occurred earlier (up to 5 years)
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1098
    1101
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    Chemotherapy Vs Atezolizumab and Chemotherapy
    Comparison groups
    Chemotherapy v Atezolizumab and Chemotherapy
    Number of subjects included in analysis
    2199
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.3846
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    1.42
    Notes
    [1] - Stratified Analysis: The stratification factors used in the analysis are axillary nodal status, surgery (breast conserving vs. mastectomy),and tumor PD-L1 status.

    Secondary: iDFS in the Subpopulation With Programmed Death-ligand 1 (PD-L1) Selected Tumor Status (IC1/2/3)

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    End point title
    iDFS in the Subpopulation With Programmed Death-ligand 1 (PD-L1) Selected Tumor Status (IC1/2/3)
    End point description
    iDFS=time from randomization until date of first occurrence of 1 of the events: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer involving same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (an invasive breast cancer in axilla, regional lymph nodes, chest wall, &/or skin of ipsilateral breast); Ipsilateral second primary invasive breast cancer; Contralateral invasive breast cancer; Distant recurrence (evidence of breast cancer in any anatomic site) that is histologically confirmed &/or clinically/radiographically diagnosed as recurrent invasive breast cancer; & Death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. Analysis = Kaplan-Meier estimates where participants with no events at time of analysis/no post-baseline data were censored. PD-L1-positive subpopulation. 9999=Median & 95% CI were not estimable due to too few events having occurred.
    End point type
    Secondary
    End point timeframe
    From randomization until the occurrence of an iDFS event or death from any cause, whichever occurred earlier (up to 5 years)
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    782
    785
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: iDFS in the Node Positive Subpopulation

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    End point title
    iDFS in the Node Positive Subpopulation
    End point description
    iDFS=time from randomization until date of first occurrence of 1 of the events: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer involving same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (an invasive breast cancer in axilla, regional lymph nodes, chest wall, &/or skin of ipsilateral breast); Ipsilateral second primary invasive breast cancer; Contralateral invasive breast cancer; Distant recurrence (evidence of breast cancer in any anatomic site) that is histologically confirmed &/or clinically/radiographically diagnosed as recurrent invasive breast cancer; & Death attributable to any cause, including breast cancer, non-breast cancer, or unknown cause. Analysis = Kaplan-Meier estimates where participants with no events at time of analysis/no post-baseline data were censored. Node positive subpopulation. 9999=Median & 95% CI were not estimable due to too few events having occurred.
    End point type
    Secondary
    End point timeframe
    From randomization until the occurrence of an iDFS event or death from any cause, whichever occurred earlier (up to 5 years)
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    533
    534
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS is defined as the time from randomization to the date of death due to any cause. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis or no post-baseline information were censored. ITT population included all randomized participants, whether or not the assigned study treatment was received. 9999 = Median and 95%CI for OS were not estimable due to too few events having occurred.
    End point type
    Secondary
    End point timeframe
    From randomization up to death from any cause, up to 5 years
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1098
    1101
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: iDFS Including Second Primary Non-Breast Invasive Cancer

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    End point title
    iDFS Including Second Primary Non-Breast Invasive Cancer
    End point description
    iDFS=time from randomization until date of first occurrence of 1 of the events: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer involving same breast parenchyma as original primary lesion); Ipsilateral local-regional invasive breast cancer recurrence (invasive breast cancer in axilla, regional lymph nodes, chest wall, &/or skin of ipsilateral breast); Ipsilateral 2nd primary invasive breast cancer; 2nd primary non-breast invasive cancer; Contralateral invasive breast cancer; Distant recurrence (evidence of breast cancer in any anatomic site) histologically confirmed &/or clinically/radiographically diagnosed as recurrent invasive breast cancer;Death attributable to any cause, including breast cancer, non-breast cancer/unknown cause. Analysis=Kaplan-Meier estimates where participants with no events at time of analysis/no post-baseline data were censored. ITT population. 9999=Median & 95% CI were not estimable due to too few events having occurred.
    End point type
    Secondary
    End point timeframe
    From randomization up to death from any cause (up to 5 years)
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1098
    1101
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Recurrence-Free Interval (RFI)

