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    Clinical Trial Results:
    A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Atezolizumab (MPDL3280A) Administered Intravenously as a Single Agent to Patients With Locally Advanced or Metastatic Solid Tumors or Hematologic Malignancies

    Summary
    EudraCT number
    		 2011-001422-23
    Trial protocol
    		 GB  
    Global end of trial date
    30 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCD4989g
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01375842
    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
    Final
    Date of interim/final analysis
    30 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the safety and tolerability of atezolizumab administered by intravenous (IV) infusion every 3 weeks (q3w) to patients with locally advanced or metastatic solid tumors or hematologic malignancies.
    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
    21 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    France: 87
    Country: Number of subjects enrolled
    United Kingdom: 54
    Country: Number of subjects enrolled
    United States: 478
    Worldwide total number of subjects
    658
    EEA total number of subjects
    180
    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)
    394
    From 65 to 84 years
    261
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 21 centers in 4 countries, comprising the US (16 centers), France (3 centers), Great Britain (1 center), and Spain (1 center).

    Pre-assignment
    Screening details
    		 A total of 955 subjects were screened for entry into the study. 295 subjects failed screening and were not enrolled into the study. 660 subjects were enrolled into the study (intent-to-treat [ITT] population). 658 subjects received any amount of atezolizumab on study (safety-evaluable population) and are reported here.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg
    Arm description
    		 Subjects received intravenous (IV) infusion of atezolizumab <=1 milligrams per kilogram (mg/kg) every 3 weeks (q3w) until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered as IV infusion at <=1 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Arm title
    		 Dose Escalation Cohort: Atezolizumab 3 mg/kg
    Arm description
    		 Subjects received IV infusion of atezolizumab 3 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered as IV infusion at 3 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Arm title
    		 Dose Escalation Cohort: Atezolizumab 10 mg/kg
    Arm description
    		 Subjects received IV infusion of atezolizumab 10 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered as IV infusion at 10 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Arm title
    		 Dose Escalation Cohort: Atezolizumab 15 mg/kg
    Arm description
    		 Subjects received IV infusion of atezolizumab 15 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered as IV infusion at 15 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Arm title
    		 Dose Escalation Cohort: Atezolizumab 20 mg/kg
    Arm description
    		 Subjects received IV infusion of atezolizumab 20 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered as IV infusion at 20 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Arm title
    		 Expansion Cohort: Atezolizumab 1200 mg
    Arm description
    		 Subjects received IV infusion of atezolizumab 1200 mg q3w up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered as IV infusion at 1200 mg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Number of subjects in period 1
    		Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Started
    9
    3
    36
    236
    146
    228
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    9
    3
    36
    236
    146
    228
         Physician decision
    1
    -
    2
    10
    10
    -
         Consent withdrawn by subject
    -
    1
    1
    11
    5
    2
         Non-Compliance
    -
    -
    -
    -
    1
    -
         Study Terminated By Sponsor
    1
    1
    6
    34
    14
    24
         Death
    1
    -
    13
    85
    39
    181
         Progressive Disease
    5
    1
    12
    87
    73
    7
         Unknown
    -
    -
    -
    3
    -
    -
         Lost to follow-up
    1
    -
    2
    6
    4
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose Escalation Cohort: Atezolizumab <=1 mg/kg
    Reporting group description
    		 Subjects received intravenous (IV) infusion of atezolizumab <=1 milligrams per kilogram (mg/kg) every 3 weeks (q3w) until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 3 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 3 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 10 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 10 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 15 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 15 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 20 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 20 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Expansion Cohort: Atezolizumab 1200 mg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 1200 mg q3w up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group values
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg Total
    Number of subjects
    		 9 3 36 236 146 228 658
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 3 3 18 137 82 151 394
        From 65-84 years
    		 6 0 18 97 63 77 261
        85 years and over
    		 0 0 0 2 1 0 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.4 ( 12.0 ) 55.3 ( 2.1 ) 63.2 ( 11.1 ) 60.5 ( 12.3 ) 61.3 ( 12.2 ) 56.9 ( 13.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 1 12 87 60 143 309
        Male
    		 3 2 24 149 86 85 349
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 1 0 8 5 9 24
        Not Hispanic or Latino
    		 8 2 35 176 118 178 517
        Not Reported
    		 0 0 0 50 20 35 105
        Unkown
    		 0 0 1 2 3 6 12
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 1 1
        Asian
    		 0 0 0 5 3 9 17
        Black or African American
    		 1 0 2 4 8 12 27
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        White
    		 8 3 34 178 110 171 504
        Other
    		 0 0 0 49 25 34 108
        Multiple
    		 0 0 0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Dose Escalation Cohort: Atezolizumab <=1 mg/kg
    Reporting group description
    		 Subjects received intravenous (IV) infusion of atezolizumab <=1 milligrams per kilogram (mg/kg) every 3 weeks (q3w) until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 3 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 3 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 10 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 10 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 15 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 15 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 20 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 20 mg/kg q3w until DLT is reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Reporting group title
    Expansion Cohort: Atezolizumab 1200 mg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 1200 mg q3w up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Subject analysis set title
    Safety-Evaluable Population: Atezolizumab
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety-Evaluable Population, defined as all enrolled subjects who received any amount of atezolizumab on study.

    Subject analysis set title
    Baseline: ADA Positive Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who had a positive ADA result at baseline.

    Subject analysis set title
    Post-Baseline: Treatment-Induced ADA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who had a baseline-negative ADA result who developed anti-drug antibodies at any time after initial drug administration.

    Subject analysis set title
    Post-Baseline: Treatment-Enhanced ADA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who had a baseline-positive ADA result in whom the assay signal was enhanced at any time after initial drug administration.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 0.01 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 0.01 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 0.03 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 0.03 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 0.1 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 0.1 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 0.3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 0.3 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 1 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 1 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 3 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 3 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 10 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 10 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 15 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 15 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 20 mg/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, dose escalation cohort: subjects who received 20 mg/kg of atezolizumab.

    Subject analysis set title
    PK Evaluable Population: Atezolizumab 1200 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PK Evaluable Population, expansion cohort: subjects who received 1200 mg IV infusion of atezolizumab q3w up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurs first.

    Subject analysis set title
    Efficacy Evaluable Subjects: HR+Breast Cancer
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with HR+ breast cancer with measurable disease at baseline.

    Subject analysis set title
    Efficacy Evaluable Subjects: BTCC
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with bladder transitional cell carcinoma

    Subject analysis set title
    Efficacy Evaluable Subjects: Head and Neck Cancer
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with head and neck cancer.

    Subject analysis set title
    Efficacy evaluable subjects: Melanoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with melanoma

    Subject analysis set title
    Efficacy evaluable subjects: Non-Small Cell Lung Cancer
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with non-small cell lung cancer.

    Subject analysis set title
    Efficacy Evaluable Subjects: Prostate Cancer
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with prostate cancer.

    Subject analysis set title
    Efficacy Evaluable Subjects: Renal Cell Carcinoma
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with renal cell carcinoma.

    Subject analysis set title
    Efficacy Evaluable Subjects: Triple Negative Breast Cancer
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with triple negative breast cancer.

    Subject analysis set title
    Efficacy Evaluable Subjects: Tumor Types Where <20 subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with tumor types where <20 subjects were enrolled.

    Subject analysis set title
    Efficacy Evaluable Subjects: HR+Breast Cancer IC0/1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Efficacy evaluable subject with HR+breast cancer IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: HR+Breast Cancer IC2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with HR+breast cancer IC2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: HR+Breast Cancer IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with HR+breast cancer IC0.

    Subject analysis set title
    Efficacy Evaluable Subjects: HR+Breast Cancer IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with HR+breast cancer IC1/2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: BTCC IC0/1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with BTCC IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: BTCC IC2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with BTCC IC2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: BTCC Unknown IC Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with BTCC unknown IC group.

    Subject analysis set title
    Efficacy Evaluable Subjects: BTCC IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with BTCC IC0.

    Subject analysis set title
    Efficacy Evaluable Subjects: BTCC IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with BTCC IC1/2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: BTCC Unknown IC Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with BTCC unknown IC group

    Subject analysis set title
    Efficacy Evaluable Subjects: Head and Neck Cancer IC0/1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with head and neck cancer IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: Head and Neck Cancer IC2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with head and neck cancer IC2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: Head and Neck Cancer IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with head and neck cancer IC0.

    Subject analysis set title
    Efficacy Evaluable Subjects: Head and Neck Cancer IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with head and neck cancer IC1/2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: Melanoma IC0/1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with melanoma IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: Melanoma IC2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with melanoma IC2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: Melanoma Unknown IC Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with melanoma unknown IC group.

    Subject analysis set title
    Efficacy Evaluable Subjects: Melanoma IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with melanoma IC0

    Subject analysis set title
    Efficacy Evaluable Subjects: Melanoma IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with melanoma IC1/2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: NSCLC TC0/1/2 and IC0/1/2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with NSCLC TC0/1/2 and IC0/1/2.

    Subject analysis set title
    Efficacy Evaluable Subjects: NSCLC TC3 or IC3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with NSCLC TC3 or IC3.

    Subject analysis set title
    Efficacy Evaluable Subjects: NSCLC Unkown TC or IC Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with NSCLC unknown TC or IC group.

