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    Clinical Trial Results:
    A Phase III, Open-Label, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Versus Observation as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Urothelial Carcinoma After Surgical Resection

    Summary
    EudraCT number
    2014-005603-25
    Trial protocol
    ES   FI   CZ   DE   BE   NL   GB   FR   GR   PL  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Nov 2020
    First version publication date
    06 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WO29636
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02450331
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    30 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this global Phase III, open-label, randomized, controlled trial is to evaluate the efficacy and safety of adjuvant treatment with atezolizumab compared with observation in patients with muscle-invasive UC, who are at high risk for recurrence following resection.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Canada: 31
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    China: 38
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Spain: 45
    Country: Number of subjects enrolled
    Finland: 14
    Country: Number of subjects enrolled
    France: 46
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 54
    Country: Number of subjects enrolled
    Japan: 55
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Netherlands: 35
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Russian Federation: 33
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    Turkey: 32
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Ukraine: 24
    Country: Number of subjects enrolled
    United States: 210
    Worldwide total number of subjects
    809
    EEA total number of subjects
    304
    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)
    338
    From 65 to 84 years
    467
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    This study included male and female participants aged >=18 years with Eastern Cooperative Oncology Group (ECOG) performance status <=2 who have histologically confirmed muscle-invasive UC of the bladder or upper urinary tract.

    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
    Observation
    Arm description
    Participants underwent observation starting on Day 1 for 16 cycles (up to 1 year).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Atezolizumab
    Arm description
    Participants received intravenous (IV) atezolizumab on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).
    Arm type
    Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered intravenously at a dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).

    Number of subjects in period 1
    Observation Atezolizumab
    Started
    403
    406
    Completed
    0
    0
    Not completed
    403
    406
         Adverse event, serious fatal
    120
    114
         In Survival follow-up
    45
    38
         Consent withdrawn by subject
    50
    39
         In Disease recurrence follow-up
    179
    208
         Lost to follow-up
    9
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Observation
    Reporting group description
    Participants underwent observation starting on Day 1 for 16 cycles (up to 1 year).

    Reporting group title
    Atezolizumab
    Reporting group description
    Participants received intravenous (IV) atezolizumab on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).

    Reporting group values
    Observation Atezolizumab Total
    Number of subjects
    403 406 809
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    169 169 338
        From 65-84 years
    232 235 467
        85 years and over
    2 2 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    65.9 ± 9.3 66.0 ± 9.0 -
    Sex: Female, Male
    Units: Participants
        Female
    87 84 171
        Male
    316 322 638
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 1 1
        Asian
    68 64 132
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    3 3 6
        White
    307 320 627
        Other
    4 6 10
        Unknown
    21 12 33
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    9 16 25
        Not Hispanic or Latino
    357 369 726
        Unknown or Not Reported
    37 21 58

    End points

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    End points reporting groups
    Reporting group title
    Observation
    Reporting group description
    Participants underwent observation starting on Day 1 for 16 cycles (up to 1 year).

    Reporting group title
    Atezolizumab
    Reporting group description
    Participants received intravenous (IV) atezolizumab on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).

    Primary: Disease-Free Survival (DFS), as Assessed by Investigator

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    End point title
    Disease-Free Survival (DFS), as Assessed by Investigator
    End point description
    DFS is defined as the time from randomization to the time of first occurrence of a DFS event. DFS events include: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); urinary tract recurrence of UC (including all pathological stages and grades); distant metastasis of UC; or death from any cause. Tumor assessment will be performed using radiographic evaluations.
    End point type
    Primary
    End point timeframe
    Randomization up to first occurrence of DFS event (up to approximately 50 months)
    End point values
    Observation Atezolizumab
    Number of subjects analysed
    403
    406
    Units: Months
        median (confidence interval 95%)
    16.6 (11.2 to 24.8)
    19.4 (15.9 to 24.8)
    Statistical analysis title
    Statistical Analysis for DFS
    Comparison groups
    Atezolizumab v Observation
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2446
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.892
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.735
         upper limit
    1.081