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    End point title
    Recurrence-Free Interval (RFI)
    End point description
    RFI was defined as the time from randomization to the first occurrence of any recurrence (local, regional [including invasive ipsilateral tumor and invasive locoregional tumor], or distant), as determined by investigators. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis, participants with no events who died, or participants with no post-baseline information were censored. ITT population included all randomized participants, whether or not the assigned study treatment was received. 9999=Median and 95%CI for RFI were not estimable due to too few events having occurred.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1098
    1101
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Distant Recurrence-Free Interval (DRFI)

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    End point title
    Distant Recurrence-Free Interval (DRFI)
    End point description
    DRFI was defined as the time from randomization to the distant breast cancer recurrence. Analysis used Kaplan-Meier estimates where participants with no events at the time of analysis, participants with no events who died, or participants with no post-baseline information were censored. ITT population included all randomized participants, whether or not the assigned study treatment was received. 9999=Median and 95%CI for DRFI were not estimable due to too few events having occurred.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1098
    1101
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Change from Baseline (CFB) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Patient reported Function (Role functioning [Q6, Q7])

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    End point title
    Change from Baseline (CFB) in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Patient reported Function (Role functioning [Q6, Q7])
    End point description
    EORTC QLQ-C30=cancer specific health-related quality-of life (QoL) questionnaire. For role functioning scale, participant responses to 2 questions “Q6: Were you limited in doing either your work or daily activities” & “Q7: Were you limited in pursuing your hobbies or other leisure time activities” were scored on a 4-point scale (1=Not at All to 4=Very Much). Scores were linearly transformed on a scale of 0 to 100, with a low score indicating better functioning. Negative change from baseline indicated improvement. Patient-reported outcome (PRO)-evaluable populations = all randomized participants, whether or not assigned study treatment was received with baseline PRO assessment & at least one post-baseline PRO assessment in the EORTC QLQC30. Overall number analyzed = number of participants with data available for analyses. Number analyzed = number of participants with data available for analyses at the specified timepoint. 9999=standard deviation was not estimable for one participant.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), Day 1 of Cycles 4, 6, 8, 10, 12, 14 & 16; end of treatment/discontinuation (approximately at Day 351); Follow up: Months 3 to 48 (Total duration is up to 5 years) Cycles 1-5= 28 day cycles; Cycles 6-16: 21 day cycles
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1083
    1088
    Units: score on scale
    arithmetic mean (standard deviation)
        Baseline (n= 1083, 1088)
    87.26 ( 18.92 )
    86.43 ( 19.66 )
        CFB: Cycle 4 Day 1 (n= 1025, 1040)
    -10.88 ( 25.00 )
    -10.26 ( 24.87 )
        CFB: Cycle 6 Day 1 (n= 938, 924)
    -17.31 ( 29.94 )
    -16.56 ( 29.18 )
        CFB: Cycle 8 Day 1 (n= 902, 881)
    -4.58 ( 23.58 )
    -4.58 ( 24.31 )
        CFB: Cycle 10 Day 1 (n= 898, 851)
    -3.77 ( 23.59 )
    -3.43 ( 22.77 )
        CFB: Cycle 12 Day 1 (n= 869, 806)
    -1.53 ( 22.39 )
    -1.59 ( 23.05 )
        CFB: Cycle 14 Day 1 (n= 830, 736)
    -1.02 ( 21.69 )
    -0.70 ( 20.61 )
        CFB: Cycle 16 Day 1 (n= 628, 489)
    -1.09 ( 23.16 )
    -0.10 ( 21.77 )
        Drug Completion/Early Discontinuation(n=896,964)
    -2.66 ( 23.48 )
    -4.37 ( 26.12 )
        CFB: Follow-up Month 3 (n= 845, 872)
    -0.26 ( 22.62 )
    -0.40 ( 23.34 )
        CFB: Follow-up Month 6 (n= 815, 818)
    0.20 ( 24.08 )
    0.02 ( 24.03 )
        CFB: Follow-up Month 9 (n= 758, 741)
    -0.18 ( 23.52 )
    0.47 ( 23.35 )
        CFB: Follow-up Month 12 (n= 677, 697)
    0.32 ( 22.42 )
    1.22 ( 21.95 )
        CFB: Follow-up Month 18 (n= 528, 548)
    -0.47 ( 24.41 )
    1.52 ( 21.82 )
        CFB: Follow-up Month 24 (n= 374, 393)
    0.67 ( 23.54 )
    1.74 ( 22.28 )
        CFB: Follow-up Month 30 (n= 223, 249)
    2.24 ( 23.36 )
    2.01 ( 24.19 )
        CFB: Follow-up Month 36 (n= 119, 130)
    3.08 ( 23.57 )
    4.74 ( 20.36 )
        CFB: Follow-up Month 48 (n= 1, 5)
    0.00 ( 9999 )
    13.33 ( 13.94 )
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS)