    Subject analysis set title
    Efficacy Evaluable Subjects: NSCLC IC0/1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with NSCLC IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: NSCLC IC2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with NSCLC IC2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: NSCLC IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with NSCLC IC0.

    Subject analysis set title
    Efficacy Evaluable Subjects: NSCLC IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with NSCLC IC1/2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: Prostate Cancer IC0/1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with prostate cancer IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: Prostate Cancer Unkown IC Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with prostate cancer unknown IC group.

    Subject analysis set title
    Efficacy Evaluable Subjects: Prostate Cancer IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with prostate cancer IC0.

    Subject analysis set title
    Efficacy Evaluable Subjects: Prostate Cancer IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with prostate cancer IC1/2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: RCC IC0/1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with RCC IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: RCC IC2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with RCC IC2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: RCC IC Group Unknown
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with RCC IC group unknown.

    Subject analysis set title
    Efficacy Evaluable Subjects: RCC IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with RCC IC0.

    Subject analysis set title
    Efficacy Evaluable Subjects: RCC IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with RCC IC1/2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: TNBC IC0/1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with TNBC IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: TNBC IC2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with TNBC IC2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: TNBC IC Group Unknown
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with TNBC IC group unknown.

    Subject analysis set title
    Efficacy Evaluable Subjects: TNBC IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with TNBC IC0.

    Subject analysis set title
    Efficacy Evaluable Subjects: TNBC IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with TNBC IC1/2/3.

    Subject analysis set title
    Efficacy Evaluable Subjects: Tumor Types <20 Subjects IC0/1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with tumor types where <20 subjects enrolled IC0/1.

    Subject analysis set title
    Efficacy Evaluable Subjects: Tumor Types <20 Subjects IC2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with tumor types where <20 subjects enrolled IC2/3.

    Subject analysis set title
    Efficacy Evaluable: Tumor Types <20 Subjects IC Group Unknown
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with tumor types where <20 subjects enrolled IC group unknown.

    Subject analysis set title
    Efficacy Evaluable Subjects: Tumor Types <20 Subjects IC0
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with tumor types <20 subjects enrolled IC0.

    Subject analysis set title
    Efficacy Evaluable Subjects: Tumor Types <20 Subjects IC1/2/3
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Efficacy evaluable subjects with tumor types where <20 Subjects Enrolled IC1/2/3.

    Primary: Number of Subjects With Dose Limiting Toxicities (DLTs)

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    End point title
    		 Number of Subjects With Dose Limiting Toxicities (DLTs) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 21
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Number of subjects analysed
    9
    3
    36
    236
    146
    228
    Units: Number of Subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Atezolizumab

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    End point title
    		 Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Atezolizumab [2] [3]
    End point description
    Maximum administered dose of atezolizumab in the safety-evaluable population.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 21
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    [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: No statistical analyses for this end point.
    End point values
    		 Expansion Cohort: Atezolizumab 1200 mg
    Number of subjects analysed
    228
    Units: mg
    1200
    No statistical analyses for this end point

    Primary: Recommended Phase 2 Dose (RP2D) of Atezolizumab

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    End point title
    		 Recommended Phase 2 Dose (RP2D) of Atezolizumab [4]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline up to time of determination of MTD (up to Day 21)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 Safety-Evaluable Population: Atezolizumab
    Number of subjects analysed
    658
    Units: mg
    1200
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Adverse Events

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    End point title
    		 Percentage of Subjects With Adverse Events [5]
    End point description
    Percentage of subjects with adverse events in safety evaluable population, defined as all enrolled patients who received any amount of atezolizumab on study.
    End point type
    Primary
    End point timeframe
    Baseline up to 90 days after the last dose of study treatment or until initiation of another anti-cancer therapy, whichever occurs first (up to approximately [approx] 7 years [yrs])
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end point.
    End point values
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Number of subjects analysed
    9
    3
    36
    236
    146
    228
    Units: Percentage of subjects
        number (not applicable)
    100
    100
    97.2
    98.3
    99.3
    98.7
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-Therapeutic Antibodies (ATAs)

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    End point title
    		 Number of Subjects With Anti-Therapeutic Antibodies (ATAs)
    End point description
    End point type
    Secondary
    End point timeframe
    Predose up to 120 days after last dose of study treatment until death/study closure (up to approximately 7 years)
    End point values
    		 Baseline: ADA Positive Subjects Post-Baseline: Treatment-Induced ADA Post-Baseline: Treatment-Enhanced ADA
    Number of subjects analysed
    638
    609
    609
    Units: Subjects
        number (not applicable)
    16
    168
    5
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve (AUC) 0-21 of Atezolizumab

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    End point title
    		 Area Under the Concentration-Time Curve (AUC) 0-21 of Atezolizumab
    End point description
    AUC from Day 1 to Day 21 in cycle 1, following multiple doses of atezolizumab given every 3 weeks by dose group in PK-evaluable population. Note: 888888 = not calculated.
    End point type
    Secondary
    End point timeframe
    Cycle 1
    End point values
    		 PK Evaluable Population: Atezolizumab 0.1 mg/kg PK Evaluable Population: Atezolizumab 0.3 mg/kg PK Evaluable Population: Atezolizumab 1 mg/kg PK Evaluable Population: Atezolizumab 3 mg/kg PK Evaluable Population: Atezolizumab 10 mg/kg PK Evaluable Population: Atezolizumab 15 mg/kg PK Evaluable Population: Atezolizumab 20 mg/kg
    Number of subjects analysed
    1
    3
    3
    3
    29
    29
    32
    Units: day*ug/mL
        geometric mean (geometric coefficient of variation)
    1.62 ( 888888 )
    31.5 ( 8.1 )
    201 ( 8.5 )
    601 ( 34 )
    2240 ( 17 )
    2730 ( 27 )
    3870 ( 21 )
    No statistical analyses for this end point

    Secondary: Maximum Serum Concentration (Cmax) of Atezolizumab

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    End point title
    		 Maximum Serum Concentration (Cmax) of Atezolizumab
    End point description
    Cmax in cycle 1, following multiple IV doses of atezolizumab given every 3 weeks by dose group in PK-evaluable population.
    End point type
    Secondary
    End point timeframe
    Cycle 1
    End point values
    		 PK Evaluable Population: Atezolizumab 0.01 mg/kg PK Evaluable Population: Atezolizumab 0.03 mg/kg PK Evaluable Population: Atezolizumab 0.1 mg/kg PK Evaluable Population: Atezolizumab 0.3 mg/kg PK Evaluable Population: Atezolizumab 1 mg/kg PK Evaluable Population: Atezolizumab 3 mg/kg PK Evaluable Population: Atezolizumab 10 mg/kg PK Evaluable Population: Atezolizumab 15 mg/kg PK Evaluable Population: Atezolizumab 20 mg/kg PK Evaluable Population: Atezolizumab 1200 mg
    Number of subjects analysed
    0 [6]
    1 [7]
    1 [8]
    3
    3
    3
    35
    228
    131
    194
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    ( )
    0.37 ( 888888 )
    0.96 ( 888888 )
    6.57 ( 1.33 )
    23.40 ( 8.55 )
    77.30 ( 19.9 )
    255 ( 51.0 )
    372 ( 199 )
    506 ( 115 )
    415 ( 107 )
    Notes
    [6] - Cmax not available due to insufficient data.
    [7] - 888888 = not calculated.
    [8] - 888888 = not calculated.
    No statistical analyses for this end point

    Secondary: Minimum Serum Concentration (Cmin) of Atezolizumab

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    End point title
    		 Minimum Serum Concentration (Cmin) of Atezolizumab
    End point description
    Cmin in Cycle 1, following multiple IV doses of atezolizumab given every 3 weeks by dose group in PK-evaluable population.
    End point type
    Secondary
    End point timeframe
    Cycle 1
    End point values
    		 PK Evaluable Population: Atezolizumab 0.01 mg/kg PK Evaluable Population: Atezolizumab 0.03 mg/kg PK Evaluable Population: Atezolizumab 0.1 mg/kg PK Evaluable Population: Atezolizumab 0.3 mg/kg PK Evaluable Population: Atezolizumab 1 mg/kg PK Evaluable Population: Atezolizumab 3 mg/kg PK Evaluable Population: Atezolizumab 10 mg/kg PK Evaluable Population: Atezolizumab 15 mg/kg PK Evaluable Population: Atezolizumab 20 mg/kg PK Evaluable Population: Atezolizumab 1200 mg
    Number of subjects analysed
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    3
    3
    34
    214
    132
    30
    Units: ug/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    3.80 ( 160 )
    12.20 ( 62 )
    54.10 ( 25 )
    67.10 ( 73 )
    91.10 ( 36 )
    95.50 ( 51 )
    Notes
    [9] - Cmin is not available due to insufficient data.
    [10] - .Cmin is not available due to insufficient data.
    [11] - Cmin is not available due to insufficient data.
    [12] - Cmin is not available due to insufficient data.
    No statistical analyses for this end point