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival is defined as the time from randomization to the date of death from any cause, regardless of whether the death occurs during study treatment or following treatment discontinuation. Note: 999999 = not estimatable.
    End point type
    Secondary
    End point timeframe
    Randomization until death due to any cause (up to approximately 50 months)
    End point values
    Observation Atezolizumab
    Number of subjects analysed
    403
    406
    Units: Months
        median (confidence interval 95%)
    999999 (38.2 to 999999)
    999999 (999999 to 999999)
    Statistical analysis title
    Statistical Analysis for OS
    Comparison groups
    Atezolizumab v Observation
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1951
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.846
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.657
         upper limit
    1.09

    Secondary: Disease-Specific Survival (DSS), as Assessed by Investigator

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    End point title
    Disease-Specific Survival (DSS), as Assessed by Investigator
    End point description
    DSS is defined as the time from randomization until the date of death from UC. Note: 999999 = not estimatable.
    End point type
    Secondary
    End point timeframe
    Randomization until death due to UC (up to approximately 50 months)
    End point values
    Observation Atezolizumab
    Number of subjects analysed
    403
    406
    Units: Months
        median (confidence interval 95%)
    999999 (999999 to 999999)
    999999 (999999 to 999999)
    Statistical analysis title
    Statistical Analysis for DSS
    Comparison groups
    Atezolizumab v Observation
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    [1]
    P-value
    = 0.2235
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.836
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.626
         upper limit
    1.116
    Notes
    [1] - Stratified Analysis

    Secondary: Distant Metastasis-Free Survival (DMFS)

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    End point title
    Distant Metastasis-Free Survival (DMFS)
    End point description
    DMFS is defined as the time from randomization to the date of diagnosis of distant (that is, non-locoregional) metastases or death from any cause. Tumor assessment will be performed using radiographic evaluations. Note: 999999 = not estimatable.
    End point type
    Secondary
    End point timeframe
    Randomization up to diagnosis of distant metastases or death from any cause (up to approximately 50 months)
    End point values
    Observation Atezolizumab
    Number of subjects analysed
    403
    406
    Units: Months
        median (confidence interval 95%)
    31.1 (21.7 to 41.4)
    27.5 (22.6 to 999999)
    Statistical analysis title
    Statistical Analysis for DMFS
    Comparison groups
    Atezolizumab v Observation
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    [2]
    P-value
    = 0.4291
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.918
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.743
         upper limit
    1.134
    Notes
    [2] - Stratified Analysis

    Secondary: Non-Urinary Tract Recurrence-Free Survival (NURFS)

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    End point title
    Non-Urinary Tract Recurrence-Free Survival (NURFS)
    End point description
    NURFS is defined as the time from randomization to the time of first occurrence of a NURFS event. NURFS events include: local (pelvic) recurrence of UC (including soft tissue and regional lymph nodes); distant metastasis of UC; or death from any cause. Tumor assessment will be performed using radiographic evaluations.
    End point type
    Secondary
    End point timeframe
    Randomization up to time of first occurrence of a NURFS event (up to approximately 50 months)
    End point values
    Observation Atezolizumab
    Number of subjects analysed
    403
    406
    Units: Months
        median (confidence interval 95%)
    19.5 (12.3 to 27.7)
    22.1 (17.2 to 27.6)
    Statistical analysis title
    Statistical Analysis for NURFS
    Comparison groups
    Atezolizumab v Observation
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    P-value
    = 0.1994
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.879
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.722
         upper limit
    1.07
    Notes
    [3] - Stratified Analysis

    Secondary: Percentage of Participants with Adverse Events (AEs)

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    End point title
    Percentage of Participants with Adverse Events (AEs)
    End point description
    Percentage of participants with at least one Adverse Event.
    End point type
    Secondary
    End point timeframe
    Screening up to approximately 50 months
    End point values
    Observation Atezolizumab
    Number of subjects analysed
    397
    390
    Units: Percentage of Participants
        number (not applicable)
    78.8
    94.4
    No statistical analyses for this end point

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

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    End point title
    Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab [4]
    End point description
    Percentage of participants with anti-therapeutic antibodies to atezolizumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 50 months
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    Atezolizumab
    Number of subjects analysed
    375
    Units: Percentage of Participants
        number (not applicable)
    29.3
    No statistical analyses for this end point

