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    Clinical Trial Results:
    A multicenter, randomized, double-blind Phase III trial to evaluate efficacy and safety of BI 695502 plus chemotherapy versus Avastin® plus chemotherapy in patients with advanced nonsquamous Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2014-002161-30
    Trial protocol
    		 HU   PT   ES   DE   PL   HR   GR  
    Global end of trial date
    16 Nov 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Jan 2020
    First version publication date
    27 Nov 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1302.5
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02272413
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.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
    16 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main trial objective was to establish statistical equivalence in terms of efficacy until 18 weeks of first-line treatment with BI 695502 plus chemotherapy versus United States (US)-licensed Avastin® plus chemotherapy followed by maintenance monotherapy with either BI 695502 or US-licensed Avastin® in patients with advanced non-squamous non-small cell lung cancer (nsNSCLC).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jul 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    Brazil: 37
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Chile: 26
    Country: Number of subjects enrolled
    Croatia: 10
    Country: Number of subjects enrolled
    Egypt: 38
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 30
    Country: Number of subjects enrolled
    Hungary: 58
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Japan: 98
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Malaysia: 13
    Country: Number of subjects enrolled
    Mexico: 56
    Country: Number of subjects enrolled
    Philippines: 25
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Russian Federation: 84
    Country: Number of subjects enrolled
    Serbia: 63
    Country: Number of subjects enrolled
    South Africa: 14
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Thailand: 61
    Country: Number of subjects enrolled
    Turkey: 64
    Country: Number of subjects enrolled
    Ukraine: 179
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Vietnam: 4
    Worldwide total number of subjects
    1030
    EEA total number of subjects
    215
    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)
    623
    From 65 to 84 years
    406
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Phase III, randomized, double-blind, multicenter, active comparator, parallel 2-arm trial in patients with advanced non-squamous non-small cell lung cancer (nsNSCLC). From 21December2017, Sponsor recommended, patients to be switched from BI 695502 to reference product Avastin® (commercially available) as soon as it was available at clinical site.

    Pre-assignment
    Screening details
    		 All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Randomized through Treatment Start
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    This was a double-blind trial. Patients, Investigators, and trial personnel, except the unblinded pharmacist or designated person, remained blinded with regard to the randomized treatment assignments until after final database lock. No unblinding of sites or patients was performed at the time of switching from BI 695502 to Avastin®, to ensure continued unbiased assessments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BI 695502
    Arm description
    		 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 695502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of BI 695502 was administered by i.v. infusion every 3 weeks (administered over 90 minutes for the first infusion; if well tolerated, administered over 60 minutes for the second infusion and subsequently administered over 30 minutes).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 mg/m^2 BSA i.v. infusion (administered according to regular institutional practice) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin target AUC dose of 6 mg/mL*min (administered as 30-to 60-minute i.v. infusion) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Arm title
    		 US-licensed Avastin®
    Arm description
    		 Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    US-licensed Avastin®
    Investigational medicinal product code
    Other name
    Bevacizumab, Avastin®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of US-licensed Avastin® was administered by i.v. infusion every 3 weeks (administered over 90 minutes for the first infusion; if well tolerated, administered over 60 minutes for the second infusion and subsequently administered over 30 minutes).

    Investigational medicinal product name
    Avastin®
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of commercially available Avastin® was administered by i.v. infusion every 3 weeks.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 mg/m^2 BSA i.v. infusion (administered according to regular institutional practice) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin target AUC dose of 6 mg/mL*min (administered as 30-to 60-minute i.v. infusion) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Number of subjects in period 1
    		BI 695502 US-licensed Avastin®
    Started
    338
    333
    Treated
    335
    328
    Completed
    335
    328
    Not completed
    3
    5
         Not treated
    3
    5
    Period 2
    Period 2 title
    Pre-switch period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    This was a double-blind trial. Patients, Investigators, and trial personnel, except the unblinded pharmacist or designated person, remained blinded with regard to the randomized treatment assignments until after final database lock. No unblinding of sites or patients was performed at the time of switching from BI 695502 to Avastin®, to ensure continued unbiased assessments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BI 695502
    Arm description
    		 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 695502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of BI 695502 was administered by i.v. infusion every 3 weeks (administered over 90 minutes for the first infusion; if well tolerated, administered over 60 minutes for the second infusion and subsequently administered over 30 minutes).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin target AUC dose of 6 mg/mL*min (administered as 30-to 60-minute i.v. infusion) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 mg/m^2 BSA i.v. infusion (administered according to regular institutional practice) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Arm title
    		 US-licensed Avastin®
    Arm description
    		 Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    US-licensed Avastin®
    Investigational medicinal product code
    Other name
    Bevacizumab, Avastin®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of US-licensed Avastin® was administered by i.v. infusion every 3 weeks (administered over 90 minutes for the first infusion; if well tolerated, administered over 60 minutes for the second infusion and subsequently administered over 30 minutes).

    Investigational medicinal product name
    Avastin®
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of commercially available Avastin® was administered by i.v. infusion every 3 weeks.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 mg/m^2 BSA i.v. infusion (administered according to regular institutional practice) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin target AUC dose of 6 mg/mL*min (administered as 30-to 60-minute i.v. infusion) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 2 (pre-switch period) is selected as baseline period as baseline characteristics were recorded based on participants who were treated and started pre-switch period (335 and 328).”
    Number of subjects in period 2 [2]
    		BI 695502 US-licensed Avastin®
    Started
    335
    328
    Completed
    42
    46
    Not completed
    293
    282
         Adverse event, serious fatal
    26
    26
         Consent withdrawn by subject
    27
    15
         Physician decision
    6
    18
         Adverse event, non-fatal
    38
    37
         Progressive disease
    185
    173
         Lost to follow-up
    -
    2
         Other than listed
    10
    11
         Protocol deviation
    1
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on the patients who were randomised after successfully completing the screening period and received at least one of the trial medication.
    Period 3
    Period 3 title
    Post-switch period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    This was a double-blind trial. Patients, Investigators, and trial personnel, except the unblinded pharmacist or designated person, remained blinded with regard to the randomized treatment assignments until after final database lock. No unblinding of sites or patients was performed at the time of switching from BI 695502 to Avastin®, to ensure continued unbiased assessments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BI 695502
    Arm description
    		 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 695502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of BI 695502 was administered by i.v. infusion every 3 weeks (administered over 90 minutes for the first infusion; if well tolerated, administered over 60 minutes for the second infusion and subsequently administered over 30 minutes).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin target AUC dose of 6 mg/mL*min (administered as 30-to 60-minute i.v. infusion) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 mg/m^2 BSA i.v. infusion (administered according to regular institutional practice) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Arm title
    		 US-licensed Avastin®
    Arm description
    		 Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    US-licensed Avastin®
    Investigational medicinal product code
    Other name
    Bevacizumab, Avastin®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of US-licensed Avastin® was administered by i.v. infusion every 3 weeks (administered over 90 minutes for the first infusion; if well tolerated, administered over 60 minutes for the second infusion and subsequently administered over 30 minutes).

    Investigational medicinal product name
    Avastin®
    Investigational medicinal product code
    Other name
    Bevacizumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 15 mg/kg bw of commercially available Avastin® was administered by i.v. infusion every 3 weeks.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 200 mg/m^2 BSA i.v. infusion (administered according to regular institutional practice) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin target AUC dose of 6 mg/mL*min (administered as 30-to 60-minute i.v. infusion) every 3 weeks (21 days, 1 cycle) for up to 6 cycles.

    Number of subjects in period 3
    		BI 695502 US-licensed Avastin®
    Started
    42
    46
    Completed
    0
    0
    Not completed
    42
    46
         Adverse event, serious fatal
    3
    2
         Consent withdrawn by subject
    1
    2
         Physician decision
    1
    1
         Adverse event, non-fatal
    4
    4
         Study terminated by sponsor
    8
    11
         Progressive disease
    21
    21
         Other than listed
    4
    5

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    BI 695502
    Reporting group description
    		 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

    Reporting group title
    US-licensed Avastin®
    Reporting group description
    		 Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

    Reporting group values
    		 BI 695502 US-licensed Avastin® Total
    Number of subjects
    		 335 328
    Age categorical
    Units: Subjects
    Age Continuous
    Full Analysis Set (FAS): The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment.
    Units: years
        arithmetic mean (standard deviation)
    		 61.2 ( 9.89 ) 61.3 ( 9.22 ) -
    Sex: Female, Male
    FAS
    Units: Subjects
        Female
    		 121 125 246
        Male
    		 214 203 417
    Race (NIH/OMB)
    FAS
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 64 71 135
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 258 248 506
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 12 8 20
    Ethnicity (NIH/OMB)
    FAS
    Units: Subjects
        Hispanic or Latino
    		 43 34 77
        Not Hispanic or Latino
    		 284 285 569
        Unknown or Not Reported
    		 8 9 17

    End points

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    End points reporting groups
    Reporting group title
    BI 695502
    Reporting group description
    		 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

    Reporting group title
    US-licensed Avastin®
    Reporting group description
    		 Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
    Reporting group title
    BI 695502
    Reporting group description
    		 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

    Reporting group title
    US-licensed Avastin®
    Reporting group description
    		 Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.
    Reporting group title
    BI 695502
    Reporting group description
    		 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

    Reporting group title
    US-licensed Avastin®
    Reporting group description
    		 Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

    Primary: Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment

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    End point title
    		 Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment
    End point description
    ORR was defined as the percentage of patients who achieved at least one visit response of complete response (CR) or partial response (PR) after the start of treatment. The response criteria evaluation was carried out according to RECIST 1.1. CR and PR did not need to be confirmed by a subsequent tumor assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Tumor assessments were performed prior to trial drug administration. The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Best ORR (CR+PR) is reported for observed values.
    End point type
    Primary
    End point timeframe
    Tumor assessment scans were performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12) and at Week 18 ±14 days. Best ORR evaluated until confirmed disease progression, unacceptable toxicity, death or up to 18 weeks, whichever happened earlier.
    End point values
    		 BI 695502 US-licensed Avastin®
    Number of subjects analysed
    335 [1]
    328 [2]
    Units: Percentage of patients (%)
        number (not applicable)
    54.0
    63.1
    Notes
    [1] - FAS
    [2] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian).
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    		 Log-binomial regression
    Parameter type
    		 Ratio of best ORR
    Point estimate
    0.855
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.7697
         upper limit
    		 0.9506
    Notes
    [3] - The null hypothesis was to be rejected in favor of equivalence if the 2-sided 90% confidence interval (CI) for the ratio in best ORR between the treatments was entirely contained within the equivalence margins of 0.736 to 1.359.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian).
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    Method
    		 Log-binomial regression
    Parameter type
    		 Ratio of best ORR
    Point estimate
    0.855
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7543
         upper limit
    		 0.97
    Notes
    [4] - Additional analysis of the primary endpoint was performed for Japan according to a local protocol amendment Japan. For the submission in Japan, to conclude on equivalence, the 2-sided 95% CI for the ratio of best ORR between the treatments had to be entirely contained within the equivalence margins of 0.736 to 1.359.

    Secondary: Percentage of Patients with Selected Treatment-Emergent Adverse Events (AE) (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin®

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    End point title
    		 Percentage of Patients with Selected Treatment-Emergent Adverse Events (AE) (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin®
    End point description
    The following selected adverse events (AEs) were evaluated for comparability assessment of BI 695502 and US-licensed Avastin®: Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions), Thromboembolic events (arterial or venous), Febrile neutropenia, Gastrointestinal perforations, · Hypertension, Proteinuria, Pulmonary hemorrhage, Other hemorrhages (not including pulmonary hemorrhages), Wound-healing complications/abscess/fistulas. The analysis of AEs was based on the concept of TEAEs. For non-switched patients, all AEs that started or worsened in severity on or after the first dose of trial drug and prior to the date of last administration of trial medication + 16 weeks inclusive were defined as TEAEs. Treated Set (TS) contained all patients who signed informed consent and who received at least 1 dose of trial drug.
    End point type
    Secondary
    End point timeframe
    From first dose of trial drug until 16 weeks after the last dose of trial medication, up to 218 days.
    End point values
    		 BI 695502 US-licensed Avastin®
    Number of subjects analysed
    335 [5]
    328 [6]
    Units: Percentage of patients (%)
    number (confidence interval 95%)
        AtLeast 1 AE selected for Comparability Assessment
    52.50 (47.04 to 57.99)
    45.10 (39.65 to 50.68)
        Infusion reactions
    16.70 (12.88 to 21.15)
    13.10 (9.65 to 17.25)
        Thromboembolic events
    6.60 (4.16 to 9.77)
    5.50 (3.28 to 8.53)
        Febrile neutropenia
    3.90 (2.08 to 6.54)
    3.40 (1.69 to 5.92)
        Gastrointestinal perforations
    2.10 (0.84 to 4.26)
    0.60 (0.07 to 2.19)
        Hypertension
    15.50 (11.82 to 19.85)
    16.20 (12.34 to 20.60)
        Proteinuria
    15.80 (12.08 to 20.18)
    14.60 (10.99 to 18.93)
        Pulmonary haemorrhage
    1.20 (0.33 to 3.03)
    0.90 (0.19 to 2.65)
        Other hemorrhages
    20.00 (15.85 to 24.69)
    16.20 (12.34 to 20.60)
        Wound-healing complications/abscess/fistulas
    2.70 (1.24 to 5.04)
    2.10 (0.86 to 4.35)
    Notes
    [5] - TS
    [6] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    At least 1 AE selected for comparability assessment, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.37
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Infusion reactions, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.88
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Thromboembolic events, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 2.32
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Febrile neutropenia, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 2.76
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Gastrointestial perforations, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    3.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 32.82
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Hypertension, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.39
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Proteinuria, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.57
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Pulmonary haemorrhage, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 10.79
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Other hemorrhages, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score exact method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.74
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Wound healing complications/ abscesses/ fistulas, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where ‘a’ was the number of patients with TEAEs selected for comparability within treatment group X, ‘a+b’ was the total number of patients in treatment group X, ‘c’ was the number of patients with TEAEs selected for comparability within treatment group Y and ‘c+d’ was the total number of patients in treatment group Y.
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Score excat method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 3.57

    Secondary: Progression-Free Survival (PFS) Time as Determined by Investigator Assessment

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    End point title
    		 Progression-Free Survival (PFS) Time as Determined by Investigator Assessment
    End point description
    PFS was defined as the time from randomization until disease progression as determined by Investigator assessment or death from any cause, whichever occurred first during the pre-switch period. Disease progression was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters. Tumor assessments were performed prior to trial drug administration. PFS was calculated using the Kaplan-Meier technique.
    End point type
    Secondary
    End point timeframe
    Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression. Analysis performed for pre-switch period only; maximum duration of up to 35 cycles (105 weeks).
    End point values
    		 BI 695502 US-licensed Avastin®
    Number of subjects analysed
    335 [7]
    328 [8]
    Units: Months
        median (confidence interval 95%)
    8.34 (7.49 to 8.77)
    9.00 (8.34 to 10.38)
    Notes
    [7] - FAS
    [8] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Cox-proportional hazards regression
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.45

    Secondary: Overall Survival (OS) Time

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    End point title
    		 Overall Survival (OS) Time
    End point description
    OS was defined as the time randomization until death from any cause during the pre-switch period. OS was calculated using the Kaplan-Meier technique.
    End point type
    Secondary
    End point timeframe
    From baseline until death due to any cause, ie., up to 35 cycles (105 weeks).
    End point values
    		 BI 695502 US-licensed Avastin®
    Number of subjects analysed
    335 [9]
    328 [10]
    Units: Months
        median (confidence interval 95%)
    15.57 (14.16 to 17.25)
    19.48 (15.87 to 20.73)
    Notes
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Cox-proportional hazards regression
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.51

    Secondary: Duration of Response (DOR) as Determined by Investigator Assessment

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    End point title
    		 Duration of Response (DOR) as Determined by Investigator Assessment
    End point description
    DOR was the time from first documented CR or PR until time of progression as determined by Investigator assessment during the pre-switch period. Tumor assessments were performed prior to trial drug administration. DOR was calculated using the Kaplan-Meier technique.
    End point type
    Secondary
    End point timeframe
    Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression., ie up to 35 cycles (105 weeks).
    End point values
    		 BI 695502 US-licensed Avastin®
    Number of subjects analysed
    175 [11]
    187 [12]
    Units: Months
        median (confidence interval 95%)
    7.66 (7.03 to 9.03)
    8.94 (7.26 to 10.28)
    Notes
    [11] - FAS patients with an objective response
    [12] - FAS patients with an objective response
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).
    Comparison groups
    BI 695502 v US-licensed Avastin®
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 Cox-proportional hazards regression
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.48

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For Pre-switch period: From first dose of trial drug until 112 days (16 weeks) after the last dose of trial medication, up to 218 days. For post-switch period: From the first dose of Avastin® until end of treatment (EOT) visit, up to 127 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    BI 695502 (pre-switch)
    Reporting group description
    		 Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

    Reporting group title
    US-licensed Avastin® (pre-switch)
    Reporting group description
    		 Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received USlicensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

    Reporting group title
    BI 695502 (post-switch)
    Reporting group description
    		 Patients switched from BI 695502 to receive commercially available Avastin®.

    Reporting group title
    US-licensed Avastin® (post-switch)
    Reporting group description
    		 Patients switched from US-licensed Avastin® to receive commercially available Avastin®.

    Serious adverse events
    		 BI 695502 (pre-switch) US-licensed Avastin® (pre-switch) BI 695502 (post-switch) US-licensed Avastin® (post-switch)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    108 / 335 (32.24%)
    89 / 328 (27.13%)
    5 / 42 (11.90%)
    2 / 46 (4.35%)
         number of deaths (all causes)
    193
    184
    3
    2
         number of deaths resulting from adverse events
    5
    2
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    4 / 335 (1.19%)
    6 / 328 (1.83%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    3 / 335 (0.90%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Internal haemorrhage
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Microembolism
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular stenosis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasoconstriction
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    11 / 335 (3.28%)
    5 / 328 (1.52%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    9 / 11
    3 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 335 (1.79%)
    4 / 328 (1.22%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    5 / 335 (1.49%)
    7 / 328 (2.13%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 9
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 335 (1.49%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 335 (0.90%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    3 / 335 (0.90%)
    1 / 328 (0.30%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial fistula
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary diseas
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Pulmonary necrosis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    3 / 335 (0.90%)
    3 / 328 (0.91%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    5 / 335 (1.49%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 335 (0.60%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood magnesium decreased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 335 (0.90%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 335 (0.60%)
    5 / 328 (1.52%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 335 (0.00%)
    3 / 328 (0.91%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioratio
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 335 (0.30%)
    3 / 328 (0.91%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 328 (0.00%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 328 (0.00%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial rupture
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 328 (0.00%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    13 / 335 (3.88%)
    11 / 328 (3.35%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    3 / 14
    4 / 11
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    6 / 335 (1.79%)
    11 / 328 (3.35%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 13
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 335 (1.19%)
    9 / 328 (2.74%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 11
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 335 (1.19%)
    5 / 328 (1.52%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 335 (0.30%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 335 (0.30%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulati
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 335 (1.19%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 335 (0.90%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 335 (0.60%)
    6 / 328 (1.83%)
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Anal incontinence
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 328 (0.00%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 328 (0.00%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder obstruction
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 335 (0.00%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exposed bone in jaw
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    9 / 335 (2.69%)
    9 / 328 (2.74%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 10
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 335 (0.60%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 335 (0.60%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mycosis
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 328 (0.00%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection bacteria
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 335 (0.00%)
    0 / 328 (0.00%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    4 / 335 (1.19%)
    3 / 328 (0.91%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 335 (0.30%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 335 (0.00%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 335 (0.00%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 335 (0.00%)
    2 / 328 (0.61%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypochloraemia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 335 (0.00%)
    1 / 328 (0.30%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BI 695502 (pre-switch) US-licensed Avastin® (pre-switch) BI 695502 (post-switch) US-licensed Avastin® (post-switch)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    293 / 335 (87.46%)
    288 / 328 (87.80%)
    20 / 42 (47.62%)
    22 / 46 (47.83%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    41 / 335 (12.24%)
    33 / 328 (10.06%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    96
    68
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    39 / 335 (11.64%)
    42 / 328 (12.80%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    121
    121
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    30 / 335 (8.96%)
    19 / 328 (5.79%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    113
    68
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    24 / 335 (7.16%)
    32 / 328 (9.76%)
    0 / 42 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    44
    59
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    22 / 335 (6.57%)
    31 / 328 (9.45%)
    1 / 42 (2.38%)
    6 / 46 (13.04%)
         occurrences all number
    55
    92
    1
    6
    Weight decreased
         subjects affected / exposed
    21 / 335 (6.27%)
    22 / 328 (6.71%)
    2 / 42 (4.76%)
    1 / 46 (2.17%)
         occurrences all number
    28
    32
    2
    1
    Blood cholesterol increased
         subjects affected / exposed
    20 / 335 (5.97%)
    16 / 328 (4.88%)
    1 / 42 (2.38%)
    3 / 46 (6.52%)
         occurrences all number
    51
    61
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 335 (5.67%)
    30 / 328 (9.15%)
    1 / 42 (2.38%)
    3 / 46 (6.52%)
         occurrences all number
    37
    47
    1
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    17 / 335 (5.07%)
    25 / 328 (7.62%)
    0 / 42 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    27
    50
    0
    3
    Haemoglobin decreased
         subjects affected / exposed
    5 / 335 (1.49%)
    17 / 328 (5.18%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    8
    31
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    49 / 335 (14.63%)
    51 / 328 (15.55%)
    3 / 42 (7.14%)
    1 / 46 (2.17%)
         occurrences all number
    69
    86
    3
    1
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    62 / 335 (18.51%)
    59 / 328 (17.99%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    95
    98
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    56 / 335 (16.72%)
    53 / 328 (16.16%)
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    85
    77
    0
    1
    Headache
         subjects affected / exposed
    26 / 335 (7.76%)
    25 / 328 (7.62%)
    1 / 42 (2.38%)
    2 / 46 (4.35%)
         occurrences all number
    34
    28
    1
    2
    Paraesthesia
         subjects affected / exposed
    20 / 335 (5.97%)
    19 / 328 (5.79%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    26
    23
    0
    0
    Dysgeusia
         subjects affected / exposed
    13 / 335 (3.88%)
    17 / 328 (5.18%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    13
    18
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    112 / 335 (33.43%)
    84 / 328 (25.61%)
    2 / 42 (4.76%)
    4 / 46 (8.70%)
         occurrences all number
    244
    189
    2
    4
    Neutropenia
         subjects affected / exposed
    61 / 335 (18.21%)
    52 / 328 (15.85%)
    0 / 42 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    129
    108
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    44 / 335 (13.13%)
    47 / 328 (14.33%)
    1 / 42 (2.38%)
    4 / 46 (8.70%)
         occurrences all number
    108
    85
    1
    4
    Leukopenia
         subjects affected / exposed
    18 / 335 (5.37%)
    23 / 328 (7.01%)
    0 / 42 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    42
    52
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    73 / 335 (21.79%)
    75 / 328 (22.87%)
    2 / 42 (4.76%)
    1 / 46 (2.17%)
         occurrences all number
    154
    128
    2
    1
    Diarrhoea
         subjects affected / exposed
    60 / 335 (17.91%)
    45 / 328 (13.72%)
    1 / 42 (2.38%)
    1 / 46 (2.17%)
         occurrences all number
    89
    72
    1
    1
    Vomiting
         subjects affected / exposed
    56 / 335 (16.72%)
    37 / 328 (11.28%)
    1 / 42 (2.38%)
    1 / 46 (2.17%)
         occurrences all number
    94
    51
    1
    1
    Constipation
         subjects affected / exposed
    51 / 335 (15.22%)
    44 / 328 (13.41%)
    1 / 42 (2.38%)
    1 / 46 (2.17%)
         occurrences all number
    66
    56
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    38 / 335 (11.34%)
    32 / 328 (9.76%)
    0 / 42 (0.00%)
    5 / 46 (10.87%)
         occurrences all number
    48
    37
    0
    5
    Epistaxis
         subjects affected / exposed
    38 / 335 (11.34%)
    32 / 328 (9.76%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    46
    38
    0
    0
    Dyspnoea
         subjects affected / exposed
    22 / 335 (6.57%)
    31 / 328 (9.45%)
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    25
    35
    0
    1
    Haemoptysis
         subjects affected / exposed
    17 / 335 (5.07%)
    10 / 328 (3.05%)
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    19
    11
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    155 / 335 (46.27%)
    149 / 328 (45.43%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    188
    176
    0
    0
    Rash
         subjects affected / exposed
    17 / 335 (5.07%)
    16 / 328 (4.88%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    17
    19
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 335 (4.48%)
    18 / 328 (5.49%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    22
    22
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    51 / 335 (15.22%)
    46 / 328 (14.02%)
    8 / 42 (19.05%)
    6 / 46 (13.04%)
         occurrences all number
    122
    130
    8
    6
    Fatigue
         subjects affected / exposed
    54 / 335 (16.12%)
    53 / 328 (16.16%)
    2 / 42 (4.76%)
    1 / 46 (2.17%)
         occurrences all number
    70
    68
    2
    1
    Asthenia
         subjects affected / exposed
    22 / 335 (6.57%)
    29 / 328 (8.84%)
    1 / 42 (2.38%)
    2 / 46 (4.35%)
         occurrences all number
    34
    45
    1
    2
    Malaise
         subjects affected / exposed
    19 / 335 (5.67%)
    13 / 328 (3.96%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    36
    24
    0
    0
    Pyrexia
         subjects affected / exposed
    17 / 335 (5.07%)
    21 / 328 (6.40%)
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    18
    21
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    40 / 335 (11.94%)
    35 / 328 (10.67%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    51
    62
    1
    0
    Myalgia
         subjects affected / exposed
    38 / 335 (11.34%)
    29 / 328 (8.84%)
    0 / 42 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    76
    54
    0
    1
    Back pain
         subjects affected / exposed
    22 / 335 (6.57%)
    14 / 328 (4.27%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    23
    18
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    18 / 335 (5.37%)
    10 / 328 (3.05%)
    0 / 42 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    20
    11
    0
    0
    Pain in extremity
         subjects affected / exposed
    12 / 335 (3.58%)
    18 / 328 (5.49%)
    1 / 42 (2.38%)
    0 / 46 (0.00%)
         occurrences all number
    14
    22
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    54 / 335 (16.12%)
    54 / 328 (16.46%)
    2 / 42 (4.76%)
    4 / 46 (8.70%)
         occurrences all number
    81
    75
    2
    4
    Hyperglycaemia
         subjects affected / exposed
    21 / 335 (6.27%)
    28 / 328 (8.54%)
    0 / 42 (0.00%)
    4 / 46 (8.70%)
         occurrences all number
    42
    53
    0
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2015
    • “US-sourced Avastin®” was updated to “US-licensed Avastin®” in order to clearly indicate the product used in this trial. • The description of the requirements for the safety follow-up (SFU) visit was clarified to state that all patients were required to attend the SFU visit after completing trial therapy. • For consistency with the informed consent form (ICF), inclusion criterion 10 was revised to specify that all patients (males and females of childbearing potential) were to continue to use an acceptable form of contraception for 6 months following completion or discontinuation of trial medication, and to add text defining childbearing potential. • The criteria for withdrawal from the trial, discontinuation from trial medication and the requirements for follow-up of patients who discontinue treatment were clarified in line with Federal Drug Agency (FDA) requirements. • It was clarified that patients who were unable to tolerate at least 3 cycles of chemotherapy or those that started a new backbone chemotherapy were not to be withdrawn from the trial but would be discontinued from trial medication.
    10 Jul 2015
    • In the section relating to chemotherapy, the text “In case of anticipated toxicity, the Investigator may start paclitaxel at a dose of 175 mg/m^2 BSA and/or carboplatin target AUC 5 mg/mL*min.” was changed to “The dose can be reduced in the event of toxicity according to the protocol guideline”. This was done to address FDA feedback regarding the starting dose of paclitaxel and/or carboplatin being consistent with prior clinical trials. • In response to FDA feedback, instructions relating to management of patients with severe hypertension, moderate to severe proteinuria, or severe infusion reactions were amended to state that these patients “will not receive further treatment with US-licensed Avastin® or BI 695502 if the event cannot be adequately controlled within 14 days” rather than allowing a 28-day treatment interruption.
    19 Feb 2016
    • Japan age requirement changed from “Age ≥20 years at visit 1” to “Age ≥20 years at Screening”. • It was specified that abdominal magnetic resonance imaging scans were to be performed with contrast using gadolinium. • Timing and frequency of, and permitted delays to, treatment cycles was further clarified. • Text was added: “During the induction phase, tumor assessments should be performed before treatment administration of Cycles 3 and 5. If an induction therapy cycle is delayed, the tumor assessment will also be delayed.” • In the event of a treatment cycle delay due to toxicity, it was clarified that the imaging assessment for the primary endpoint was to be performed at Week 18 ±14 days (fixed time point), regardless of the number of cycles administered to date. • The list of reasons patients could be discontinued from the trial drug was updated for consistency with other sections of the protocol, and to clarify that progressive disease required trial drug discontinuation. • To clarify, the following text was added: “Patients discontinued from trial treatment or withdrawn from the trial will not be replaced, regardless of the reason for discontinuation/withdrawal.” • Clarification was added to state that the correct dose of Avastin®/BI 695502 was to be recalculated prior to each infusion. • It was clarified that progression of cancer (underlying disease) was exempted from reporting as an AE. • In the definition of protocol-specified AEs of special interest, for patients with impaired liver function at baseline, the specified elevated levels of liver enzymes to define hepatic injury were clarified. • Text was added to clarify that pregnant participants had to be excluded from the study and to provide detail on the procedure when a patient’s partner became pregnant.
    17 Jan 2018
    As a consequence of the observation of particles for certain investigational medicinal product batches, the Sponsor recommended that patients be switched from BI 695502 to the reference medicinal product (Avastin®) as soon as it was available at the respective clinical site. The following changes relating to the switch were included: A description of the ‘switch visit’ and assessments to be done were added. It was specified that the dose of Avastin® remained the same after the switch from BI 695502 and that the first infusion for all patients after the switch visit should be delivered over 90 minutes. If tolerated the second infusion was to be delivered over 60 minutes, and if this was tolerated all subsequent infusions could be administered over 30 minutes. Text was added to clarify that no unblinding of patients or sites would occur as a result of the switch. Relabeling of commercially available Avastin® was not required, sites were instructed to monitor the storage conditions of Avastin® in accordance with local requirements, and after patients switched from BI 695502/US-Licensed Avastin® to Avastin® drug accountability details were recorded. Text was modified to state that the 18-week SFU visit was to take place 18 weeks after the last dose of trial medication prior to the switch visit. Patients who were receiving treatment with Avastin® at 18 weeks post the last BI 695502/US-Licensed Avastin® dose were not to have a SFU visit. The End of Treatment definition was updated so that patients could continue to receive Avastin® after the SFU. Clarification on statistical methods to be used to analyze data as a result of the switch were added. Patients were informed orally by the Investigator about the switch, and once the updated ICF was available consent was obtained. All added text that the Sponsor highly recommended the use of the same filters as for BI 695502 administration, and to clarify the recommended concentration of Avastin® after switching.

    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.
    From 21 December 2017, after Week 18 primary analysis data cut-off, the Sponsor recommended to switch patients from BI 695502/US-licensed Avastin® to Avastin®. The main analyses to report all endpoint and AE results was the pre-switch period.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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