    Secondary: Clearance (CL) of Atezolizumab

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    End point title
    		 Clearance (CL) of Atezolizumab
    End point description
    CL in cycle 1, following multiple IV doses of atezolizumab given every 3 weeks by dose group in PK-evaluable population. Estimates are considered to be approximate in nature given the 18.0-26.6 day t1/2 and the fact that AUC0-inf was calculated using Cycle 1 data only. Note: 888888 = not calculated.
    End point type
    Secondary
    End point timeframe
    Cycle 1
    End point values
    		 PK Evaluable Population: Atezolizumab 0.1 mg/kg PK Evaluable Population: Atezolizumab 0.3 mg/kg PK Evaluable Population: Atezolizumab 1 mg/kg PK Evaluable Population: Atezolizumab 3 mg/kg PK Evaluable Population: Atezolizumab 10 mg/kg PK Evaluable Population: Atezolizumab 15 mg/kg PK Evaluable Population: Atezolizumab 20 mg/kg
    Number of subjects analysed
    1
    2
    2
    2
    9
    17
    10
    Units: L/day
        geometric mean (geometric coefficient of variation)
    4.23 ( 888888 )
    0.603 ( 888888 )
    0.296 ( 888888 )
    0.420 ( 888888 )
    0.329 ( 33 )
    0.365 ( 23 )
    0.288 ( 30 )
    No statistical analyses for this end point

    Secondary: Volume at Steady State (Vss) of Atezolizumab

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    End point title
    		 Volume at Steady State (Vss) of Atezolizumab
    End point description
    Vss in Cycle 1, following multiple IV doses of atezolizumab given every 3 weeks by dose group in PK-evaluable population. Estimates are considered to be approximate in nature given the 18.0-26.6 day t1/2 and the fact that AUC0-inf was calculated using Cycle 1 data only. Note: 888888 = not calculated.
    End point type
    Secondary
    End point timeframe
    Cycle 1
    End point values
    		 PK Evaluable Population: Atezolizumab 0.1 mg/kg PK Evaluable Population: Atezolizumab 0.3 mg/kg PK Evaluable Population: Atezolizumab 1 mg/kg PK Evaluable Population: Atezolizumab 3 mg/kg PK Evaluable Population: Atezolizumab 10 mg/kg PK Evaluable Population: Atezolizumab 15 mg/kg PK Evaluable Population: Atezolizumab 20 mg/kg
    Number of subjects analysed
    1
    2
    2
    2
    9
    17
    10
    Units: Liter
        geometric mean (geometric coefficient of variation)
    5.30 ( 888888 )
    2.79 ( 888888 )
    2.66 ( 888888 )
    5.20 ( 888888 )
    4.28 ( 39 )
    4.89 ( 22 )
    3.89 ( 30 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD), Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    		 Percentage of Subjects With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD), Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
    End point description
    Percentage of subjects with best overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) in efficacy evaluable subjects with measurable disease at baseline by tumor type and IC group. Note: 000000 = not calculated. 888888 = not calculated.
    End point type
    Secondary
    End point timeframe
    From Baseline up to the first occurrence of progression or death, whichever occurs first (up to approx 7 yrs)
    End point values
    		 Efficacy Evaluable Subjects: HR+Breast Cancer IC0/1 Efficacy Evaluable Subjects: HR+Breast Cancer IC2/3 Efficacy Evaluable Subjects: HR+Breast Cancer IC0 Efficacy Evaluable Subjects: HR+Breast Cancer IC1/2/3 Efficacy Evaluable Subjects: BTCC IC0/1 Efficacy Evaluable Subjects: BTCC IC2/3 Efficacy Evaluable Subjects: BTCC Unknown IC Group Efficacy Evaluable Subjects: BTCC IC0 Efficacy Evaluable Subjects: BTCC IC1/2/3 Efficacy Evaluable Subjects: BTCC Unknown IC Group Efficacy Evaluable Subjects: Head and Neck Cancer IC0/1 Efficacy Evaluable Subjects: Head and Neck Cancer IC2/3 Efficacy Evaluable Subjects: Head and Neck Cancer IC0 Efficacy Evaluable Subjects: Head and Neck Cancer IC1/2/3 Efficacy Evaluable Subjects: Melanoma IC0/1 Efficacy Evaluable Subjects: Melanoma IC2/3 Efficacy Evaluable Subjects: Melanoma Unknown IC Group Efficacy Evaluable Subjects: Melanoma IC0 Efficacy Evaluable Subjects: Melanoma IC1/2/3 Efficacy Evaluable Subjects: NSCLC TC0/1/2 and IC0/1/2 Efficacy Evaluable Subjects: NSCLC TC3 or IC3 Efficacy Evaluable Subjects: NSCLC Unkown TC or IC Group Efficacy Evaluable Subjects: NSCLC IC0/1 Efficacy Evaluable Subjects: NSCLC IC2/3 Efficacy Evaluable Subjects: NSCLC IC0 Efficacy Evaluable Subjects: NSCLC IC1/2/3 Efficacy Evaluable Subjects: Prostate Cancer IC0/1 Efficacy Evaluable Subjects: Prostate Cancer Unkown IC Group Efficacy Evaluable Subjects: Prostate Cancer IC0 Efficacy Evaluable Subjects: Prostate Cancer IC1/2/3 Efficacy Evaluable Subjects: RCC IC0/1 Efficacy Evaluable Subjects: RCC IC2/3 Efficacy Evaluable Subjects: RCC IC Group Unknown Efficacy Evaluable Subjects: RCC IC0 Efficacy Evaluable Subjects: RCC IC1/2/3 Efficacy Evaluable Subjects: TNBC IC0/1 Efficacy Evaluable Subjects: TNBC IC2/3 Efficacy Evaluable Subjects: TNBC IC Group Unknown Efficacy Evaluable Subjects: TNBC IC0 Efficacy Evaluable Subjects: TNBC IC1/2/3 Efficacy Evaluable Subjects: Tumor Types <20 Subjects IC0/1 Efficacy Evaluable Subjects: Tumor Types <20 Subjects IC2/3 Efficacy Evaluable: Tumor Types <20 Subjects IC Group Unknown Efficacy Evaluable Subjects: Tumor Types <20 Subjects IC0 Efficacy Evaluable Subjects: Tumor Types <20 Subjects IC1/2/3
    Number of subjects analysed
    15
    5
    11
    9
    48
    22
    25
    18
    52
    25
    7
    25
    3
    29
    20
    18
    5
    16
    22
    59
    22
    8
    43
    38
    28
    53
    33
    2
    28
    5
    38
    25
    9
    22
    41
    38
    74
    4
    21
    91
    67
    68
    15
    45
    90
    Units: Subjects
    number (confidence interval 95%)
        Complete Response (CR)
    0 (0.00 to 21.80)
    0 (0.00 to 52.18)
    0 (0.00 to 28.49)
    0 (0.00 to 33.63)
    6.3 (1.31 to 17.20)
    18.2 (5.19 to 40.28)
    12.0 (2.55 to 31.22)
    5.6 (0.14 to 27.29)
    11.5 (4.35 to 23.44)
    12.0 (2.55 to 31.22)
    0 (0.00 to 40.96)
    0 (0.00 to 13.72)
    0 (0.00 to 70.76)
    0 (0.00 to 11.94)
    10.0 (1.23 to 31.70)
    11.1 (1.38 to 34.71)
    0 (0.00 to 52.18)
    0 (0.00 to 20.59)
    18.2 (5.19 to 40.28)
    1.7 (0.04 to 9.09)
    0 (0.00 to 15.44)
    0 (0.00 to 36.94)
    0 (0.00 to 8.22)
    2.6 (0.07 to 13.81)
    0 (0.00 to 12.34)
    1.9 (0.05 to 10.07)
    0 (0.00 to 14.25)
    0 (0.00 to 97.50)
    0 (0.00 to 17.65)
    0 (0.00 to 52.18)
    0 (0.00 to 9.25)
    4.0 (0.10 to 20.35)
    0 (0.00 to 33.63)
    0 (0.00 to 15.44)
    2.4 (0.06 to 12.86)
    0 (0.00 to 9.49)
    6.8 (2.23 to 15.07)
    0 (0.00 to 60.24)
    0 (0.00 to 16.84)
    5.5 (1.81 to 12.36)
    0 (0.00 to 5.60)
    1.5 (0.04 to 8.04)
    0 (0.00 to 33.63)
    0 (0.00 to 8.41)
    1.1 (0.03 to 6.10)
        Partial Response (PR)
    0 (0.00 to 21.80)
    0 (0.00 to 52.18)
    0 (0.00 to 28.49)
    0 (0.00 to 33.63)
    16.7 (7.48 to 30.22)
    18.2 (5.19 to 40.28)
    12.0 (2.55 to 31.22)
    11.1 (1.38 to 34.71)
    19.2 (9.63 to 32.53)
    12.0 (2.55 to 31.22)
    14.3 (0.36 to 57.87)
    24.0 (9.36 to 45.13)
    33.3 (0.84 to 90.57)
    20.7 (7.99 to 39.72)
    20.0 (5.73 to 43.66)
    22.2 (6.41 to 47.64)
    20.0 (0.51 to 71.64)
    18.8 (4.05 to 45.65)
    22.7 (7.82 to 45.37)
    13.6 (6.04 to 24.98)
    50.0 (28.22 to 71.78)
    0 (0.00 to 36.94)
    16.3 (6.81 to 30.70)
    31.6 (17.50 to 48.65)
    14.3 (4.03 to 32.67)
    28.3 (16.79 to 42.35)
    4.2 (0.11 to 21.12)
    0 (0.00 to 97.50)
    5.3 (0.13 to 26.03)
    0 (0.00 to 52.18)
    13.2 (4.41 to 28.09)
    12.0 (2.55 to 31.22)
    11.1 (0.28 to 48.25)
    9.1 (1.12 to 29.16)
    14.6 (5.57 to 29.17)
    5.4 (0.66 to 18.19)
    5.4 (1.49 to 13.27)
    0 (0.00 to 60.24)
    0 (0.00 to 16.84)
    6.6 (2.46 to 13.80)
    1.6 (0.04 to 8.40)
    6.0 (1.65 to 14.59)
    0 (0.00 to 33.63)
    0 (0.00 to 8.41)
    5.6 (1.85 to 12.63)
        Stable Disease (SD)
    26.7 (7.79 to 55.10)
    0 (0.00 to 52.18)
    18.2 (2.28 to 51.78)
    22.2 (2.81 to 60.01)
    18.8 (8.95 to 32.63)
    22.7 (7.82 to 45.37)
    16.0 (4.54 to 36.08)
    11.1 (1.38 to 34.71)
    23.1 (12.53 to 36.84)
    16.0 (4.54 to 36.08)
    42.9 (9.90 to 81.59)
    12.0 (2.55 to 31.22)
    33.3 (0.84 to 90.57)
    17.2 (5.85 to 35.77)
    0 (0.00 to 16.84)
    44.4 (21.53 to 69.24)
    60.0 (14.66 to 94.73)
    0 (0.00 to 20.59)
    36.4 (17.20 to 59.34)
    30.5 (19.19 to 43.87)
    9.1 (1.12 to 29.16)
    62.5 (24.49 to 91.48)
    32.6 (19.08 to 48.54)
    15.8 (6.02 to 31.25)
    42.9 (24.46 to 62.82)
    15.1 (6.75 to 27.59)
    25.0 (9.77 to 46.71)
    100 (2.50 to 100.00)
    21.1 (6.05 to 45.57)
    40.0 (5.27 to 85.34)
    47.4 (30.98 to 64.18)
    40.0 (21.13 to 61.33)
    66.7 (29.93 to 92.51)
    45.5 (24.39 to 67.79)
    43.9 (28.47 to 60.25)
    10.8 (3.03 to 25.42)
    13.5 (6.68 to 23.45)
    25.0 (0.63 to 80.59)
    15.0 (3.21 to 37.89)
    12.1 (6.19 to 20.60)
    14.1 (6.64 to 25.02)
    22.4 (13.11 to 34.22)
    0 (0.00 to 33.63)
    11.9 (3.98 to 25.63)
    21.3 (13.37 to 331.31)
        Progressive Disease (PD)
    60 (32.29 to 83.66)
    100 (47.82 to 100.00)
    72.7 (39.03 to 93.98)
    66.7 (29.93 to 92.51)
    47.9 (33.29 to 62.81)
    27.3 (10.73 to 50.22)
    52.0 (31.31 to 72.20)
    61.1 (35.75 to 82.70)
    34.6 (21.97 to 49.09)
    52.0 (31.31 to 72.20)
    28.6 (3.67 to 70.96)
    48.0 (27.80 to 68.69)
    33.3 (0.84 to 90.57)
    44.8 (26.45 to 64.31)
    65.0 (40.78 to 84.61)
    22.2 (6.41 to 47.64)
    20.0 (0.51 to 71.64)
    75.0 (47.62 to 92.73)
    22.7 (7.82 to 45.37)
    45.8 (32.72 to 59.25)
    40.9 (20.71 to 63.65)
    37.5 (8.52 to 75.51)
    44.2 (29.08 to 60.12)
    44.7 (28.62 to 61.70)
    35.7 (18.64 to 55.93)
    49.1 (35.06 to 63.16)
    62.5 (40.59 to 81.20)
    0 (0.00 to 97.50)
    68.4 (43.45 to 87.42)
    40.0 (5.27 to 85.34)
    31.6 (17.50 to 48.65)
    44.0 (24.40 to 65.07)
    22.2 (2.81 to 60.01)
    36.4 (17.20 to 59.34)
    36.6 (22.12 to 53.06)
    70.3 (53.02 to 84.13)
    60.8 (48.77 to 71.96)
    50.0 (6.76 to 93.24)
    80.0 (56.34 to 94.27)
    60.4 (49.64 to 70.54)
    53.1 (40.23 to 65.72)
    53.7 (41.12 to 66.00)
    77.8 (39.99 to 97.19)
    52.4 (36.42 to 68.00)
    53.9 (43.04 to 64.56)
        Missing or unevaluable
    13.3 (000000 to 888888)
    0 (000000 to 888888)
    9.1 (000000 to 888888)
    11.1 (000000 to 888888)
    10.4 (000000 to 888888)
    13.6 (000000 to 888888)
    8.0 (000000 to 888888)
    11.1 (000000 to 888888)
    11.5 (000000 to 888888)
    8.0 (000000 to 888888)
    14.3 (000000 to 888888)
    16.0 (000000 to 888888)
    0 (000000 to 888888)
    17.2 (000000 to 888888)
    5.0 (000000 to 888888)
    0 (000000 to 888888)
    0 (000000 to 888888)
    6.3 (000000 to 888888)
    0 (000000 to 888888)
    8.5 (000000 to 888888)
    0 (000000 to 888888)
    0 (000000 to 888888)
    7.0 (000000 to 888888)
    5.3 (000000 to 888888)
    7.1 (000000 to 888888)
    5.7 (000000 to 888888)
    8.3 (000000 to 888888)
    0 (000000 to 888888)
    5.3 (000000 to 888888)
    20.0 (000000 to 888888)
    7.9 (000000 to 888888)
    0 (000000 to 888888)
    0 (000000 to 888888)
    9.1 (000000 to 888888)
    2.4 (000000 to 888888)
    13.5 (000000 to 888888)
    13.5 (000000 to 888888)
    25.0 (000000 to 888888)
    5.0 (000000 to 888888)
    51.4 (000000 to 888888)
    31.3 (000000 to 888888)
    16.4 (000000 to 888888)
    22.2 (000000 to 888888)
    35.7 (000000 to 888888)
    18.0 (000000 to 888888)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD), Assessed by Immune-Related Response Criteria (irRC)

