Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    LUX-Breast 1: An open-label, randomised phase III trial of BIBW 2992 and vinorelbine versus trastuzumab and vinorelbine in patients with metastatic Human Epidermal Growth Factor Receptor 2 (HER2)-overexpressing breast cancer failing one prior trastuzumab teatment

    Summary
    EudraCT number
    		 2009-015476-98
    Trial protocol
    		 NL   BE   DE   SK   PT   CZ   FR   AT   IT   ES   FI   LT   LV   SI   GB   IE   NO  
    Global end of trial date
    06 Jul 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Dec 2021
    First version publication date
    20 Jul 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1200.75
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01125566
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55612
    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
    30 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jun 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of afatinib in combination with vinorelbine with trastuzumab in combination with vinorelbine as treatment in patients with metastatic Human Epidermal Growth Factor Receptor 2 (HER2)-overexpressing breast cancer failing 1 prior trastuzumab treatment.
    Protection of trial subjects
    Only participants that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All participants were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all participants was adhered to throughout the trial conduct. Rescue medication was allowed for all participants as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jun 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    China: 141
    Country: Number of subjects enrolled
    Taiwan: 74
    Country: Number of subjects enrolled
    Korea, Republic of: 82
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Belarus: 13
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Ireland: 14
    Country: Number of subjects enrolled
    Lithuania: 8
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Poland: 51
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Slovenia: 3
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    United States: 27
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Egypt: 2
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    India: 53
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Singapore: 9
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    South Africa: 17
    Worldwide total number of subjects
    745
    EEA total number of subjects
    198
    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)
    628
    From 65 to 84 years
    107
    85 years and over
    10

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Randomised, active-controlled, open-label, parallel-group trial in participants with metastatic human epidermal growth factor receptor2(HER2)-overexpressing breast cancer failing one prior trastuzumab treatment. 508 randomized, 2 were not treated. 75 were switched treatment in which 1 was wrongly classified as discontinued prior to the switch.

    Pre-assignment
    Screening details
    		 Participants were treated in the study until disease progression, undue toxicity, or withdrawal of consent. The cut-off date for RECIST-based efficacy was 08 June 2013; a second analysis (primarily for assessing Overall Survival (OS)) contains all data until final database lock (30 July 2018).

    Period 1
    Period 1 title
    Patients before the switch (26Apr2013)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open label trial. Blinding was not performed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Afatinib + Vinorelbine (AV)
    Arm description
    		 Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dose-reduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine. 339 participants were randomised to the AV arm, however 2 were not treated and 1 center with 5 participants was excluded from the analysis. Consequently, number of subjects that started is 339 but only 332 reported to ensure consistent reporting with baseline characteristics.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dosereduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine.

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dosereduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine.

    Arm title
    		 Trastuzumab + Vinorelbine (TV)
    Arm description
    		 Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. 169 participants were randomised to the TV arm, however 1 center with 1 participants was excluded from the analysis. Consequently, number of subjects that started is 169 but only 168 reported to ensure consistent reporting with baseline characteristics.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days.

    Number of subjects in period 1 [1]
    		Afatinib + Vinorelbine (AV) Trastuzumab + Vinorelbine (TV)
    Started
    332
    168
    Completed
    75
    0
    Not completed
    257
    168
         Adverse event, non-fatal
    24
    5
         Refused to continue taking medication
    24
    23
         Other than listed above
    23
    13
         Lost to follow-up
    -
    1
         Progressive disease according to RECIST
    180
    118
         Worsening of underlying cancer disease
    6
    6
         Protocol deviation
    -
    2
    Notes
    [1] - 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: 745 patients were enrolled worldwide whereof 500 patients actually started in this trial.
    Period 2
    Period 2 title
    Patients who switched from AV to TV
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open label trial. Blinding was not performed.

    Arms
    Arm title
    		 AV switched to TV
    Arm description
    		 This group describes participants who discontinued AV treatment and switched to TV, provided they were without disease progression on AV, following data monitoring committee (DMC) recommendation to terminate recruitment on 26 April 2013.
    Arm type
    		 Other

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dosereduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dosereduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days.