    Secondary: EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score

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    End point title
    EuroQol 5-Dimension 5-Level (EQ-5D-5L) Visual Analogue Scale Score
    End point description
    The EQ-5D-5L is a generic preference-based HRQoL questionnaire that provides a single index value for health status and is used to inform pharmacoeconomic evaluations and to measure general health status. Visual analog scale (VAS) allows the patient to indicate, on a scale of 0-100, how his or her health is on the day of assessment, with 100 being the “best imaginable health state” and 0 being the “worst imaginable health state.”
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1 up to approximately 50 months (Cycle length = 21 days)
    End point values
    Observation Atezolizumab
    Number of subjects analysed
    403
    406
    Units: Score on scale
    arithmetic mean (standard deviation)
        Cycle 1 Day 1
    77.41 ± 15.74
    78.89 ± 16.13
        Cycle 3 Day 1
    78.64 ± 15.73
    81.05 ± 14.96
        Cycle 5 Day 1
    79.94 ± 16.32
    81.95 ± 14.32
        Cycle 7 Day 1
    80.81 ± 16.37
    82.39 ± 14.43
        Cycle 9 Day 1
    81.24 ± 15.70
    82.06 ± 15.34
        Cycle 11 Day 1
    81.39 ± 17.02
    82.81 ± 14.96
        Cycle 13 Day 1
    81.39 ± 16.99
    82.59 ± 14.81
        Cycle 15 Day 1
    82.78 ± 16.01
    83.67 ± 14.47
        Treatment Discontinuation
    82.68 ± 16.19
    81.91 ± 15.96
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Atezolizumab Concentration (Cmin)

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    End point title
    Minimum Observed Serum Atezolizumab Concentration (Cmin) [5]
    End point description
    Minimum observed serum atezolizumab concentration (Cmin) prior to infusion on Day 1 of Cycles 1, 2, 3, and 4; every 8 cycles starting on Cycle 8; at treatment discontinuation; and at 120 days after the last dose of atezolizumab.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) on Day 1 of Cycles 1, 2, 3, 4, every 8 cycles from Cycle 8, at treatment discontinuation, 120 days after treatment discontinuation (up to approximately 50 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    Atezolizumab
    Number of subjects analysed
    380
    Units: µg/mL
    arithmetic mean (standard deviation)
        Cycle 2 Day 1
    78.4 ± 25.2
        Cycle 3 Day 1
    125 ± 46.0
        Cycle 4 Day 1
    152 ± 71.1
        Cycle 8 Day 1
    203 ± 92.0
        Cycle 16 Day 1
    225 ± 106
        Day 120 Post Last Dose MPDL3280A
    15.9 ± 19.5
        Study Drug or Study Phase Comp or Early Disc
    164 ± 106
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Atezolizumab Concentration (Cmax)

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    End point title
    Maximum Observed Serum Atezolizumab Concentration (Cmax) [6]
    End point description
    Maximum observed serum atezolizumab concentration (Cmax) after infusion on Day 1 of Cycle 1.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1 (Cycle length = 21 days)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    Atezolizumab
    Number of subjects analysed
    300
    Units: µg/mL
        arithmetic mean (standard deviation)
    365 ± 121
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug to the data cutoff date: 30 November 2019 (up to 50 months)
    Adverse event reporting additional description
    The safety-evaluable population for atezolizumab was defined as patients who received at least one dose of atezolizumab. The safety-evaluable population for observation was defined as patients randomized to observation who had at least one post-baseline safety assessment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    OBSERVATION
    Reporting group description
    Participants underwent observation starting on Day 1 for 16 cycles (up to 1 year).

    Reporting group title
    ATEZOLIZUMAB
    Reporting group description
    Participants received intravenous (IV) atezolizumab on Day 1 of each 21-day cycle for 16 cycles (up to 1 year).

    Serious adverse events
    OBSERVATION ATEZOLIZUMAB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 397 (17.88%)
    122 / 390 (31.28%)
         number of deaths (all causes)
    124
    114
         number of deaths resulting from adverse events
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 397 (0.76%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour of ampulla of Vater
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic immune activation
         subjects affected / exposed
    0 / 397 (0.00%)
    2 / 390 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia pain
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 397 (0.25%)
    3 / 390 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Hyperthermia
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         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 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lithiasis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 397 (1.01%)
    11 / 390 (2.82%)
         occurrences causally related to treatment / all
    0 / 4
    6 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    2 / 397 (0.50%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Incision site impaired healing
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         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 / 397 (0.00%)
    2 / 390 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stoma obstruction
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomal hernia
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric anastomosis complication
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urostomy complication
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 397 (0.00%)
    2 / 390 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 397 (0.00%)
    3 / 390 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 397 (1.26%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated neuropathy
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         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 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 397 (0.50%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 397 (0.00%)
    4 / 390 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 397 (0.50%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 397 (0.00%)
    5 / 390 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune-mediated enterocolitis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 397 (0.50%)
    4 / 390 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 397 (0.00%)
    2 / 390 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 397 (0.50%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine ulcer
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 397 (1.01%)
    8 / 390 (2.05%)
         occurrences causally related to treatment / all
    0 / 4
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 397 (0.25%)
    2 / 390 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinoma
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vesicoureteric reflux
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 397 (0.00%)
    2 / 390 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 397 (0.00%)
    2 / 390 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         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 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 397 (0.50%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroborreliosis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 397 (0.50%)
    4 / 390 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    9 / 397 (2.27%)
    12 / 390 (3.08%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 397 (0.25%)
    3 / 390 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 397 (0.25%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    19 / 397 (4.79%)
    30 / 390 (7.69%)
         occurrences causally related to treatment / all
    0 / 22
    1 / 41
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 397 (0.25%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 397 (0.76%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 397 (0.00%)
    1 / 390 (0.26%)
         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
    OBSERVATION ATEZOLIZUMAB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    232 / 397 (58.44%)
    324 / 390 (83.08%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 397 (1.76%)
    24 / 390 (6.15%)
         occurrences all number
    8
    32
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 397 (1.26%)
    20 / 390 (5.13%)
         occurrences all number
    6
    25
    Blood alkaline phosphatase increased
         subjects affected / exposed
    8 / 397 (2.02%)
    20 / 390 (5.13%)
         occurrences all number
    8
    29
    Blood creatinine increased
         subjects affected / exposed
    17 / 397 (4.28%)
    37 / 390 (9.49%)
         occurrences all number
    20
    42
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 397 (5.79%)
    47 / 390 (12.05%)
         occurrences all number
    23
    60
    Dyspnoea
         subjects affected / exposed
    7 / 397 (1.76%)
    27 / 390 (6.92%)
         occurrences all number
    7
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    32 / 397 (8.06%)
    42 / 390 (10.77%)
         occurrences all number
    34
    53
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 397 (2.77%)
    20 / 390 (5.13%)
         occurrences all number
    11
    22
    Headache
         subjects affected / exposed
    8 / 397 (2.02%)
    35 / 390 (8.97%)
         occurrences all number
    8
    39
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 397 (4.03%)
    35 / 390 (8.97%)
         occurrences all number
    16
    41
    Chills
         subjects affected / exposed
    7 / 397 (1.76%)
    23 / 390 (5.90%)
         occurrences all number
    9
    25
    Fatigue
         subjects affected / exposed
    42 / 397 (10.58%)
    89 / 390 (22.82%)
         occurrences all number
    49
    118
    Oedema peripheral
         subjects affected / exposed
    23 / 397 (5.79%)
    34 / 390 (8.72%)
         occurrences all number
    26
    38
    Pyrexia
         subjects affected / exposed
    30 / 397 (7.56%)
    71 / 390 (18.21%)
         occurrences all number
    43
    90
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    29 / 397 (7.30%)
    31 / 390 (7.95%)
         occurrences all number
    32
    39
    Constipation
         subjects affected / exposed
    39 / 397 (9.82%)
    51 / 390 (13.08%)
         occurrences all number
    40
    60
    Diarrhoea
         subjects affected / exposed
    25 / 397 (6.30%)
    81 / 390 (20.77%)
         occurrences all number
    29
    103
    Nausea
         subjects affected / exposed
    20 / 397 (5.04%)
    52 / 390 (13.33%)
         occurrences all number
    21
    60
    Vomiting
         subjects affected / exposed
    14 / 397 (3.53%)
    26 / 390 (6.67%)
         occurrences all number
    16
    34
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 397 (0.50%)
    29 / 390 (7.44%)
         occurrences all number
    2
    30
    Pruritus
         subjects affected / exposed
    10 / 397 (2.52%)
    92 / 390 (23.59%)
         occurrences all number
    14
    113
    Rash
         subjects affected / exposed
    5 / 397 (1.26%)
    38 / 390 (9.74%)
         occurrences all number
    6
    48
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 397 (6.05%)
    43 / 390 (11.03%)
         occurrences all number
    26
    48
    Back pain
         subjects affected / exposed
    44 / 397 (11.08%)
    26 / 390 (6.67%)
         occurrences all number
    54
    31
    Myalgia
         subjects affected / exposed
    6 / 397 (1.51%)
    21 / 390 (5.38%)
         occurrences all number
    8
    30
    Pain in extremity
         subjects affected / exposed
    9 / 397 (2.27%)
    22 / 390 (5.64%)
         occurrences all number
    9
    29
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 397 (0.00%)
    35 / 390 (8.97%)
         occurrences all number
    0
    38
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    20 / 397 (5.04%)
    45 / 390 (11.54%)
         occurrences all number
    21
    54
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 397 (4.53%)
    21 / 390 (5.38%)
         occurrences all number
    19
    27
    Urinary tract infection
         subjects affected / exposed
    59 / 397 (14.86%)
    63 / 390 (16.15%)
         occurrences all number
    84
    88