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    End point title
    		 Percentage of Subjects With Best Overall Response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD), Assessed by Immune-Related Response Criteria (irRC)
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to the first occurrence of progression or death, whichever occurs first (up to approx 7 yrs)
    End point values
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: Subjects
        number (confidence interval 95%)
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [13] - This outcome measure is not being evaluated.
    [14] - This outcome measure is not being evaluated.
    [15] - This outcome measure is not being evaluated.
    [16] - This outcome measure is not being evaluated.
    [17] - This outcome measure is not being evaluated.
    [18] - This outcome measure is not being evaluated.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Objective Response (Complete Response [CR] or Partial Response [PR]), Assessed by RECIST v1.1

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    End point title
    		 Number of Subjects With Objective Response (Complete Response [CR] or Partial Response [PR]), Assessed by RECIST v1.1
    End point description
    Objective Response (Complete Response [CR] or Partial Response [PR]) in efficacy evaluable population.
    End point type
    Secondary
    End point timeframe
    From Baseline up to the first occurrence of progression or death, whichever occurs first (up to approx 7 yrs)
    End point values
    		 Efficacy Evaluable Subjects: HR+Breast Cancer Efficacy Evaluable Subjects: BTCC Efficacy Evaluable Subjects: Head and Neck Cancer Efficacy evaluable subjects: Melanoma Efficacy evaluable subjects: Non-Small Cell Lung Cancer Efficacy Evaluable Subjects: Prostate Cancer Efficacy Evaluable Subjects: Renal Cell Carcinoma Efficacy Evaluable Subjects: Triple Negative Breast Cancer Efficacy Evaluable Subjects: Tumor Types Where <20 subjects
    Number of subjects analysed
    20
    95
    32
    43
    89
    25
    72
    115
    150
    Units: Subjects
    number (not applicable)
        Complete Response (CR)
    0
    10
    0
    4
    1
    0
    1
    5
    1
        Partial Response (PR)
    0
    15
    7
    9
    19
    1
    9
    6
    5
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response (CR or PR), Assessed by irRC

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    End point title
    		 Percentage of Participants With Objective Response (CR or PR), Assessed by irRC
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to the first occurrence of progression or death, whichever occurs first (up to approx 7 yrs)
    End point values
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    Units: Participants
        number (not applicable)
    Notes
    [19] - This outcome measure is not being evaluated.
    [20] - This outcome measure is not being evaluated.
    [21] - This outcome measure is not being evaluated.
    [22] - This outcome measure is not being evaluated.
    [23] - This outcome measure is not being evaluated.
    [24] - This outcome measure is not being evaluated.
    No statistical analyses for this end point