    Number of subjects in period 2
    		AV switched to TV
    Started
    75
    Completed
    2
    Not completed
    73
         Refused to continue taking medication
    7
         Other than listed above
    4
         Progressive disease according to RECIST
    59
         Worsening of underlying cancer disease
    3

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Afatinib + Vinorelbine (AV)
    Reporting group description
    		 Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dose-reduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine. 339 participants were randomised to the AV arm, however 2 were not treated and 1 center with 5 participants was excluded from the analysis. Consequently, number of subjects that started is 339 but only 332 reported to ensure consistent reporting with baseline characteristics.

    Reporting group title
    Trastuzumab + Vinorelbine (TV)
    Reporting group description
    		 Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. 169 participants were randomised to the TV arm, however 1 center with 1 participants was excluded from the analysis. Consequently, number of subjects that started is 169 but only 168 reported to ensure consistent reporting with baseline characteristics.

    Reporting group values
    		 Afatinib + Vinorelbine (AV) Trastuzumab + Vinorelbine (TV) Total
    Number of subjects
    		 332 168 500
    Age categorical
    Units: Subjects
    Age Continuous
    Treated Set (TS): The TS included all randomised participantsbwho were documented to have taken at least 1 dose of study medication (i.e. afatinib, trastuzumab, or vinorelbine). One centre with 6 subjects was excluded from analysis.
    Units: years
        arithmetic mean (standard deviation)
    		 51.8 ( 11.3 ) 53.1 ( 12.3 ) -
    Sex: Female, Male
    TS
    Units: Subjects
        Female
    		 332 168 500
        Male
    		 0 0 0
    Race (NIH/OMB)
    TS. Ethnicity data was not reported for the trial.
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 172 81 253
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 6 3 9
        White
    		 136 72 208
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 17 11 28

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Afatinib + Vinorelbine (AV)
    Reporting group description
    		 Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dose-reduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine. 339 participants were randomised to the AV arm, however 2 were not treated and 1 center with 5 participants was excluded from the analysis. Consequently, number of subjects that started is 339 but only 332 reported to ensure consistent reporting with baseline characteristics.

    Reporting group title
    Trastuzumab + Vinorelbine (TV)
    Reporting group description
    		 Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. 169 participants were randomised to the TV arm, however 1 center with 1 participants was excluded from the analysis. Consequently, number of subjects that started is 169 but only 168 reported to ensure consistent reporting with baseline characteristics.
    Reporting group title
    AV switched to TV
    Reporting group description
    		 This group describes participants who discontinued AV treatment and switched to TV, provided they were without disease progression on AV, following data monitoring committee (DMC) recommendation to terminate recruitment on 26 April 2013.

    Subject analysis set title
    Afatinib + Vinorelbine (AV)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dose-reduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine. 339 participants were randomised to the AV arm, however 2 were not treated and 1 center with 5 participants was excluded from the analysis. Consequently, number of subjects that started is 339 but only 332 reported to ensure consistent reporting with baseline characteristics.

    Subject analysis set title
    Trastuzumab + Vinorelbine (TV)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. 169 participants were randomised to the TV arm, however 1 center with 1 participants was excluded from the analysis. Consequently, number of subjects that started is 169 but only 168 reported to ensure consistent reporting with baseline characteristics.

    Primary: Progression-free Survival (PFS)

    		 Close Top of page
    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS is defined as time from randomisation to disease progression or death whichever occurs first. Assessed by investigator according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). RECIST is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize") or worsen ("progress") during treatment. Only data collected until the cut-off date for RECIST 1.1 based endpoints (08Jun2013) were considered. Progression of disease was determined if at least 1 of the following criteria applied: - At least a 20% increase in the sum of the diameters (SoD) of target lesions taking as reference the smallest SoD recorded since the treatment started, together with an absolute increase in the SoD of at least 5 mm - Appearance of 1 or more new lesions - Unequivocal progression of existing non-target lesions. Randomised set (RS): The RS included all participants who were randomised to receive treatment, whether treated or not.
    End point type
    Primary
    End point timeframe
    From randomization (07Sep2010) until disease progression, death or data cut-off (08Jun2013); Up to 34 months
    End point values
    		 Afatinib + Vinorelbine (AV) Trastuzumab + Vinorelbine (TV)
    Number of subjects analysed
    339 [1]
    169 [2]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    5.49 (3.55 to 9.07)
    5.55 (3.55 to 10.84)
    Notes
    [1] - RS
    [2] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Two sided p-value was derived from a log rank test stratified by the setting of prior Trastuzumab failure, hormone receptors status and region of the investigational site.
    Comparison groups
    Afatinib + Vinorelbine (AV) v Trastuzumab + Vinorelbine (TV)
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.4224 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.41
    Notes
    [3] - Hazard ratio is derived from Cox proportional hazard model stratified by prior Trastuzumab failure, hormone receptors status and region of the investigational site.
    [4] - Two sided p-value was derived from a log rank test stratified by the setting of prior Trastuzumab failure, hormone receptors status and region of the investigational site.