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2015
    Protocol was amended under inclusion criteria with the removal of cytology as one of the methods to diagnose muscle-invasive transitional cell carcinoma (TCC) of the bladder given that histopathology is the standard. Under the exclusion criteria, the requirement of participants to be taken off denosumab has been removed. Because participants in this adjuvant trial would not have bone disease at baseline, there is not a need for denosumab to treat cancer-related bone disease.
    04 Apr 2016
    Protocol was amended under inclusion criteria. High risk participants with muscle-invasive urothelial carcinoma (UC) of the upper urinary tract, or participants with carcinoma in situ at the distal ureteral or urethral margin after cystectomy, have been added to the eligible study population given that those participants may benefit from study treatment. The criteria for participants who have received prior neoadjuvant chemotherapy have been clarified to describe participants who have received at least two cycles of a platinum-containing regimen. The requirement for tumor specimens for central testing of PD-L1 expression prior to study enrollment has been clarified to include samples from cystectomy (or radical tumor resection for patients with muscle-invasive UC of the renal pelvis or ureters) or lymph node dissection. The randomization window after cystectomy has been increased from 12 weeks to 14 weeks to allow additional time for potential eligible participants to recover from surgery.
    14 Jul 2016
    Protocol was amended to revise the study design from a diagnostically selected (PD-L1 IHC score of IC2/3 only) study to include all participants regardless of PD-L1 status as a result of data from the ongoing Phase II IMvigor210 study showing that treatment-naive cisplatin-ineligible participants with advanced urothelial carcinoma may benefit from first-line atezolizumab treatment regardless of PD-L1 status. The total sample size has been increased from 440 to 700. Non-urinary tract recurrence-free survival (NURFS) has been added as a secondary efficacy objective to distinguish non-urinary tract recurrence from urinary tract recurrence.
    04 Oct 2017
    Protocol was amended to increase the total sample size from 700 to 800. The end of study projection has been updated from 79 months from first patient in (FPI) to 95 months from FPI to accommodate the increased sample size. Tumor stage M0 has been added to the tumor staging inclusion criterion to further clarify that participants with metastatic disease at the time of surgical resection are ineligible for the study.
    19 Nov 2018
    Protocol was amended to include an update to the timing of the analysis of the primary endpoint of disease-free survival (DFS) in order to ensure a minimum of 12 months of follow-up for efficacy and safety for the study population.
    13 Apr 2020
    Protocol was amended to include following the primary analysis, participants who are in Years 1-3 or Years 2-3, as applicable,of the study and are in disease recurrence follow-up may now be assessed for recurrence every 24 weeks. EQ-5D-5L assessments are no longer required for participants who are in disease recurrence follow-up or for participants who have had a DFS event.

    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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