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    End point title
    Disease-Free Survival (DFS)
    End point description
    DFS was defined as the time from randomization to the first occurrence of disease recurrence or death from any cause. DFS events include: Ipsilateral invasive breast tumor recurrence; Ipsilateral local-regional invasive breast cancer recurrence; Distant recurrence that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer; Contralateral invasive breast cancer; Ipsilateral or contralateral DCIS; Second primary non-breast invasive cancer; Death attributable to any cause. Analysis using Kaplan-Meier estimates where participants with no events at the time of analysis or no post-baseline information were censored. ITT population included all randomized participants, whether or not the assigned study treatment was received. 9999=Median and 95%CI for DFS were not estimable due to too few events having occurred.
    End point type
    Secondary
    End point timeframe
    From randomization up to first disease recurrence or death from any cause (up to 5 years)
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1098
    1101
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Change from Baseline in EORTC QLQ-C30 Patient-reported Function (Physical functioning [Q1-Q5])

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    End point title
    Change from Baseline in EORTC QLQ-C30 Patient-reported Function (Physical functioning [Q1-Q5])
    End point description
    EORTC QLQ-C30 = cancer specific health-related quality-of life (QoL) questionnaire. For physical functioning scale, participant responses to 5 questions about daily activities (strenuous activities, long walks, short walks, bed/chair rest & needing help with eating, dressing, washing themselves, or using the toilet) were scored on a 4-point scale (1=Not at All to 4=Very Much). Scores were linearly transformed on a scale of 0 to 100, with a high score indicating worst functioning. Negative change from baseline = improvement in functioning. PRO-evaluable populations=all randomized participants, whether or not the assigned study treatment was received with baseline PRO assessment and at least one post-baseline PRO assessment in the EORTC QLQC30. Overall number analyzed = number of participants with data available for analyses. Number analyzed=number of participants with data available for analyses at the specified timepoint. 9999=standard deviation was not estimable for one participant.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), Day 1 of Cycles 4, 6, 8, 10, 12, 14 & 16; end of treatment/discontinuation (approximately at Day 351); Follow up: Months 3 to 48 (Total duration is up to 5 years) Cycles 1-5= 28 day cycles; Cycles 6-16: 21 day cycles
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1083
    1089
    Units: score on scale
    arithmetic mean (standard deviation)
        CFB: Cycle 4 Day 1 (n=1025,1042)
    -8.93 ( 14.97 )
    -8.69 ( 14.91 )
        CFB: Cycle 6 Day 1 (n=938, 925)
    -13.30 ( 18.63 )
    -13.55 ( 18.47 )
        CFB: Cycle 8 Day 1 (n=901, 882)
    -5.33 ( 13.79 )
    -6.42 ( 14.41 )
        CFB: Cycle 10 Day 1 (n=898, 852)
    -3.71 ( 13.28 )
    -4.42 ( 13.15 )
        CFB: Cycle 12 Day 1 (n=871, 807)
    -2.41 ( 12.87 )
    -3.42 ( 12.95 )
        CFB: Cycle 14 Day 1 (n=829, 736)
    -1.41 ( 12.87 )
    -1.92 ( 12.11 )
        CFB: Cycle 16 Day 1 (n=627, 489)
    -1.65 ( 12.78 )
    -1.82 ( 12.12 )
        Drug Completion/Early Discontinuation(n=895, 965)
    -2.56 ( 13.72 )
    -4.68 ( 16.69 )
        CFB: Follow-up Month 3 (n=844, 871)
    -1.62 ( 12.71 )
    -2.29 ( 13.47 )
        CFB: Follow-up Month 6 (n=815, 818)
    -1.70 ( 13.46 )
    -1.96 ( 13.78 )
        CFB: Follow-up Month 9 (n=757, 741)
    -1.55 ( 13.75 )
    -1.33 ( 13.91 )
        CFB: Follow-up Month 12 (n=676, 697)
    -1.70 ( 13.85 )
    -1.37 ( 13.39 )
        CFB: Follow-up Month 18 (n=527, 548)
    -1.92 ( 13.60 )
    -0.91 ( 13.79 )
        CFB: Follow-up Month 24 (n=374, 392)
    -1.37 ( 13.89 )
    -0.72 ( 12.91 )
        Follow-up Month 30 (n=223, 249)
    -1.61 ( 15.61 )
    -0.74 ( 12.72 )
        CFB: Follow-up Month 36 (n=119, 130)
    -0.42 ( 14.40 )
    0.82 ( 13.18 )
        CFB: Follow-up Month 48 (n=1, 5)
    -13.33 ( 9999 )
    -2.67 ( 3.65 )
        Baseline (n=1083, 1089)
    89.86 ( 12.14 )
    89.92 ( 11.57 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EORTC QLQ-C30 Global Health Status (GHS) [Q29] and Health-Related Quality of Life (HRQoL) [Q30] Combined Score