    Secondary: Overall Survival (OS)

    		 Close Top of page
    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as time from randomisation to death irrespective of the cause of the death. For patients who had not died up to the cut-off date (03Sep2013), the date they were last known to be alive was derived from the patient status records, the trial completion record, radiological imaging assessments, the study treatment termination record, and the randomisation date.
    End point type
    Secondary
    End point timeframe
    From randomisation (07Sep2010) to database lock (30Jul2018), up to 95 months.
    End point values
    		 Afatinib + Vinorelbine (AV) Trastuzumab + Vinorelbine (TV)
    Number of subjects analysed
    339 [5]
    169 [6]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    20.17 (10.74 to 39.52)
    29.60 (13.34 to 43.99)
    Notes
    [5] - RS including participants with available data for OS
    [6] - RS including participants with available data for OS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Results of presented analyses are to be seen as exploratory (no confirmatory testing was performed). Two sided p-value from a log rank test stratified by the setting of prior Trastuzumab failure, hormone receptors status and region of the investigational site.
    Comparison groups
    Afatinib + Vinorelbine (AV) v Trastuzumab + Vinorelbine (TV)
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.024 [8]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 1.63
    Notes
    [7] - Hazard ratio is derived from Cox proportional hazard model stratified by prior Trastuzumab failure, hormone receptors status and region of the investigational site.
    [8] - Two sided p-value from a log rank test stratified by the setting of prior Trastuzumab failure, hormone receptors status and region of the investigational site.

    Secondary: Best RECIST assessment

    		 Close Top of page
    End point title
    		 Best RECIST assessment
    End point description
    Best RECIST assessment is defined as CR, PR, stable disease (SD), PD or not evaluable by investigator (RECIST version 1.1). CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (<10mm short axis). PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study. PD: At least a 20% increase in the SoD of target lesions, taking as references the smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must also demonstrate an absolute increase of a least 5mm. Appearance of one or more new lesions.
    End point type
    Secondary
    End point timeframe
    From randomization (07Sep2010) until disease progression, death or data cut-off (08Jun2013); Up to 34 months
    End point values
    		 Afatinib + Vinorelbine (AV) Trastuzumab + Vinorelbine (TV)
    Number of subjects analysed
    334 [9]
    168 [10]
    Units: Percentage of participants
    number (not applicable)
        Complete response (CR)
    3.3
    3.0
        Partial response (PR)
    43.1
    41.0
        Stable disease (SD)
    31.7
    26.8
        Progressive Disease (PD)
    12.6
    17.9
        Missing
    9.3
    8.3
    Notes
    [9] - RS including participants with available data for best RECIST assessment
    [10] - RS including participants with available data for best RECIST assessment
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Results of presented analyses are to be seen as exploratory (no confirmatory testing was performed). Logistic regression stratified by prior Trastuzumab failure, hormone receptors status and region of the investigational site.
    Comparison groups
    Afatinib + Vinorelbine (AV) v Trastuzumab + Vinorelbine (TV)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.6431
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.756
         upper limit
    		 1.572
    Notes
    [11] - The odds ratio for the comparison afatinib + vinorelbine vs. trastuzumab + vinorelbine below 1 favours Afatinib.