    Secondary: Duration of Objective Response, Assessed by RECIST v1.1

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    End point title
    		 Duration of Objective Response, Assessed by RECIST v1.1
    End point description
    Duration of objective response in efficacy evaluable population. Note: 999999= not available.
    End point type
    Secondary
    End point timeframe
    Time from the first occurrence of a documented objective response to the time of relapse or death from any cause (up to approx 7 yrs)
    End point values
    		 Efficacy Evaluable Subjects: HR+Breast Cancer Efficacy Evaluable Subjects: BTCC Efficacy Evaluable Subjects: Head and Neck Cancer Efficacy evaluable subjects: Melanoma Efficacy evaluable subjects: Non-Small Cell Lung Cancer Efficacy Evaluable Subjects: Prostate Cancer Efficacy Evaluable Subjects: Renal Cell Carcinoma Efficacy Evaluable Subjects: Triple Negative Breast Cancer Efficacy Evaluable Subjects: Tumor Types Where <20 subjects
    Number of subjects analysed
    20
    95
    32
    43
    89
    25
    72
    115
    150
    Units: Months
        number (not applicable)
    999999
    22.11
    7.36
    62.39
    16.38
    7.23
    13.09
    21.06
    7.69
    No statistical analyses for this end point

    Secondary: Duration of Objective Response, Assessed by irRC

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    End point title
    		 Duration of Objective Response, Assessed by irRC
    End point description
    End point type
    Secondary
    End point timeframe
    Time from the first occurrence of a documented objective response to the time of relapse or death from any cause (up to approx 7 yrs)
    End point values
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Number of subjects analysed
    0 [25]
    0 [26]
    0 [27]
    0 [28]
    0 [29]
    0 [30]
    Units: Months
        number (not applicable)
    Notes
    [25] - This outcome measure is not being evaluated.
    [26] - This outcome measure is not being evaluated.
    [27] - This outcome measure is not being evaluated.
    [28] - This outcome measure is not being evaluated.
    [29] - This outcome measure is not being evaluated.
    [30] - This outcome measure is not being evaluated.
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS), Assessed by RECIST v1.1

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    End point title
    		 Progression-Free Survival (PFS), Assessed by RECIST v1.1
    End point description
    Progression-free survival in efficacy evaluable population.
    End point type
    Secondary
    End point timeframe
    From Baseline up to the first occurrence of progression or death, whichever occurs first (up to approx 7 yrs)
    End point values
    		 Efficacy Evaluable Subjects: HR+Breast Cancer Efficacy Evaluable Subjects: BTCC Efficacy Evaluable Subjects: Head and Neck Cancer Efficacy evaluable subjects: Melanoma Efficacy evaluable subjects: Non-Small Cell Lung Cancer Efficacy Evaluable Subjects: Prostate Cancer Efficacy Evaluable Subjects: Renal Cell Carcinoma Efficacy Evaluable Subjects: Triple Negative Breast Cancer Efficacy Evaluable Subjects: Tumor Types Where <20 subjects
    Number of subjects analysed
    20
    95
    32
    43
    89
    25
    72
    115
    150
    Units: Months
        number (not applicable)
    1.40
    2.66
    2.64
    4.17
    3.02
    3.14
    5.39
    1.40
    2.50
    No statistical analyses for this end point

    Secondary: PFS, Assessed by irRC

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    End point title
    		 PFS, Assessed by irRC
    End point description
    End point type
    Secondary
    End point timeframe
    From Baseline up to the first occurrence of progression or death, whichever occurs first (up to approx 7 yrs)
    End point values
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Number of subjects analysed
    0 [31]
    0 [32]
    0 [33]
    0 [34]
    0 [35]
    0 [36]
    Units: Months
        number (not applicable)
    Notes
    [31] - This outcome measure is not being evaluated.
    [32] - This outcome measure is not being evaluated.
    [33] - This outcome measure is not being evaluated.
    [34] - This outcome measure is not being evaluated.
    [35] - This outcome measure is not being evaluated.
    [36] - This outcome measure is not being evaluated.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug administration to the data cutoff date: 30 September 2018.
    Adverse event reporting additional description
    Includes safety evaluable population, defined as all enrolled patients who received any amount of atezolizumab on study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Dose Escalation Cohort: Atezolizumab <=1 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab <=1 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurred first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 3 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 3 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurred first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 10 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 10 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurred first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 15 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 15 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurred first.

    Reporting group title
    Dose Escalation Cohort: Atezolizumab 20 mg/kg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 20 mg/kg q3w until DLT was reached or up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurred first.

    Reporting group title
    Expansion Cohort: Atezolizumab 1200 mg
    Reporting group description
    		 Subjects received IV infusion of atezolizumab 1200 mg q3w up to end of study or treatment discontinuation or death or until initiation of another anti cancer therapy, whichever occurred first.