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    End point title
    Change From Baseline in EORTC QLQ-C30 Global Health Status (GHS) [Q29] and Health-Related Quality of Life (HRQoL) [Q30] Combined Score
    End point description
    EORTC QLQ-C30=cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to questions regarding GHS (Q29: "How would you rate your overall health during past week?") & QoL (Q30: "How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. Higher score = a better outcome. Negative change from Baseline values indicated deterioration in QOL or functioning and positive values indicated improvement. PRO-evaluable populations = participants in ITT population with baseline PRO assessment and at least one post-baseline PRO assessment in EORTC QLQC30. Overall number analyzed = number of participants with data available for analyses. Number analyzed = number of participants with data available for analysis at the specified time point. 9999=standard deviation was not estimable for 1 participant.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), Day 1 of Cycles 4, 6, 8, 10, 12, 14 & 16; end of treatment/discontinuation (approximately at Day 351); Follow up: Months 3 to 48 (Total duration is up to 5 years) Cycles 1-5= 28 day cycles; Cycles 6-16: 21 day cycles
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1081
    1087
    Units: score on scale
    arithmetic mean (standard deviation)
        Baseline (n=1081, 1087)
    76.26 ( 18.15 )
    75.90 ( 18.52 )
        CFB:Cycle 4 Day 1 (n=1022, 1040)
    -10.49 ( 20.25 )
    -10.02 ( 19.48 )
        CFB:Cycle 6 Day 1 (n= 933, 924)
    -15.87 ( 23.83 )
    -15.68 ( 22.32 )
        CFB:Cycle 8 Day 1 (n= 899, 881)
    -3.54 ( 19.72 )
    -5.09 ( 18.88 )
        CFB:Cycle 10 Day 1(n= 893, 851)
    -1.84 ( 19.57 )
    -2.82 ( 18.38 )
        CFB:Cycle 12 Day 1 (n= 869, 805)
    -0.71 ( 19.41 )
    -2.31 ( 18.91 )
        CFB:Cycle 14 Day 1 (n= 828, 736)
    -0.37 ( 19.04 )
    -1.25 ( 18.35 )
        CFB:Cycle 16 Day 1 (n= 627, 489)
    0.08 ( 18.56 )
    -1.30 ( 18.34 )
        Drug Completion/Early Discontinuation(n= 894, 962)
    -1.56 ( 20.68 )
    -4.39 ( 22.01 )
        CFB: Follow-up Month 3 (n= 843, 871)
    1.01 ( 20.25 )
    -0.74 ( 20.50 )
        CFB: Follow-up Month 6 (n= 813, 815)
    1.10 ( 20.23 )
    -0.90 ( 20.72 )
        CFB: Follow-up Month 9 (n= 756, 740)
    0.62 ( 20.47 )
    0.07 ( 20.83 )
        CFB: Follow-up Month 12 (n= 675, 697)
    1.21 ( 20.42 )
    0.19 ( 19.84 )
        CFB: Follow-up Month 18 (n= 526, 547)
    1.09 ( 22.18 )
    0.47 ( 20.77 )
        CFB: Follow-up Month 24 (n= 373, 390)
    2.32 ( 22.30 )
    0.43 ( 21.33 )
        CFB: Follow-up Month 30 (n= 222, 248)
    1.54 ( 21.36 )
    -0.57 ( 22.43 )
        CFB: Follow-up Month 36 (n= 117, 129)
    2.64 ( 20.95 )
    0.58 ( 23.57 )
        CFB: Follow-up Month 48 (n=1, 4)
    0.00 ( 9999 )
    6.25 ( 31.46 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events

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    End point title
    Number of Participants With Adverse Events
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs are reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. Safety Evaluable Population included all participants who received any amount of any study drug.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    1084
    1093
    Units: participants
    1074
    1090
    No statistical analyses for this end point

    Secondary: Serum Concentration of Atezolizumab

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    End point title
    Serum Concentration of Atezolizumab [2]
    End point description
    Pharmacokinetic (PK)-evaluable population included all participants who received any dose of study medication and who have at least one evaluable postbaseline PK sample. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point. Number analyzed=number of participants with data available for analyses at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Postdose Day 1 of Cycle 1; Predose Day 1 of Cycles 2, 3, and 4; Predose Cycles 6, 10, and 14; Predose Day 1 of Cycle 16; Cycles 1-5= 28-day cycles; Cycles 6-16: 21-day cycles
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive statistic were planned to be analyzed for this end point.
    End point values
    Atezolizumab and Chemotherapy
    Number of subjects analysed
    952
    Units: microgram per milliliter (µg/mL)
    geometric mean (geometric coefficient of variation)
        Postdose Cycle 1 Day 1 (n=853)
    319 ( 43.3 )
        Pre-dose: Cycle 2 Day 1 (n=854)
    153 ( 85.2 )
        Pre-dose: Cycle 3 Day 1 (n=833)
    220 ( 62.0 )
        Pre-dose: Cycle 4 Day 1 (n=819)
    221 ( 120.4 )
        Pre-dose: Cycle 6 (n=727)
    239 ( 146.9 )
        Pre-dose: Cycle 10 (n=650)
    250 ( 92.2 )
        Pre-dose: Cycle 14 (n=556)
    258 ( 118.7 )
        Pre-dose: Cycle 16 Day 2 (n=2)
    355 ( 29.5 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab

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    End point title
    Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab [3]
    End point description
    Baseline evaluable participant= participant with an ADA assay result from a baseline sample(s). Post-baseline evaluable participant= participant with an ADA assay result from at least one postbaseline sample. Number analyzed at baseline and postbaseline are unique number of participants out of all the assessed participants who may have been ADA positive at that timepoint. Different participants may have contributed data for baseline and postbaseline. Safety Evaluable Population included all participants who received any amount of any study drug.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive statistic were planned to be analyzed for this end point.
    End point values
    Atezolizumab and Chemotherapy
    Number of subjects analysed
    1093
    Units: percentage of participants
    number (not applicable)
        Baseline (n=899)
    2.1
        Post-baseline (n=901)
    11.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 5 years
    Adverse event reporting additional description
    All-cause Mortality: ITT population population included all randomized participants, whether or not the assigned study treatment was received; Adverse Events: Safety Evaluable Population included all participants who received any amount of any study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Participants were administered paclitaxel, 80 mg/m^2, IV infusion QW for maximum of 36 weeks followed by dose-dense doxorubicin, 60 mg/m^2 or dose-dense epirubicin, 90 mg/m^2 IV (investigator’s choice) plus cyclophosphamide, 600 mg/m^2, IV repeated Q2W for a maximum of 20 weeks supported with G-CSF or GM-CSF treatment.

    Reporting group title
    Atezolizumab and Chemotherapy
    Reporting group description
    Participants were administered atezolizumab 840 mg, IV infusion, Q2W in combination with chemotherapy (paclitaxel 80 mg/m^2, IV infusion QW for maximum of 22 weeks followed by dose-dense doxorubicin, 60 mg/m^2 or dose-dense epirubicin, 90 mg/m^2, IV (investigator’s choice) plus cyclophosphamide, 600 mg/m^2, IV repeated Q2W for maximum of 17 weeks supported with G-CSF or GM-CSF treatment followed by atezolizumab, 1200 mg IV infusion Q3W as a maintenance therapy to complete 1 year of atezolizumab treatment from the first dose.