    Secondary: Objective Response (OR)

    		 Close Top of page
    End point title
    		 Objective Response (OR)
    End point description
    OR is defined as complete response (CR) and partial response (PR). Assessed by investigator according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. Complete Response (CR) for target lesions (TL): Disappearance of all target lesions. Complete Response (CR) for non-target lesions (NTL): Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (<10mm short axis) Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. Other factors which add to the overall response of an imaging timepoint as PR are as below:- - CR in TL, but non-CR/Non-PD in NTL leads to PR - CR in TL, but not evaluated NTL leads to PR - PR in TL, but non-PD NTL or not all evaluated NTL leads to PR
    End point type
    Secondary
    End point timeframe
    Post baseline tumour-imaging was performed at Week 8, 16, 24, 32, 40, 48, 56 and then every 12 weeks (Until final data-base lock on 30 Jul 2018; Up to 95 months)
    End point values
    		 Afatinib + Vinorelbine (AV) Trastuzumab + Vinorelbine (TV)
    Number of subjects analysed
    334 [12]
    168 [13]
    Units: Percentage of participants (%)
        number (not applicable)
    46.4
    47.0
    Notes
    [12] - RS including participants with available data for OR
    [13] - RS including participants with available data for OR
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Results of presented analyses are to be seen as exploratory (no confirmatory testing was performed). Logistic regression stratified by prior Trastuzumab failure, hormone receptors status and region of the investigational site.
    Comparison groups
    Afatinib + Vinorelbine (AV) v Trastuzumab + Vinorelbine (TV)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.8829
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.707
         upper limit
    		 1.496
    Notes
    [14] - The odds ratio for the comparison afatinib + vinorelbine vs. trastuzumab + vinorelbine below 1 favours AV.

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first administration of treatment within the trial until last administration of treatment within the trial, up to 76 months.
    Adverse event reporting additional description
    Treated set was used for reporting the other adverse event and serious adverse event.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Afatinib + Vinorelbine (AV)
    Reporting group description
    		 Participants received oral treatment of film-coated Afatinib tablet at a starting dose of 40 milligram (mg) once daily and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/meter^2 (meter=m) on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days. For Afatinib, a protocol-defined dose-reduction scheme was to be followed if a participant experienced certain pre-specified adverse events. From 26 April 2013, any participant who had been randomised to the AV arm stopped treatment, had the option to switch to Trastuzamb + Vinorelbine.

    Reporting group title
    Trastuzumab + Vinorelbine (TV)
    Reporting group description
    		 Participants received an intravenous infusion of Trastuzumab 2 mg/kilogram (kg) weekly, following an initial loading dose of 4 mg/kg and weekly 10 minutes intravenous infusion of Vinorelbine 25 mg/m^2 on days 1, 8, 15, and 22 of each course. The treatment was administered in treatment courses of 28 days.

    Reporting group title
    AV switched to TV
    Reporting group description
    		 This group describes participants who discontinued AV treatment and switched to TV, provided they were without disease progression on AV, following data monitoring committee (DMC) recommendation to terminate recruitment on 26 April 2013.