    Serious adverse events
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    20 / 36 (55.56%)
    115 / 236 (48.73%)
    65 / 146 (44.52%)
    103 / 228 (45.18%)
         number of deaths (all causes)
    1
    0
    13
    85
    39
    181
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    3 / 236 (1.27%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular compression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    5 / 236 (2.12%)
    3 / 146 (2.05%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    2 / 5
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    3 / 236 (1.27%)
    3 / 146 (2.05%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    9 / 236 (3.81%)
    4 / 146 (2.74%)
    6 / 228 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    7 / 9
    2 / 4
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast necrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Female genital tract fistula
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    7 / 236 (2.97%)
    9 / 146 (6.16%)
    8 / 228 (3.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 7
    3 / 13
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    4 / 236 (1.69%)
    4 / 146 (2.74%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    2 / 4
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    4 / 146 (2.74%)
    5 / 228 (2.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    2 / 146 (1.37%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    2 / 236 (0.85%)
    2 / 146 (1.37%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    5 / 228 (2.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alphavirus test positive
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urostomy complication
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Arrhythmia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    2 / 146 (1.37%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial mass
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vith nerve disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    4 / 236 (1.69%)
    2 / 146 (1.37%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 4
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    4 / 236 (1.69%)
    4 / 146 (2.74%)
    4 / 228 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    1 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune colitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    3 / 228 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder rupture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hepatic haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    4 / 236 (1.69%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    4 / 236 (1.69%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retenion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hypothyroidism
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    3 / 228 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    5 / 236 (2.12%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    3 / 146 (2.05%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    3 / 228 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    5 / 236 (2.12%)
    0 / 146 (0.00%)
    4 / 228 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 5
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Erysipelas
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Necrotising ulcerative gingivostomatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    4 / 236 (1.69%)
    2 / 146 (1.37%)
    3 / 228 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    1 / 4
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    4 / 236 (1.69%)
    0 / 146 (0.00%)
    4 / 228 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 6
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    6 / 236 (2.54%)
    1 / 146 (0.68%)
    5 / 228 (2.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 6
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    3 / 236 (1.27%)
    1 / 146 (0.68%)
    6 / 228 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    4 / 228 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumor lysis syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dose Escalation Cohort: Atezolizumab <=1 mg/kg Dose Escalation Cohort: Atezolizumab 3 mg/kg Dose Escalation Cohort: Atezolizumab 10 mg/kg Dose Escalation Cohort: Atezolizumab 15 mg/kg Dose Escalation Cohort: Atezolizumab 20 mg/kg Expansion Cohort: Atezolizumab 1200 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    3 / 3 (100.00%)
    35 / 36 (97.22%)
    219 / 236 (92.80%)
    143 / 146 (97.95%)
    207 / 228 (90.79%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    Malignant melanoma
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Melanocytic naevus
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    4 / 236 (1.69%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    1
    5
    0
    0
    Skin papilloma
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    4 / 236 (1.69%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    0
    4
    0
    1
    Tumour necrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Tumour pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    4 / 236 (1.69%)
    10 / 146 (6.85%)
    1 / 228 (0.44%)
         occurrences all number
    0
    0
    0
    6
    10
    1
    Tumour ulceration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    4 / 236 (1.69%)
    3 / 146 (2.05%)
    1 / 228 (0.44%)
         occurrences all number
    2
    0
    1
    4
    3
    1
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    11 / 236 (4.66%)
    6 / 146 (4.11%)
    11 / 228 (4.82%)
         occurrences all number
    0
    2
    1
    12
    8
    16
    Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    10 / 236 (4.24%)
    8 / 146 (5.48%)
    4 / 228 (1.75%)
         occurrences all number
    0
    0
    0
    10
    8
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    47 / 236 (19.92%)
    28 / 146 (19.18%)
    27 / 228 (11.84%)
         occurrences all number
    1
    0
    2
    72
    62
    40
    Chest discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    4 / 236 (1.69%)
    3 / 146 (2.05%)
    1 / 228 (0.44%)
         occurrences all number
    2
    0
    5
    4
    4
    1
    Chills
         subjects affected / exposed
    4 / 9 (44.44%)
    3 / 3 (100.00%)
    5 / 36 (13.89%)
    26 / 236 (11.02%)
    19 / 146 (13.01%)
    11 / 228 (4.82%)
         occurrences all number
    6
    3
    10
    27
    22
    12
    Fatigue
         subjects affected / exposed
    7 / 9 (77.78%)
    3 / 3 (100.00%)
    18 / 36 (50.00%)
    98 / 236 (41.53%)
    56 / 146 (38.36%)
    88 / 228 (38.60%)
         occurrences all number
    17
    3
    35
    151
    78
    122
    Hernia pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    6 / 36 (16.67%)
    13 / 236 (5.51%)
    18 / 146 (12.33%)
    11 / 228 (4.82%)
         occurrences all number
    0
    0
    9
    19
    22
    12
    Mucosal Inflammation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    7 / 236 (2.97%)
    4 / 146 (2.74%)
    1 / 228 (0.44%)
         occurrences all number
    0
    0
    2
    9
    5
    1
    Nodule
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    1 / 236 (0.42%)
    5 / 146 (3.42%)
    2 / 228 (0.88%)
         occurrences all number
    3
    0
    2
    1
    5
    2
    Oedema peripheral
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    9 / 36 (25.00%)
    32 / 236 (13.56%)
    20 / 146 (13.70%)
    20 / 228 (8.77%)
         occurrences all number
    3
    1
    12
    44
    23
    26
    Pain
         subjects affected / exposed
    4 / 9 (44.44%)
    1 / 3 (33.33%)
    4 / 36 (11.11%)
    20 / 236 (8.47%)
    13 / 146 (8.90%)
    13 / 228 (5.70%)
         occurrences all number
    5
    1
    4
    22
    14
    15
    Pyrexia
         subjects affected / exposed
    4 / 9 (44.44%)
    3 / 3 (100.00%)
    9 / 36 (25.00%)
    54 / 236 (22.88%)
    31 / 146 (21.23%)
    34 / 228 (14.91%)
         occurrences all number
    6
    3
    16
    79
    43
    40
    Temperature intolerance
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    5 / 36 (13.89%)
    7 / 236 (2.97%)
    7 / 146 (4.79%)
    14 / 228 (6.14%)
         occurrences all number
    1
    0
    6
    8
    10
    16
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    2 / 146 (1.37%)
    2 / 228 (0.88%)
         occurrences all number
    0
    1
    0
    1
    2
    3
    Breast tenderness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vaginal mucosal blistering
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    3 / 9 (33.33%)
    3 / 3 (100.00%)
    9 / 36 (25.00%)
    63 / 236 (26.69%)
    34 / 146 (23.29%)
    30 / 228 (13.16%)
         occurrences all number
    3
    5
    14
    78
    44
    40
    Dyspnoea
         subjects affected / exposed
    4 / 9 (44.44%)
    1 / 3 (33.33%)
    13 / 36 (36.11%)
    36 / 236 (15.25%)
    42 / 146 (28.77%)
    35 / 228 (15.35%)
         occurrences all number
    7
    1
    25
    47
    59
    44
    Dyspnoea exertional
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    4 / 36 (11.11%)
    9 / 236 (3.81%)
    6 / 146 (4.11%)
    14 / 228 (6.14%)
         occurrences all number
    0
    1
    4
    9
    6
    14
    Nasal congestion
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 3 (66.67%)
    4 / 36 (11.11%)
    15 / 236 (6.36%)
    12 / 146 (8.22%)
    4 / 228 (1.75%)
         occurrences all number
    2
    2
    7
    17
    13
    4
    Oropharyngeal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    7 / 36 (19.44%)
    12 / 236 (5.08%)
    11 / 146 (7.53%)
    10 / 228 (4.39%)
         occurrences all number
    1
    0
    7
    12
    15
    11
    Pleural effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    5 / 236 (2.12%)
    2 / 146 (1.37%)
    11 / 228 (4.82%)
         occurrences all number
    0
    0
    2
    6
    2
    11
    Pneumonitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    3 / 236 (1.27%)
    5 / 146 (3.42%)
    2 / 228 (0.88%)
         occurrences all number
    0
    1
    1
    3
    5
    2
    Productive cough
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    5 / 36 (13.89%)
    9 / 236 (3.81%)
    14 / 146 (9.59%)
    5 / 228 (2.19%)
         occurrences all number
    2
    0
    9
    11
    19
    5
    Pulmonary embolism
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    4 / 236 (1.69%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences all number
    0
    0
    4
    5
    1
    1
    Sinus congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    5 / 36 (13.89%)
    3 / 236 (1.27%)
    2 / 146 (1.37%)
    2 / 228 (0.88%)
         occurrences all number
    0
    0
    5
    3
    3
    2
    Sinus disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Upper airway cough syndrome
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    4 / 36 (11.11%)
    7 / 236 (2.97%)
    4 / 146 (2.74%)
    4 / 228 (1.75%)
         occurrences all number
    1
    0
    6
    7
    4
    4
    Wheezing
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    3 / 36 (8.33%)
    7 / 236 (2.97%)
    5 / 146 (3.42%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    5
    8
    6
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    6 / 36 (16.67%)
    18 / 236 (7.63%)
    12 / 146 (8.22%)
    8 / 228 (3.51%)
         occurrences all number
    6
    1
    7
    19
    12
    9
    Confusional state
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    5 / 236 (2.12%)
    4 / 146 (2.74%)
    7 / 228 (3.07%)
         occurrences all number
    0
    0
    2
    5
    4
    7
    Depression
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    18 / 236 (7.63%)
    11 / 146 (7.53%)
    8 / 228 (3.51%)
         occurrences all number
    0
    0
    3
    19
    12
    8
    Insomnia
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    11 / 36 (30.56%)
    28 / 236 (11.86%)
    21 / 146 (14.38%)
    13 / 228 (5.70%)
         occurrences all number
    2
    1
    12
    30
    21
    14
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    0 / 236 (0.00%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    15 / 236 (6.36%)
    10 / 146 (6.85%)
    22 / 228 (9.65%)
         occurrences all number
    0
    0
    1
    20
    13
    28
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    21 / 236 (8.90%)
    10 / 146 (6.85%)
    23 / 228 (10.09%)
         occurrences all number
    0
    0
    1
    29
    12
    30
    Bleeding time prolonged
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    15 / 236 (6.36%)
    3 / 146 (2.05%)
    19 / 228 (8.33%)
         occurrences all number
    0
    0
    0
    21
    4
    22
    Blood creatinine increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    22 / 236 (9.32%)
    3 / 146 (2.05%)
    8 / 228 (3.51%)
         occurrences all number
    1
    0
    1
    30
    4
    9
    Body temperature increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    4 / 236 (1.69%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences all number
    0
    0
    2
    7
    1
    2
    Platelet count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    3 / 236 (1.27%)
    1 / 146 (0.68%)
    3 / 228 (1.32%)
         occurrences all number
    0
    0
    3
    4
    1
    3
    Weight decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    17 / 236 (7.20%)
    15 / 146 (10.27%)
    17 / 228 (7.46%)
         occurrences all number
    0
    0
    3
    20
    19
    21
    Weight increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    3 / 146 (2.05%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    0
    2
    4
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    2 / 228 (0.88%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    4 / 236 (1.69%)
    8 / 146 (5.48%)
    1 / 228 (0.44%)
         occurrences all number
    0
    0
    3
    5
    12
    1
    Muscle strain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    0
    2
    1
    1
    Splinter
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    1 / 236 (0.42%)
    3 / 146 (2.05%)
    3 / 228 (1.32%)
         occurrences all number
    0
    0
    3
    1
    3
    3
    Tendon rupture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Wound complication
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences all number
    2
    0
    2
    2
    1
    1
    Palpitations
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    3 / 236 (1.27%)
    3 / 146 (2.05%)
    0 / 228 (0.00%)
         occurrences all number
    2
    0
    3
    3
    3
    0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    3 / 228 (1.32%)
         occurrences all number
    0
    0
    2
    1
    1
    3
    Tachycardia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    5 / 236 (2.12%)
    2 / 146 (1.37%)
    4 / 228 (1.75%)
         occurrences all number
    1
    0
    2
    5
    2
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    9 / 36 (25.00%)
    24 / 236 (10.17%)
    20 / 146 (13.70%)
    20 / 228 (8.77%)
         occurrences all number
    3
    1
    11
    29
    20
    24
    Dysgeusia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    9 / 236 (3.81%)
    7 / 146 (4.79%)
    3 / 228 (1.32%)
         occurrences all number
    4
    0
    2
    9
    7
    3
    Headache
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 3 (33.33%)
    14 / 36 (38.89%)
    36 / 236 (15.25%)
    30 / 146 (20.55%)
    32 / 228 (14.04%)
         occurrences all number
    4
    2
    24
    47
    41
    36
    Hypoesthesia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    6 / 236 (2.54%)
    5 / 146 (3.42%)
    2 / 228 (0.88%)
         occurrences all number
    2
    0
    3
    6
    6
    3
    Neuropathy peripheral
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    14 / 236 (5.93%)
    6 / 146 (4.11%)
    9 / 228 (3.95%)
         occurrences all number
    1
    0
    1
    15
    6
    10
    Paraesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    4 / 36 (11.11%)
    6 / 236 (2.54%)
    3 / 146 (2.05%)
    4 / 228 (1.75%)
         occurrences all number
    0
    0
    4
    6
    3
    4
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences all number
    0
    0
    2
    2
    2
    2
    Sciatica
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    4 / 146 (2.74%)
    2 / 228 (0.88%)
         occurrences all number
    1
    0
    0
    0
    5
    2
    Tremor
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    2 / 236 (0.85%)
    3 / 146 (2.05%)
    0 / 228 (0.00%)
         occurrences all number
    0
    0
    3
    2
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    6 / 36 (16.67%)
    58 / 236 (24.58%)
    28 / 146 (19.18%)
    42 / 228 (18.42%)
         occurrences all number
    2
    0
    20
    80
    38
    62
    Anaemia Macrocytic
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    3 / 146 (2.05%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    1
    1
    3
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    8 / 236 (3.39%)
    2 / 146 (1.37%)
    12 / 228 (5.26%)
         occurrences all number
    0
    0
    1
    16
    2
    14
    Ear and labyrinth disorders
    Ear Congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ear Discomfort
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    5 / 236 (2.12%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences all number
    1
    0
    0
    5
    1
    1
    Ear Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    4 / 236 (1.69%)
    2 / 146 (1.37%)
    1 / 228 (0.44%)
         occurrences all number
    0
    0
    2
    4
    2
    1
    Vertigo
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    5 / 236 (2.12%)
    2 / 146 (1.37%)
    2 / 228 (0.88%)
         occurrences all number
    0
    1
    1
    5
    2
    2
    Eye disorders
    Altered visual depth perception
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye Pruritus
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    2
    1
    1
    2
    1
    0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    5 / 236 (2.12%)
    7 / 146 (4.79%)
    7 / 228 (3.07%)
         occurrences all number
    0
    0
    3
    5
    7
    7
    Vitreous floaters
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    1 / 236 (0.42%)
    2 / 146 (1.37%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    3
    1
    2
    0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 3 (0.00%)
    8 / 36 (22.22%)
    33 / 236 (13.98%)
    16 / 146 (10.96%)
    13 / 228 (5.70%)
         occurrences all number
    3
    0
    9
    47
    19
    18
    Abdominal pain upper
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    4 / 36 (11.11%)
    11 / 236 (4.66%)
    12 / 146 (8.22%)
    7 / 228 (3.07%)
         occurrences all number
    2
    0
    4
    13
    16
    7
    Constipation
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    9 / 36 (25.00%)
    59 / 236 (25.00%)
    35 / 146 (23.97%)
    43 / 228 (18.86%)
         occurrences all number
    3
    1
    11
    81
    39
    52
    Diarrhoea
         subjects affected / exposed
    5 / 9 (55.56%)
    0 / 3 (0.00%)
    18 / 36 (50.00%)
    53 / 236 (22.46%)
    31 / 146 (21.23%)
    43 / 228 (18.86%)
         occurrences all number
    12
    0
    36
    92
    63
    56
    Dry mouth
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    9 / 236 (3.81%)
    11 / 146 (7.53%)
    8 / 228 (3.51%)
         occurrences all number
    1
    0
    1
    9
    11
    8
    Dyspepsia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    6 / 236 (2.54%)
    5 / 146 (3.42%)
    5 / 228 (2.19%)
         occurrences all number
    1
    0
    2
    7
    7
    5
    Dysphagia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    15 / 236 (6.36%)
    8 / 146 (5.48%)
    3 / 228 (1.32%)
         occurrences all number
    1
    0
    2
    18
    8
    3
    Frequent bowl movements
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    2 / 36 (5.56%)
    6 / 236 (2.54%)
    8 / 146 (5.48%)
    7 / 228 (3.07%)
         occurrences all number
    3
    1
    3
    6
    8
    7
    Haemorrhoids
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    1 / 236 (0.42%)
    6 / 146 (4.11%)
    1 / 228 (0.44%)
         occurrences all number
    0
    0
    2
    1
    6
    1
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Loose tooth
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    7 / 9 (77.78%)
    2 / 3 (66.67%)
    10 / 36 (27.78%)
    63 / 236 (26.69%)
    47 / 146 (32.19%)
    63 / 228 (27.63%)
         occurrences all number
    9
    2
    17
    94
    70
    72
    Oesophagitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    Oral pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    3 / 236 (1.27%)
    2 / 146 (1.37%)
    3 / 228 (1.32%)
         occurrences all number
    1
    0
    0
    3
    2
    4
    Rectal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    2 / 228 (0.88%)
         occurrences all number
    0
    0
    3
    2
    1
    2
    Retching
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    Stomatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    7 / 236 (2.97%)
    3 / 146 (2.05%)
    1 / 228 (0.44%)
         occurrences all number
    2
    0
    0
    7
    3
    1
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    5 / 146 (3.42%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    0
    2
    6
    1
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    7 / 36 (19.44%)
    44 / 236 (18.64%)
    35 / 146 (23.97%)
    45 / 228 (19.74%)
         occurrences all number
    2
    1
    8
    56
    45
    49
    Salvary gland enlargement
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    3 / 236 (1.27%)
    5 / 146 (3.42%)
    2 / 228 (0.88%)
         occurrences all number
    0
    0
    3
    3
    5
    2
    Dry skin
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    2 / 36 (5.56%)
    25 / 236 (10.59%)
    9 / 146 (6.16%)
    6 / 228 (2.63%)
         occurrences all number
    1
    1
    3
    30
    9
    6
    Erythema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    2 / 36 (5.56%)
    8 / 236 (3.39%)
    5 / 146 (3.42%)
    3 / 228 (1.32%)
         occurrences all number
    0
    2
    2
    11
    5
    3
    Hyperhidrosis
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    3 / 236 (1.27%)
    5 / 146 (3.42%)
    10 / 228 (4.39%)
         occurrences all number
    4
    0
    2
    3
    6
    11
    Hyperkeratosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    Madarosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 3 (100.00%)
    3 / 36 (8.33%)
    13 / 236 (5.51%)
    8 / 146 (5.48%)
    7 / 228 (3.07%)
         occurrences all number
    3
    3
    3
    15
    8
    8
    Pruritus
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    10 / 36 (27.78%)
    41 / 236 (17.37%)
    15 / 146 (10.27%)
    28 / 228 (12.28%)
         occurrences all number
    2
    1
    17
    50
    30
    31
    Pruritus generalised
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    3 / 236 (1.27%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences all number
    1
    0
    0
    3
    0
    1
    Psoriasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    3 / 236 (1.27%)
    0 / 146 (0.00%)
    1 / 228 (0.44%)
         occurrences all number
    0
    1
    1
    4
    0
    1
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 3 (66.67%)
    9 / 36 (25.00%)
    35 / 236 (14.83%)
    25 / 146 (17.12%)
    18 / 228 (7.89%)
         occurrences all number
    2
    2
    12
    46
    38
    22
    Rash maculo-papular
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    4 / 36 (11.11%)
    10 / 236 (4.24%)
    3 / 146 (2.05%)
    2 / 228 (0.88%)
         occurrences all number
    1
    2
    5
    12
    4
    2
    Rash pruritic
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    2 / 236 (0.85%)
    2 / 146 (1.37%)
    1 / 228 (0.44%)
         occurrences all number
    1
    0
    2
    3
    2
    1
    Rash vesicular
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Transient acantholytic dermatosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Vitiligo
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    1
    2
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 3 (66.67%)
    3 / 36 (8.33%)
    12 / 236 (5.08%)
    4 / 146 (2.74%)
    3 / 228 (1.32%)
         occurrences all number
    0
    2
    3
    14
    5
    4
    Nocturia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    4 / 236 (1.69%)
    3 / 146 (2.05%)
    1 / 228 (0.44%)
         occurrences all number
    1
    0
    1
    4
    3
    1
    Pollakiuria
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    4 / 36 (11.11%)
    9 / 236 (3.81%)
    4 / 146 (2.74%)
    1 / 228 (0.44%)
         occurrences all number
    2
    0
    4
    9
    5
    1
    Proteinuria
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    6 / 236 (2.54%)
    2 / 146 (1.37%)
    3 / 228 (1.32%)
         occurrences all number
    0
    1
    1
    11
    2
    5
    Urethral obstruction
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    4 / 36 (11.11%)
    11 / 236 (4.66%)
    6 / 146 (4.11%)
    10 / 228 (4.39%)
         occurrences all number
    0
    0
    4
    12
    6
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 3 (33.33%)
    10 / 36 (27.78%)
    44 / 236 (18.64%)
    27 / 146 (18.49%)
    21 / 228 (9.21%)
         occurrences all number
    4
    2
    18
    71
    35
    29
    Arthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    3 / 236 (1.27%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    0
    0
    3
    3
    1
    0
    Back pain
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    10 / 36 (27.78%)
    45 / 236 (19.07%)
    29 / 146 (19.86%)
    26 / 228 (11.40%)
         occurrences all number
    2
    1
    12
    53
    38
    29
    Bone pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    5 / 236 (2.12%)
    4 / 146 (2.74%)
    4 / 228 (1.75%)
         occurrences all number
    0
    0
    2
    6
    4
    5
    Chrondrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    10 / 236 (4.24%)
    8 / 146 (5.48%)
    4 / 228 (1.75%)
         occurrences all number
    2
    0
    6
    10
    8
    4
    Joint swelling
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    2
    0
    0
    3
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    14 / 236 (5.93%)
    7 / 146 (4.79%)
    3 / 228 (1.32%)
         occurrences all number
    1
    0
    3
    17
    8
    3
    Muscular weakness
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    4 / 36 (11.11%)
    14 / 236 (5.93%)
    7 / 146 (4.79%)
    6 / 228 (2.63%)
         occurrences all number
    1
    0
    6
    17
    9
    7
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    4 / 36 (11.11%)
    7 / 236 (2.97%)
    6 / 146 (4.11%)
    11 / 228 (4.82%)
         occurrences all number
    1
    1
    5
    14
    7
    13
    Musculoskeletal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    8 / 36 (22.22%)
    14 / 236 (5.93%)
    19 / 146 (13.01%)
    16 / 228 (7.02%)
         occurrences all number
    0
    0
    11
    15
    23
    18
    Myalgia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    20 / 236 (8.47%)
    11 / 146 (7.53%)
    13 / 228 (5.70%)
         occurrences all number
    4
    0
    4
    24
    12
    13
    Neck pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    4 / 36 (11.11%)
    18 / 236 (7.63%)
    9 / 146 (6.16%)
    9 / 228 (3.95%)
         occurrences all number
    0
    0
    4
    19
    10
    10
    Osteoarthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    2 / 236 (0.85%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 9 (33.33%)
    0 / 3 (0.00%)
    6 / 36 (16.67%)
    20 / 236 (8.47%)
    13 / 146 (8.90%)
    10 / 228 (4.39%)
         occurrences all number
    5
    0
    7
    26
    21
    12
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    10 / 236 (4.24%)
    2 / 146 (1.37%)
    5 / 228 (2.19%)
         occurrences all number
    2
    2
    1
    13
    2
    7
    Candida infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    2 / 236 (0.85%)
    3 / 146 (2.05%)
    3 / 228 (1.32%)
         occurrences all number
    0
    0
    3
    2
    3
    3
    Ear infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    Fungal infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    2 / 236 (0.85%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    2
    0
    2
    2
    1
    0
    Herpes Zoster
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    7 / 236 (2.97%)
    1 / 146 (0.68%)
    0 / 228 (0.00%)
         occurrences all number
    1
    1
    0
    7
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 36 (2.78%)
    1 / 236 (0.42%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    Lung infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 36 (8.33%)
    0 / 236 (0.00%)
    2 / 146 (1.37%)
    1 / 228 (0.44%)
         occurrences all number
    0
    0
    3
    0
    2
    1
    Nail bed infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    0 / 146 (0.00%)
    0 / 228 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    12 / 236 (5.08%)
    8 / 146 (5.48%)
    4 / 228 (1.75%)
         occurrences all number
    0
    0
    1
    16
    10
    4
    Pneumonia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    3 / 236 (1.27%)
    6 / 146 (4.11%)
    4 / 228 (1.75%)
         occurrences all number
    0
    1
    0
    4
    6
    4
    Sinusitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    9 / 236 (3.81%)
    9 / 146 (6.16%)
    1 / 228 (0.44%)
         occurrences all number
    1
    0
    2
    12
    11
    1
    Tooth abscess
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    5 / 236 (2.12%)
    1 / 146 (0.68%)
    1 / 228 (0.44%)
         occurrences all number
    1
    0
    1
    5
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 9 (33.33%)
    2 / 3 (66.67%)
    6 / 36 (16.67%)
    27 / 236 (11.44%)
    23 / 146 (15.75%)
    14 / 228 (6.14%)
         occurrences all number
    8
    4
    6
    37
    31
    19
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    4 / 36 (11.11%)
    31 / 236 (13.14%)
    13 / 146 (8.90%)
    13 / 228 (5.70%)
         occurrences all number
    0
    0
    7
    42
    20
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 3 (33.33%)
    10 / 36 (27.78%)
    69 / 236 (29.24%)
    43 / 146 (29.45%)
    54 / 228 (23.68%)
         occurrences all number
    3
    1
    13
    92
    58
    66
    Dehydration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    5 / 36 (13.89%)
    16 / 236 (6.78%)
    15 / 146 (10.27%)
    13 / 228 (5.70%)
         occurrences all number
    0
    0
    6
    17
    29
    15
    Hypercalcaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 36 (0.00%)
    12 / 236 (5.08%)
    1 / 146 (0.68%)
    4 / 228 (1.75%)
         occurrences all number
    0
    0
    0
    15
    2
    6
    Hyperglycaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    6 / 36 (16.67%)
    8 / 236 (3.39%)
    7 / 146 (4.79%)
    6 / 228 (2.63%)
         occurrences all number
    0
    1
    12
    15
    12
    7
    Hyperkalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    9 / 236 (3.81%)
    4 / 146 (2.74%)
    14 / 228 (6.14%)
         occurrences all number
    0
    0
    3
    12
    4
    20
    Hyperuricaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 36 (0.00%)
    0 / 236 (0.00%)
    3 / 146 (2.05%)
    0 / 228 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 36 (5.56%)
    9 / 236 (3.81%)
    4 / 146 (2.74%)
    14 / 228 (6.14%)
         occurrences all number
    0
    0
    3
    12
    4
    20
    Hypomagnesaemia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    1 / 36 (2.78%)
    11 / 236 (4.66%)
    5 / 146 (3.42%)
    12 / 228 (5.26%)
         occurrences all number
    2
    0
    7
    15
    5
    13
    Hyponatraemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    2 / 36 (5.56%)
    15 / 236 (6.36%)
    6 / 146 (4.11%)
    18 / 228 (7.89%)
         occurrences all number
    0
    4
    3
    16
    8
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2012
    Protocol was amended to include a broader patient population in expansion cohorts to better characterize the safety, tolerability, PD variability, and preliminary efficacy of single agent atezolizumab in different disease areas.
    18 May 2012
    Protocol was amended to include patients with other tumor types (e.g., head and neck cancer, esophageal cancer, gastric cancer, CRC, malignant lymphoma, or multiple myeloma) to further understand the indication-specific safety, immunogenicity, and pharmacodynamics of aPD-L1. Disease specific eligibility criteria, response assessments, and response criteria to evaluate anti-tumor activity in patients with malignant lymphoma or multiple myeloma were added. Exclusion criteria was modified to allow low risk patients with oligometastatic brain metastasis to participate in the trial, in order to understand the safety and antitumor activity of atezolizumab in patients with brain lesions. Eligibility criteria for a potential predictive biomarker dose expansion cohort (i.e., PD-L1 IHC selection criteria) was added, in order to identify patients who may derive more benefit from treatment with atezolizumab.
    28 Nov 2012
    Protocol was amended to include patients with other tumor types (e.g., pancreatic cancer, bladder cancer, sarcoma, acute myeloid leukemia, prostate, etc.) to further understand the indication-specific safety, immunogenicity, and pharmacodynamics of aPD-L1. Disease-specific eligibility criteria, response assessments, and response criteria to properly evaluate patients with acute myeloid leukemia (AML) were added. Up to 16 cycles of additional treatment for patients who remained in PR or CR at the end of initial treatment but who later relapsed within 2 years after the end of Cycle 16 was added. Clarification was added to the exclusion criteria regarding patients with risk of pulmonary toxicity; patients with pneumonitis (including drug-induced pneumonitis) or organizing pneumonia were added to the exclusion list, whereas patients with a history of radiation pneumonitis in the radiation field (fibrosis) were permitted. Revision of the exclusion criteria were made to exclude patients with secondary malignancy except for patients with non-melanoma skin cancer, carcinoma in situ of the cervix, or other malignancy from which the patient has been disease free for at least 5 years.
    16 Aug 2013
    Protocol was amended to update inclusion/exclusion criteria to exclude patients who may have been eligible for potentially curative therapies. Indication AML was removed; to better evaluate the safety of atezolizumab in patients with AML a separate first-in-human study was needed. Criteria for treatment with atezolizumab beyond progression was modified, to clearly define the minimal criteria that must be met by a patient with documented progressive disease. Dose and schedule of study treatment administered during the re-treatment stage as 15 mg/kg administered by IV infusion q3w was confirmed, regardless of which dose level the patients received during the initial treatment stage. Exclusion criteria was revised regarding autoimmune disease to allow patients with controlled Type 1 diabetes mellitus on a stable insulin regimen to enroll in the study.
    30 Apr 2014
    Protocol was amended with the addition of OS as an exploratory endpoint. Formulation and dosing of atezolizumab was updated with Phase III formulation and fixed dosing of 1200 mg. Treatment duration of atezolizumab was updated so that patients can receive atezolizumab treatment for as long as they continue to experience clinical benefit.
    27 Jun 2014
    Protocol was amended to include addition of patients with GBM, HCC, prostate cancer, and endometrial cancer to the tumor types for enrollment in the dose-expansion cohorts. Total number of patients for enrollment in the expansion cohort was updated from 295 patients to 495 patients; the total number of patients to be enrolled in the trial was revised from 456-489 patients to 656-689 patients. Mandatory tumor biopsy was added - if clinically feasible - at the first evidence of early radiographic disease progression, in order to characterize the kinetics and biological basis of the potential anti-tumor activity of atezolizumab. Inclusion criteria was revised to allow patients with certain autoimmune disease with dermatologic manifestations only, to be considered for enrollment if they meet the requirements specified in the protocol.
    28 Oct 2015
    Protocol was amended to include replacement of MPDL3280A (name of test product) with the approved international nonproprietary name, atezolizumab. Systemic immune activation (SIA) was identified as a potential risk of atezolizumab when given in combination with other immunomodulating agents. Management recommendations for early identification and management of SIA were included.
    01 Dec 2016
    Protocol was amended to include t1/2 of atezolizumab was updated to 27 days based upon clinical data, resulting in a change in the period during which female patients must remain abstinent or use contraception and the length of follow-up of pregnancy reporting from 90 days to 5 months after the last dose of atezolizumab and a change in the period during which patients must agree not to receive live, attenuated vaccine from 90 days to 5 months after the last dose of atezolizumab.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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