    Serious adverse events
    Chemotherapy Atezolizumab and Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    173 / 1084 (15.96%)
    280 / 1093 (25.62%)
         number of deaths (all causes)
    58
    72
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid cancer
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobular breast carcinoma in situ
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachiocephalic vein thrombosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Postoperative care
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 1084 (0.00%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Device related thrombosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site inflammation
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         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 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    4 / 1084 (0.37%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    10 / 1084 (0.92%)
    13 / 1093 (1.19%)
         occurrences causally related to treatment / all
    4 / 10
    10 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 1084 (0.18%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian vein thrombosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 1084 (0.37%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 1084 (0.37%)
    18 / 1093 (1.65%)
         occurrences causally related to treatment / all
    4 / 4
    17 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 1084 (0.28%)
    6 / 1093 (0.55%)
         occurrences causally related to treatment / all
    3 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilic pneumonia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    14 / 1084 (1.29%)
    11 / 1093 (1.01%)
         occurrences causally related to treatment / all
    14 / 14
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 1084 (0.00%)
    7 / 1093 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 1084 (0.18%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 1084 (0.18%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    6 / 1084 (0.55%)
    10 / 1093 (0.91%)
         occurrences causally related to treatment / all
    6 / 6
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 1084 (0.09%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post lumbar puncture syndrome
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 1084 (0.00%)
    6 / 1093 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunisation reaction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access site inflammation
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac asthma
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrasystoles
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocarditis
         subjects affected / exposed
    0 / 1084 (0.00%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (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
    Anaemia
         subjects affected / exposed
    3 / 1084 (0.28%)
    6 / 1093 (0.55%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia macrocytic
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    23 / 1084 (2.12%)
    29 / 1093 (2.65%)
         occurrences causally related to treatment / all
    25 / 25
    35 / 35
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    5 / 1084 (0.46%)
    18 / 1093 (1.65%)
         occurrences causally related to treatment / all
    6 / 6
    28 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         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 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Methaemoglobinaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    3 / 1084 (0.28%)
    4 / 1093 (0.37%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    31 / 1084 (2.86%)
    40 / 1093 (3.66%)
         occurrences causally related to treatment / all
    41 / 41
    76 / 76
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 1084 (0.18%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 1084 (0.00%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 1084 (0.18%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated hepatitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 1084 (0.00%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 1084 (0.00%)
    4 / 1093 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis noninfective
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenocorticotropic hormone deficiency
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Addison's disease
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    0 / 1084 (0.00%)
    6 / 1093 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 1084 (0.00%)
    4 / 1093 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue disorder
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torticollis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    7 / 1084 (0.65%)
    9 / 1093 (0.82%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 1084 (0.18%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cellulitis
         subjects affected / exposed
    2 / 1084 (0.18%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complicated appendicitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 1084 (0.18%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected seroma
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis bacterial
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    17 / 1084 (1.57%)
    18 / 1093 (1.65%)
         occurrences causally related to treatment / all
    8 / 17
    13 / 18
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 1084 (0.09%)
    3 / 1093 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 1084 (0.09%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 1084 (0.09%)
    4 / 1093 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral rash
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 1084 (0.09%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 1084 (0.28%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 1084 (0.00%)
    2 / 1093 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 1084 (0.18%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 1084 (0.09%)
    0 / 1093 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 1084 (0.00%)
    1 / 1093 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Chemotherapy Atezolizumab and Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1068 / 1084 (98.52%)
    1082 / 1093 (98.99%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    50 / 1084 (4.61%)
    63 / 1093 (5.76%)
         occurrences all number
    52
    65
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    230 / 1084 (21.22%)
    234 / 1093 (21.41%)
         occurrences all number
    373
    455
    Fatigue
         subjects affected / exposed
    268 / 1084 (24.72%)
    325 / 1093 (29.73%)
         occurrences all number
    348
    490
    Malaise
         subjects affected / exposed
    73 / 1084 (6.73%)
    81 / 1093 (7.41%)
         occurrences all number
    83
    92
    Oedema peripheral
         subjects affected / exposed
    76 / 1084 (7.01%)
    73 / 1093 (6.68%)
         occurrences all number
    84
    83
    Pyrexia
         subjects affected / exposed
    105 / 1084 (9.69%)
    160 / 1093 (14.64%)
         occurrences all number
    126
    211
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    79 / 1084 (7.29%)
    132 / 1093 (12.08%)
         occurrences all number
    85
    158
    Dyspnoea
         subjects affected / exposed
    56 / 1084 (5.17%)
    84 / 1093 (7.69%)
         occurrences all number
    64
    105
    Epistaxis
         subjects affected / exposed
    73 / 1084 (6.73%)
    56 / 1093 (5.12%)
         occurrences all number
    92
    63
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    116 / 1084 (10.70%)
    140 / 1093 (12.81%)
         occurrences all number
    122
    158
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    240 / 1084 (22.14%)
    296 / 1093 (27.08%)
         occurrences all number
    319
    457
    Aspartate aminotransferase increased
         subjects affected / exposed
    159 / 1084 (14.67%)
    246 / 1093 (22.51%)
         occurrences all number
    215
    372
    Blood alkaline phosphatase increased
         subjects affected / exposed
    38 / 1084 (3.51%)
    61 / 1093 (5.58%)
         occurrences all number
    43
    92
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    57 / 1084 (5.26%)
    51 / 1093 (4.67%)
         occurrences all number
    106
    67
    Lymphocyte count decreased
         subjects affected / exposed
    86 / 1084 (7.93%)
    113 / 1093 (10.34%)
         occurrences all number
    162
    214
    Neutrophil count decreased
         subjects affected / exposed
    254 / 1084 (23.43%)
    273 / 1093 (24.98%)
         occurrences all number
    473
    558
    White blood cell count decreased
         subjects affected / exposed
    196 / 1084 (18.08%)
    232 / 1093 (21.23%)
         occurrences all number
    392
    526
    Weight decreased
         subjects affected / exposed
    27 / 1084 (2.49%)
    63 / 1093 (5.76%)
         occurrences all number
    30
    67
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    70 / 1084 (6.46%)
    74 / 1093 (6.77%)
         occurrences all number
    95
    90
    Radiation skin injury
         subjects affected / exposed
    13 / 1084 (1.20%)
    95 / 1093 (8.69%)
         occurrences all number
    13
    98
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    58 / 1084 (5.35%)
    71 / 1093 (6.50%)
         occurrences all number
    68
    104
    Dysgeusia
         subjects affected / exposed
    117 / 1084 (10.79%)
    116 / 1093 (10.61%)
         occurrences all number
    127
    129
    Headache
         subjects affected / exposed
    135 / 1084 (12.45%)
    176 / 1093 (16.10%)
         occurrences all number
    178
    284
    Hypoaesthesia
         subjects affected / exposed
    94 / 1084 (8.67%)
    91 / 1093 (8.33%)
         occurrences all number
    106
    111
    Neuropathy peripheral
         subjects affected / exposed
    151 / 1084 (13.93%)
    158 / 1093 (14.46%)
         occurrences all number
    179
    181
    Paraesthesia
         subjects affected / exposed
    75 / 1084 (6.92%)
    72 / 1093 (6.59%)
         occurrences all number
    99
    117
    Peripheral sensory neuropathy
         subjects affected / exposed
    185 / 1084 (17.07%)
    196 / 1093 (17.93%)
         occurrences all number
    193
    207
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    422 / 1084 (38.93%)
    420 / 1093 (38.43%)
         occurrences all number
    546
    586
    Neutropenia
         subjects affected / exposed
    240 / 1084 (22.14%)
    236 / 1093 (21.59%)
         occurrences all number
    437
    474
    Leukopenia
         subjects affected / exposed
    139 / 1084 (12.82%)
    137 / 1093 (12.53%)
         occurrences all number
    274
    317
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    61 / 1084 (5.63%)
    72 / 1093 (6.59%)
         occurrences all number
    73
    79
    Vomiting
         subjects affected / exposed
    146 / 1084 (13.47%)
    177 / 1093 (16.19%)
         occurrences all number
    212
    242
    Stomatitis
         subjects affected / exposed
    120 / 1084 (11.07%)
    143 / 1093 (13.08%)
         occurrences all number
    133
    166
    Nausea
         subjects affected / exposed
    531 / 1084 (48.99%)
    553 / 1093 (50.59%)
         occurrences all number
    865
    958
    Dyspepsia
         subjects affected / exposed
    58 / 1084 (5.35%)
    65 / 1093 (5.95%)
         occurrences all number
    73
    71
    Diarrhoea
         subjects affected / exposed
    188 / 1084 (17.34%)
    287 / 1093 (26.26%)
         occurrences all number
    260
    430
    Constipation
         subjects affected / exposed
    210 / 1084 (19.37%)
    231 / 1093 (21.13%)
         occurrences all number
    252
    270
    Abdominal pain upper
         subjects affected / exposed
    52 / 1084 (4.80%)
    79 / 1093 (7.23%)
         occurrences all number
    53
    92
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    41 / 1084 (3.78%)
    79 / 1093 (7.23%)
         occurrences all number
    50
    91
    Rash
         subjects affected / exposed
    89 / 1084 (8.21%)
    167 / 1093 (15.28%)
         occurrences all number
    110
    200
    Pruritus
         subjects affected / exposed
    50 / 1084 (4.61%)
    127 / 1093 (11.62%)
         occurrences all number
    56
    160
    Nail discolouration
         subjects affected / exposed
    99 / 1084 (9.13%)
    106 / 1093 (9.70%)
         occurrences all number
    108
    113
    Dry skin
         subjects affected / exposed
    36 / 1084 (3.32%)
    55 / 1093 (5.03%)
         occurrences all number
    38
    57
    Alopecia
         subjects affected / exposed
    715 / 1084 (65.96%)
    735 / 1093 (67.25%)
         occurrences all number
    733
    752
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    6 / 1084 (0.55%)
    161 / 1093 (14.73%)
         occurrences all number
    6
    173
    Hyperthyroidism
         subjects affected / exposed
    3 / 1084 (0.28%)
    62 / 1093 (5.67%)
         occurrences all number
    3
    65
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    73 / 1084 (6.73%)
    116 / 1093 (10.61%)
         occurrences all number
    92
    145
    Arthralgia
         subjects affected / exposed
    150 / 1084 (13.84%)
    218 / 1093 (19.95%)
         occurrences all number
    246
    333
    Bone pain
         subjects affected / exposed
    62 / 1084 (5.72%)
    68 / 1093 (6.22%)
         occurrences all number
    72
    79
    Pain in extremity
         subjects affected / exposed
    50 / 1084 (4.61%)
    66 / 1093 (6.04%)
         occurrences all number
    58
    82
    Myalgia
         subjects affected / exposed
    175 / 1084 (16.14%)
    202 / 1093 (18.48%)
         occurrences all number
    309
    347
    Infections and infestations
    COVID-19
         subjects affected / exposed
    34 / 1084 (3.14%)
    71 / 1093 (6.50%)
         occurrences all number
    34
    72
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    51 / 1084 (4.70%)
    73 / 1093 (6.68%)
         occurrences all number
    64
    89
    Decreased appetite
         subjects affected / exposed
    144 / 1084 (13.28%)
    213 / 1093 (19.49%)
         occurrences all number
    185
    275

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2017
    Protocol Amendment 1: The guidelines for managing patients who experienced atezolizumab-associated adverse events were revised to include guidelines for hypophysitis and myocarditis. The interval for the periodic safety iDMC reviews was established to occur on a 6-month basis.
    20 May 2018
    Protocol Amendment 2: The study design was modified to align with recommendations by European Health authorities, including clarifying the secondary efficacy endpoint related to recurrence-free interval and some eligibility criteria.
    15 Nov 2018
    Protocol Amendment 3: The protocol was amended primarily to update safety information, including risks for atezolizumab and management guidelines, eligibility criteria, and changes to the adverse event severity grading scale.
    12 Nov 2019
    Protocol Amendment 4: Safety information was updated and recommendations implemented in response to Health Authority request.
    14 Feb 2020
    Protocol Amendment 5: The protocol converged country-specific criteria into the global amendment. In addition, requirements for membership in the iDMC were clarified. Additional safety-related updates were also added.
    17 Feb 2021
    Protocol Amendment 6: The protocol was amended to update the risks and management guidelines for atezolizumab to align with the latest Atezolizumab Investigator’s Brochure (Version 17).
    24 Nov 2021
    Protocol Amendment 7: The interim analysis timeline was updated and the adverse event management guidelines were revised to align with the latest Atezolizumab Investigator’s Brochure (Version 18).
    01 Mar 2023
    Protocol Amendment 8: A formal efficacy and futility analysis was added due to FDA request to determine the ability of the study to provide an acceptable benefit-risk assessment upon trial conclusion.

    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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