    Serious adverse events
    		 Afatinib + Vinorelbine (AV) Trastuzumab + Vinorelbine (TV) AV switched to TV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    123 / 337 (36.50%)
    45 / 169 (26.63%)
    15 / 75 (20.00%)
         number of deaths (all causes)
    235
    111
    3
         number of deaths resulting from adverse events
    18
    5
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain cancer metastatic
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    3 / 337 (0.89%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Breast cancer recurrent
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    10 / 337 (2.97%)
    5 / 169 (2.96%)
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
    Metastases to liver
         subjects affected / exposed
    3 / 337 (0.89%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 337 (0.00%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Breast operation
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 337 (0.59%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 337 (0.59%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 337 (0.59%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    5 / 337 (1.48%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    15 / 337 (4.45%)
    5 / 169 (2.96%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    9 / 16
    3 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site inflammation
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast pain
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 337 (0.59%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 337 (0.00%)
    4 / 169 (2.37%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 337 (0.00%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus disorder
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mood altered
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    3 / 337 (0.89%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 337 (0.00%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 337 (0.00%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 337 (0.00%)
    2 / 169 (1.18%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gliosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 337 (0.59%)
    3 / 169 (1.78%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 337 (0.00%)
    2 / 169 (1.18%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 337 (0.59%)
    2 / 169 (1.18%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    21 / 337 (6.23%)
    7 / 169 (4.14%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    24 / 25
    6 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    18 / 337 (5.34%)
    4 / 169 (2.37%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    22 / 25
    9 / 9
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 337 (0.00%)
    2 / 169 (1.18%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 337 (0.00%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 337 (0.00%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 337 (0.59%)
    2 / 169 (1.18%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    21 / 337 (6.23%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    20 / 21
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic ascites
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 337 (0.89%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 337 (2.97%)
    3 / 169 (1.78%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    7 / 12
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurogenic bladder
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle disorder
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 337 (0.00%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess intestinal
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac infection
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 337 (1.19%)
    2 / 169 (1.18%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 337 (0.30%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Genital infection
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 337 (0.59%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 337 (0.89%)
    1 / 169 (0.59%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 337 (0.00%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 337 (1.19%)
    2 / 169 (1.18%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 337 (0.89%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viraemia
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 337 (0.30%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    4 / 337 (1.19%)
    0 / 169 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 337 (1.19%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 337 (0.00%)
    1 / 169 (0.59%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Afatinib + Vinorelbine (AV) Trastuzumab + Vinorelbine (TV) AV switched to TV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    331 / 337 (98.22%)
    163 / 169 (96.45%)
    64 / 75 (85.33%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    24 / 337 (7.12%)
    16 / 169 (9.47%)
    7 / 75 (9.33%)
         occurrences all number
    33
    26
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 337 (6.53%)
    11 / 169 (6.51%)
    8 / 75 (10.67%)
         occurrences all number
    27
    18
    9
    Haemoglobin decreased
         subjects affected / exposed
    28 / 337 (8.31%)
    6 / 169 (3.55%)
    5 / 75 (6.67%)
         occurrences all number
    45
    13
    6
    Neutrophil count decreased
         subjects affected / exposed
    16 / 337 (4.75%)
    13 / 169 (7.69%)
    6 / 75 (8.00%)
         occurrences all number
    73
    57
    18
    Weight decreased
         subjects affected / exposed
    48 / 337 (14.24%)
    10 / 169 (5.92%)
    6 / 75 (8.00%)
         occurrences all number
    55
    12
    13
    White blood cell count decreased
         subjects affected / exposed
    23 / 337 (6.82%)
    3 / 169 (1.78%)
    5 / 75 (6.67%)
         occurrences all number
    107
    33
    12
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    34 / 337 (10.09%)
    18 / 169 (10.65%)
    5 / 75 (6.67%)
         occurrences all number
    51
    25
    5
    Headache
         subjects affected / exposed
    47 / 337 (13.95%)
    25 / 169 (14.79%)
    10 / 75 (13.33%)
         occurrences all number
    73
    39
    14
    Hypoaesthesia
         subjects affected / exposed
    9 / 337 (2.67%)
    11 / 169 (6.51%)
    2 / 75 (2.67%)
         occurrences all number
    10
    12
    2
    Neuropathy peripheral
         subjects affected / exposed
    15 / 337 (4.45%)
    16 / 169 (9.47%)
    3 / 75 (4.00%)
         occurrences all number
    16
    18
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    15 / 337 (4.45%)
    11 / 169 (6.51%)
    2 / 75 (2.67%)
         occurrences all number
    16
    13
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    103 / 337 (30.56%)
    62 / 169 (36.69%)
    25 / 75 (33.33%)
         occurrences all number
    206
    161
    86
    Leukopenia
         subjects affected / exposed
    115 / 337 (34.12%)
    68 / 169 (40.24%)
    28 / 75 (37.33%)
         occurrences all number
    467
    401
    136
    Neutropenia
         subjects affected / exposed
    256 / 337 (75.96%)
    139 / 169 (82.25%)
    46 / 75 (61.33%)
         occurrences all number
    1164
    1022
    340
    Bone marrow failure
         subjects affected / exposed
    18 / 337 (5.34%)
    11 / 169 (6.51%)
    5 / 75 (6.67%)
         occurrences all number
    75
    39
    22
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    63 / 337 (18.69%)
    25 / 169 (14.79%)
    5 / 75 (6.67%)
         occurrences all number
    103
    38
    9
    Fatigue
         subjects affected / exposed
    106 / 337 (31.45%)
    51 / 169 (30.18%)
    10 / 75 (13.33%)
         occurrences all number
    197
    106
    23
    Mucosal inflammation
         subjects affected / exposed
    82 / 337 (24.33%)
    15 / 169 (8.88%)
    4 / 75 (5.33%)
         occurrences all number
    119
    27
    5
    Oedema peripheral
         subjects affected / exposed
    11 / 337 (3.26%)
    11 / 169 (6.51%)
    1 / 75 (1.33%)
         occurrences all number
    12
    15
    1
    Pain
         subjects affected / exposed
    23 / 337 (6.82%)
    7 / 169 (4.14%)
    2 / 75 (2.67%)
         occurrences all number
    31
    8
    2
    Pyrexia
         subjects affected / exposed
    74 / 337 (21.96%)
    32 / 169 (18.93%)
    11 / 75 (14.67%)
         occurrences all number
    127
    53
    21
    Chills
         subjects affected / exposed
    10 / 337 (2.97%)
    9 / 169 (5.33%)
    3 / 75 (4.00%)
         occurrences all number
    10
    19
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    40 / 337 (11.87%)
    16 / 169 (9.47%)
    1 / 75 (1.33%)
         occurrences all number
    53
    23
    4
    Abdominal pain upper
         subjects affected / exposed
    34 / 337 (10.09%)
    14 / 169 (8.28%)
    5 / 75 (6.67%)
         occurrences all number
    37
    17
    7
    Constipation
         subjects affected / exposed
    35 / 337 (10.39%)
    27 / 169 (15.98%)
    6 / 75 (8.00%)
         occurrences all number
    50
    42
    8
    Diarrhoea
         subjects affected / exposed
    270 / 337 (80.12%)
    45 / 169 (26.63%)
    7 / 75 (9.33%)
         occurrences all number
    786
    67
    18
    Dyspepsia
         subjects affected / exposed
    16 / 337 (4.75%)
    12 / 169 (7.10%)
    3 / 75 (4.00%)
         occurrences all number
    18
    14
    3
    Mouth ulceration
         subjects affected / exposed
    40 / 337 (11.87%)
    5 / 169 (2.96%)
    1 / 75 (1.33%)
         occurrences all number
    61
    7
    1
    Nausea
         subjects affected / exposed
    102 / 337 (30.27%)
    47 / 169 (27.81%)
    6 / 75 (8.00%)
         occurrences all number
    169
    77
    14
    Stomatitis
         subjects affected / exposed
    87 / 337 (25.82%)
    19 / 169 (11.24%)
    4 / 75 (5.33%)
         occurrences all number
    136
    31
    4
    Vomiting
         subjects affected / exposed
    85 / 337 (25.22%)
    22 / 169 (13.02%)
    5 / 75 (6.67%)
         occurrences all number
    204
    35
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    39 / 337 (11.57%)
    27 / 169 (15.98%)
    10 / 75 (13.33%)
         occurrences all number
    51
    36
    12
    Dyspnoea
         subjects affected / exposed
    27 / 337 (8.01%)
    15 / 169 (8.88%)
    4 / 75 (5.33%)
         occurrences all number
    41
    23
    5
    Epistaxis
         subjects affected / exposed
    58 / 337 (17.21%)
    6 / 169 (3.55%)
    3 / 75 (4.00%)
         occurrences all number
    95
    7
    5
    Oropharyngeal pain
         subjects affected / exposed
    30 / 337 (8.90%)
    9 / 169 (5.33%)
    5 / 75 (6.67%)
         occurrences all number
    36
    12
    6
    Rhinorrhoea
         subjects affected / exposed
    20 / 337 (5.93%)
    10 / 169 (5.92%)
    5 / 75 (6.67%)
         occurrences all number
    24
    10
    7
    Productive cough
         subjects affected / exposed
    6 / 337 (1.78%)
    3 / 169 (1.78%)
    4 / 75 (5.33%)
         occurrences all number
    7
    3
    7
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    22 / 337 (6.53%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    26
    0
    0
    Alopecia
         subjects affected / exposed
    34 / 337 (10.09%)
    13 / 169 (7.69%)
    0 / 75 (0.00%)
         occurrences all number
    34
    15
    0
    Dermatitis acneiform
         subjects affected / exposed
    45 / 337 (13.35%)
    0 / 169 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    59
    0
    0
    Dry skin
         subjects affected / exposed
    20 / 337 (5.93%)
    1 / 169 (0.59%)
    1 / 75 (1.33%)
         occurrences all number
    22
    1
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    42 / 337 (12.46%)
    2 / 169 (1.18%)
    0 / 75 (0.00%)
         occurrences all number
    55
    2
    0
    Pruritus
         subjects affected / exposed
    31 / 337 (9.20%)
    8 / 169 (4.73%)
    2 / 75 (2.67%)
         occurrences all number
    41
    10
    2
    Rash
         subjects affected / exposed
    160 / 337 (47.48%)
    19 / 169 (11.24%)
    8 / 75 (10.67%)
         occurrences all number
    213
    22
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    26 / 337 (7.72%)
    28 / 169 (16.57%)
    3 / 75 (4.00%)
         occurrences all number
    34
    32
    4
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    21 / 337 (6.23%)
    3 / 169 (1.78%)
    1 / 75 (1.33%)
         occurrences all number
    25
    4
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 337 (5.34%)
    8 / 169 (4.73%)
    4 / 75 (5.33%)
         occurrences all number
    26
    10
    4
    Back pain
         subjects affected / exposed
    24 / 337 (7.12%)
    15 / 169 (8.88%)
    7 / 75 (9.33%)
         occurrences all number
    33
    25
    10
    Muscle spasms
         subjects affected / exposed
    27 / 337 (8.01%)
    16 / 169 (9.47%)
    5 / 75 (6.67%)
         occurrences all number
    38
    21
    5
    Musculoskeletal pain
         subjects affected / exposed
    12 / 337 (3.56%)
    12 / 169 (7.10%)
    4 / 75 (5.33%)
         occurrences all number
    15
    14
    5
    Myalgia
         subjects affected / exposed
    34 / 337 (10.09%)
    18 / 169 (10.65%)
    5 / 75 (6.67%)
         occurrences all number
    39
    26
    9
    Pain in extremity
         subjects affected / exposed
    21 / 337 (6.23%)
    20 / 169 (11.83%)
    3 / 75 (4.00%)
         occurrences all number
    27
    26
    3
    Bone pain
         subjects affected / exposed
    11 / 337 (3.26%)
    10 / 169 (5.92%)
    0 / 75 (0.00%)
         occurrences all number
    14
    12
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    30 / 337 (8.90%)
    11 / 169 (6.51%)
    2 / 75 (2.67%)
         occurrences all number
    41
    17
    6
    Paronychia
         subjects affected / exposed
    63 / 337 (18.69%)
    2 / 169 (1.18%)
    2 / 75 (2.67%)
         occurrences all number
    81
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    32 / 337 (9.50%)
    27 / 169 (15.98%)
    8 / 75 (10.67%)
         occurrences all number
    33
    52
    21
    Urinary tract infection
         subjects affected / exposed
    35 / 337 (10.39%)
    15 / 169 (8.88%)
    4 / 75 (5.33%)
         occurrences all number
    50
    25
    4
    Conjunctivitis
         subjects affected / exposed
    12 / 337 (3.56%)
    4 / 169 (2.37%)
    4 / 75 (5.33%)
         occurrences all number
    13
    4
    4
    Influenza
         subjects affected / exposed
    7 / 337 (2.08%)
    0 / 169 (0.00%)
    4 / 75 (5.33%)
         occurrences all number
    10
    0
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    98 / 337 (29.08%)
    31 / 169 (18.34%)
    5 / 75 (6.67%)
         occurrences all number
    122
    51
    6
    Hypokalaemia
         subjects affected / exposed
    43 / 337 (12.76%)
    7 / 169 (4.14%)
    2 / 75 (2.67%)
         occurrences all number
    53
    32
    2

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2010
    The restricted medications during treatment with afatinib were changed. An additional explanatory paragraph was added that the concomitant use of potent P-glycoprotein (P-gp) inhibitors and inducers was to be avoided during treatment with afatinib. The background was that a trial (1200.79) in healthy volunteers indicated that co-administration of these drugs affected the harmacokinetics of afatinib. Note: This restriction was loosened again with protocol amendment 4.
    02 Sep 2010
    Several changes and corrections were introduced with the second amendment to the protocol; major changes are presented below. In line with the requirements by the Health Canada’s Food and Drug regulations, the source of trastuzumab for Canada was changed from the EU source to the US source. Statistical information was adjusted regarding the early benefit-risk assessment by the DMC. The ranking of the secondary endpoints was changed to reflect their importance. A reduced timeframe between prior trastuzumab treatment and study entry was allowed (changed from 4 weeks to 3 weeks); this resulted in a modified wording of exclusion criterion 4. The visit and vinorelbine-administration process in case of vinorelbine-related AEs was clarified. Corticosteroids were added to the allowed concomitant medications. Further recommendations regarding interstitial lung disease were added, including instructions for the assessment of pulmonary symptoms and actions to be taken with the study medication. A paragraph about the status of patients after discontinuation of study medication was clarified.
    28 Oct 2011
    The third amendment to the protocol again introduced several changes and corrections; major changes are presented below. It was clarified that the left ventricular ejection fraction (LVEF) assessment was not to be repeated at the screening visit if a valid result was available from an assessment performed as part of routine clinical practice within 28 days prior to start of treatment. The dose reduction scheme for afatinib in case of drug-related diarrhoea and the instructions for the treatment of afatinib-related diarrhoea were clarified. The introduction of the requirement for a TMA repository for potential retrospective analyses was added. The definition of the completion of the trial was clarified. New scientific methodologies were implemented to investigate the potential effect of subsequent anti-cancer therapies on OS. The requirements regarding contraception were changed based on new information in the trastuzumab Summary of Product Characteristics (SPC).
    12 Oct 2012
    Keratitis and ulcerative keratitis was observed in 0.8% of patients exposed to afatinib and they were reported after treatment with approved epidermal growth factor receptor (EGFR) inhibitors for cancer was added. European Medicines Agency requested a class labelling. Restriction that patients randomised to treatment with afatinib were not to receive treatment with potent P-gp inhibitors or inducers was removed. Based on new data, it was clarified that caution is warranted in concomitant use of P-glycoprotein (P-gp) inhibitors or inducers with afatinib, but their use in patients need such therapies is no longer prohibited. Exclusion criterion 6 was modified. Based on the current SPC for vinorelbine, exclusion criterion 12 was modified. In exclusion criterion 13 the MDRD formula was then accepted for the estimation of the glomerular filtration rate (GFR). Denosumab treatment for patients with bone metastasis was allowed. AE reporting guidance was changed. It was specified that worsening of the underlying disease or of other pre-existing conditions was to be recorded as an (S)AE in the electronic case report form ((e)CRF). Changes in vital signs, electrocardiogram (ECG), physical examination and laboratory test results were to be recorded as an (S)AE in the eCRF, if they were judged clinically relevant by the investigator. Drug-induced liver injury (DILI) was defined as a significant AE and a list of always serious AEs was defined; the reporting obligations of the investigator were specified. Further details about the planned second analysis of overall survival (OS) were added. Several new documents were added to the appendix. The rationale behind this were the modification of exclusion criterion 13.
    14 May 2013
    An independent DMC monitored the safety of patients who participated in the trial and benefit-risk assessment that was pre-defined in the clinical trial protocol. The DMC concluded that there was a low likelihood of the study meeting the pre-defined criteria for increased efficacy in terms of PFS. In addition, a high rate of treatment discontinuations and dose reductions as well as a higher rate of SAEs and deaths were observed in the afatinib + vinorelbine arm. The DMC recommended stopping recruitment of patients. Further recruitment into this study was therefore stopped as of 26 Apr 2013.
    23 Aug 2013
    Amendment 6 specified which procedures were no longer needed due to the premature discontinuation of the trial (e.g. additional FU visits, collection of health-related quality of life questionnaires, information about healthcare-resource use, biomarker sub-study, central independent review of images). In addition, the handling of unscheduled pharmacokinetic samples was specified. In addition, it was clarified that the primary endpoint changed from PFS based on central independent review to PFS based on investigator assessment. A list clearly defining the primary, secondary, and other endpoints of the trial was added. The sections about statistical methods were updated and several analyses were cancelled. Amendment 6 also defined that on trial level, the trial was considered complete when the last patient had completed the EOT visit and the FU visit 28 days after EOT.
    12 Jun 2014
    Several clarifications and updated information were introduced with the seventh amendment to the protocol; major changes are presented below. Based on the current SPC for trastuzumab, the instructions for management of trastuzumab cardiotoxicity were modified. Following the request by regulatory authorities, further recommendations for the assessment of keratitis were added to the section about rescue medication, emergency procedures, and additional treatments. The period for the collection of OS data was prolonged to ensure an adequate follow-up of patients and appropriate reporting of OS data: the observation period could have proceeded until at least 50% of patients per arm, or up to 75% of patients overall had died.

    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.
    The Data Monitoring Committee recommended termination of recruitment due to low likelihood of the study meeting its primary objectives.
    For support, Contact us.
    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.

    European Medicines Agency © 1995-Sat Apr 27 09:57:43 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA