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    Clinical Trial Results:
    A randomised, open-label, phase III study to evaluate the efficacy and safety of oral afatinib (BIBW 2992) versus intravenous methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who have progressed after platinum-based therapy

    Summary
    EudraCT number
    2011-000391-34
    Trial protocol
    BE   DK   FR   DE   GR   ES   AT   CZ   SE   IT  
    Global end of trial date
    06 Dec 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Dec 2021
    First version publication date
    21 Dec 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1200.43
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01345682
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 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
    17 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of afatinib versus methotrexate therapy in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who have progressed during or after platinum-based therapy given for R/M HNSCC.
    Protection of trial subjects
    Regular and frequent assessments of clinical benefit throughout the trial ensured that patients not deriving clinical benefit were withdrawn from study medication. Furthermore, an independent data monitoring committee (DMC) evaluated the safety of patients on an ongoing basis.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Jan 2012
    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
    Brazil: 46
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Japan: 49
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Russian Federation: 37
    Country: Number of subjects enrolled
    South Africa: 8
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Belgium: 38
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 131
    Country: Number of subjects enrolled
    Germany: 76
    Country: Number of subjects enrolled
    Italy: 63
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    Greece: 15
    Worldwide total number of subjects
    593
    EEA total number of subjects
    401
    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)
    428
    From 65 to 84 years
    162
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The screening visit was to be performed within 14 days prior to the first administration of study medication. Eligible patients were to be randomised and treatment was to be started within 4 calendar days after randomisation.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Randomised, multicenter, open-label, active-control study with 2 parallel arms.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Afatinib (BIBW 2992)
    Arm description
    Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
    Arm type
    Experimental

    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
    Starting dose 40 mg once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Arm title
    Methotrexate
    Arm description
    Intravenous bolus injection of Methotrexate Starting dose 40 milligram per square meter mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.
    Arm type
    Active comparator

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Number of subjects in period 1 [1]
    Afatinib (BIBW 2992) Methotrexate
    Started
    322
    161
    Completed
    0
    0
    Not completed
    322
    161
         Refused to continue trial medication
    16
    9
         Non-compliance with protocol
    -
    1
         Adverse event, serious fatal
    29
    19
         Worsening of underlying cancer disease
    23
    12
         Adverse event, non-fatal
    22
    22
         Progressive disease per RECIST
    226
    93
         Reason other than those specified above
    4
    3
         Lost to follow-up
    -
    1
         Not treated
    2
    1
    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: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Afatinib (BIBW 2992)
    Reporting group description
    Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Reporting group title
    Methotrexate
    Reporting group description
    Intravenous bolus injection of Methotrexate Starting dose 40 milligram per square meter mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Reporting group values
    Afatinib (BIBW 2992) Methotrexate Total
    Number of subjects
    322 161 483
    Age categorical
    The randomised set (RS) included all patients who were randomised to receive treatment, whether treated or not
    Units: Subjects
    Age Continuous
    The randomised set (RS) included all patients who were randomised to receive treatment, whether treated or not
    Units: years
        arithmetic mean (standard deviation)
    60.0 ± 8.8 59.3 ± 9.7 -
    Gender, Male/Female
    The randomised set (RS) included all patients who were randomised to receive treatment, whether treated or not
    Units: Subjects
        Female
    47 24 71
        Male
    275 137 412

    End points

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    End points reporting groups
    Reporting group title
    Afatinib (BIBW 2992)
    Reporting group description
    Oral administration of Afatinib (film-coated tablets). Starting dose 40 milligram (mg) once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Reporting group title
    Methotrexate
    Reporting group description
    Intravenous bolus injection of Methotrexate Starting dose 40 milligram per square meter mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Primary: Progression-free survival (PFS) based on central independent review

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    End point title
    Progression-free survival (PFS) based on central independent review
    End point description
    PFS was defined as the time from the date of randomisation to disease progression or death, whichever occurred first. The primary analysis of PFS considered PFS events as assessed by central independent review, including all data collected until the study completion (06 December 2016). The date of disease progression was recorded based on RECIST version 1.1. Unequivocal progression of disease was determined if at least one of the following criteria applied: - At least 20% increase in the 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 one or more new lesions - Unequivocal progression of existing non-target lesions. The randomised set (RS) included all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Primary
    End point timeframe
    From randomization until disease progression, death or study completion date (06Dec2016); Up to 60 months
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    322 [1]
    161 [2]
    Units: months
        median (confidence interval 95%)
    2.63 (2.10 to 2.73)
    1.74 (1.48 to 2.40)
    Notes
    [1] - RS
    [2] - RS
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0257 [3]
    Method
    Stratified Log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.792
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.643
         upper limit
    0.977
    Notes
    [3] - Log−rank test stratified by baseline Eastern Cooperative Oncology Group (ECOG) Performance score (PS)(0 or 1) and prior use of Epidermal Growth Factor Receptor (EGFR)−targeted antibody in the Recurrent and/or Metastatic (R/M) setting (Yes or No).

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    Overall survival (OS) was a key secondary endpoint of this trial. OS was defined as the time from randomisation to death (irrespective of the cause of death). Patients for whom there was no evidence of death at the study completion date (06 December 2016) were to be censored on the date that they were last known to be alive.
    End point type
    Secondary
    End point timeframe
    From randomization until death or study completion date (06Dec2016); Up to 60 months
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    322 [4]
    161 [5]
    Units: months
        median (confidence interval 95%)
    6.87 (6.14 to 7.79)
    6.01 (5.16 to 7.75)
    Notes
    [4] - RS
    [5] - RS
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6755 [6]
    Method
    Stratified Log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.958
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.786
         upper limit
    1.169
    Notes
    [6] - Log−rank test stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No).

    Secondary: Objective Response (OR)

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    End point title
    Objective Response (OR)
    End point description
    OR is defined as the best overall response of complete response (CR) and partial response (PR) according to 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. All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: 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; All the above scenarios should also satisfy 'No occurrence of new lesions'.
    End point type
    Secondary
    End point timeframe
    Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    322 [7]
    161 [8]
    Units: percentage of participants
        number (confidence interval 95%)
    10.2 (7.16 to 14.09)
    5.6 (2.58 to 10.34)
    Notes
    [7] - RS
    [8] - RS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Odds ratio, 95% CI and p−value (two−sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.101
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    4.14

    Secondary: Disease Control (DC)

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    End point title
    Disease Control (DC)
    End point description
    DC is defined as the best overall response of CR, PR, stable disease (SD) and non-CR/non-PD. CR for target lesions (TL): Disappearance of all target lesions. CR for non-target lesions (NTL): Disappearance of all non-target lesions . All lymph nodes must be non-pathological in size (<10mm short axis). PR for TL: 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; SD for TL: change in the sum of diameters does not satisfy PR or PD. SD in TL, non-PD in NTL lead to overall response of SD, provided there is no appearance of new lesions.
    End point type
    Secondary
    End point timeframe
    Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    322 [9]
    161 [10]
    Units: percentage of participants
        number (confidence interval 95%)
    49.1 (43.48 to 54.67)
    38.5 (30.95 to 46.49)
    Notes
    [9] - RS
    [10] - RS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Odds ratio, 95% CI and p−value (two−sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0353
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    2.26

    Secondary: Tumour shrinkage

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    End point title
    Tumour shrinkage
    End point description
    Tumour shrinkage, defined as the maximum decrease from baseline in the sum of diameters of the target lesions, as measured by central imaging. The longest diameter of target lesions was recorded, except for lymph nodes, which were measured by their short axis. Negative values indicate a reduction in the sum of target lesion diameters and positive values an increase. Percentage of Participants with Tumour shrinkage as per the categories (>=20% increase, >=0 − <20% increase, >0 − <30% decrease, >=30 − <50% decrease, >=50% decrease) are presented.
    End point type
    Secondary
    End point timeframe
    Tumour imaging was to be performed every 6 weeks during the first 24 weeks of treatment, and hereafter every 8 weeks (data cut-off 07May2014); Up to 28 months
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    248 [11]
    121 [12]
    Units: percentage of participants
    number (not applicable)
        >=20% increase
    16.5
    21.1
        >=0 − <20% increase
    24.2
    31.1
        >0 − <30% decrease
    23.6
    16.1
        >=30 − <50% decrease
    6.2
    4.3
        >=50% decrease
    5.0
    1.9
    Notes
    [11] - RS (Only patients with observed cases (OC) values were analysed)
    [12] - RS (Only patients with observed cases (OC) values were analysed)
    No statistical analyses for this end point

    Secondary: Health related quality of life (HRQOL)- Change in Pain scores over time

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    End point title
    Health related quality of life (HRQOL)- Change in Pain scores over time
    End point description
    The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    265 [13]
    117 [14]
    Units: scores on a scale
        arithmetic mean (standard error)
    11.8 ± 3.16
    16.2 ± 3.43
    Notes
    [13] - RS (Only patients with observed cases (OC) values were analysed)
    [14] - RS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Changes in scores over time were assessed using longitudinal models, i.e. mixed effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG performance score (PS) and prior use of EGFR-targeted antibody for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    = 0.03 [16]
    Method
    longitudinal models
    Parameter type
    Adjusted mean difference
    Point estimate
    -4.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.31
         upper limit
    -0.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.01
    Notes
    [15] - Afatinib (BIBW 2992) vs Methotrexate
    [16] - Adjusted for baseline ECOG performance score (0 or 1) and prior use of EGFR−targeted antibody for R/M HNSCC (Yes or No).

    Secondary: Health related quality of life (HRQOL)- Change in Swallowing scores over time

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    End point title
    Health related quality of life (HRQOL)- Change in Swallowing scores over time
    End point description
    The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    257 [17]
    112 [18]
    Units: scores on a scale
        arithmetic mean (standard error)
    20.0 ± 3.40
    20.1 ± 3.66
    Notes
    [17] - RS (Only patients with observed cases (OC) values were analysed)
    [18] - RS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Changes in scores over time were assessed using longitudinal models, i.e. mixed effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG PS and prior use of EGFR-targeted antibody for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    other [19]
    P-value
    = 0.9773 [20]
    Method
    longitudinal models
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    4.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.16
    Notes
    [19] - Afatinib (BIBW 2992) vs Methotrexate
    [20] - Adjusted for baseline ECOG performance score (0 or 1) and prior use of EGFR−targeted antibody for R/M HNSCC (Yes or No).

    Secondary: Health related quality of life (HRQOL)- Change in Global health scores over time

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    End point title
    Health related quality of life (HRQOL)- Change in Global health scores over time
    End point description
    The HRQOL analyses focused on pain, swallowing, and global health status measured by the European Organisation for Research and Treatment of Cancer [EORTC] quality of life questionnaires Core 30 [QLQ-C30], and head and neck cancer specific supplementary module EORTC QLQ-H&N35: Pain scale from H&N35, Swallowing scale from H&N35 and Global health status/QoL scale from C30. Pain scale includes items 31-34 from H&N 35; Swallowing scale includes items 35-38 from H&N35 and Global health status/QoL scale includes items 29-30 from C30. The scores of these scales were averaged from the scores of the component items, transformed and analyzed on 0 - 100 scale. For pain and swallowing scales, higher scores represent worse outcome; for the global health/QoL scale, higher scores represent better outcome. Changes in scores over time were assessed using longitudinal models. The analyses of HRQOL are presented for the 07 May 2014 cut-off date.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    267 [21]
    117 [22]
    Units: scores on a scale
        arithmetic mean (standard error)
    28.7 ± 3.54
    28.2 ± 3.76
    Notes
    [21] - RS (Only patients with observed cases (OC) values were analysed)
    [22] - RS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Changes in scores over time were assessed using longitudinal models, i.e. mixed effects growth curve models with the average profile over time for each endpoint described by a piecewise linear model adjusted for the fixed effects baseline ECOG PS and prior use of EGFR-targeted antibody for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    = 0.7767 [24]
    Method
    longitudinal models
    Parameter type
    Adjusted mean difference
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.28
         upper limit
    4.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.95
    Notes
    [23] - Afatinib (BIBW 2992) vs Methotrexate
    [24] - Adjusted for baseline ECOG performance score (0 or 1) and prior use of EGFR−targeted antibody for R/M HNSCC (Yes or No).

    Secondary: Status change in pain scale

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    End point title
    Status change in pain scale
    End point description
    Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    265 [25]
    117 [26]
    Units: percentage of participants
    number (not applicable)
        Improved
    26.4
    23.1
        Stable
    32.1
    31.6
        Worsened
    41.5
    45.3
    Notes
    [25] - RS (Only patients with observed cases (OC) values were analysed)
    [26] - RS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Odds ratio, 95% CI and p−value (two−sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.494
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.717
         upper limit
    1.99

    Secondary: Status change in swallowing scale

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    End point title
    Status change in swallowing scale
    End point description
    Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    257 [27]
    112 [28]
    Units: percentage of participants
    number (not applicable)
        Improved
    26.1
    23.2
        Stable
    34.2
    29.5
        Worsened
    39.7
    47.3
    Notes
    [27] - RS (Only patients with observed cases (OC) values were analysed)
    [28] - RS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Odds ratio, 95% CI and p−value (two−sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.584
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.687
         upper limit
    1.95

    Secondary: Status change in global health status scale

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    End point title
    Status change in global health status scale
    End point description
    Distribution of patients with improved, stable or worsened HRQOL: Improvement was defined as a score improved by at least 10 points from baseline (on the 0-100 point scale) at any time during the trial. If a patient had not improved, worsening was defined as a 10-point worsening at any time during the trial. Otherwise, a patient was considered as stable.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    267 [29]
    117 [30]
    Units: percentage of participants
    number (not applicable)
        Improved
    30.3
    29.1
        Stable
    26.6
    25.6
        Worsened
    43.1
    45.3
    Notes
    [29] - RS (Only patients with observed cases (OC) values were analysed)
    [30] - RS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Odds ratio, 95% CI and p−value (two−sided) from logistic regression stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    384
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.816
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.657
         upper limit
    1.705

    Secondary: Time to deterioration in Pain

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    End point title
    Time to deterioration in Pain
    End point description
    The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    322 [31]
    161 [32]
    Units: months
        median (confidence interval 95%)
    3.02 (2.83 to 3.75)
    2.30 (1.64 to 3.32)
    Notes
    [31] - RS
    [32] - RS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No).
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0217 [33]
    Method
    Stratified Log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    0.96
    Notes
    [33] - Log−rank test stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No).

    Secondary: Time to deterioration in Swallowing

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    End point title
    Time to deterioration in Swallowing
    End point description
    The time to deterioration was defined as the time from randomisation to a score increased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    322 [34]
    161 [35]
    Units: months
        median (confidence interval 95%)
    3.75 (2.83 to 4.30)
    2.10 (1.48 to 3.32)
    Notes
    [34] - RS
    [35] - RS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.004 [36]
    Method
    Stratified Log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.89
    Notes
    [36] - Log−rank test stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No).

    Secondary: Time to deterioration in global health status

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    End point title
    Time to deterioration in global health status
    End point description
    The time to deterioration was defined as the time from randomisation to a score decreased (i.e. worsened) by at least 10 points from baseline (0-100 point scale). If score is missing, and patient died within 28 days after scheduled time for completion, the patient was considered deteriorated. In this case, time to deterioration is time to death.
    End point type
    Secondary
    End point timeframe
    From randomization until one month after discontinuation of study medication, death or data cut-off (07May2014); Up to 28 months.
    End point values
    Afatinib (BIBW 2992) Methotrexate
    Number of subjects analysed
    322 [37]
    161 [38]
    Units: months
        median (confidence interval 95%)
    3.25 (2.83 to 4.01)
    2.69 (1.61 to 2.86)
    Notes
    [37] - RS
    [38] - RS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard ratio from Cox proportional hazards model stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No). Afatinib (BIBW 2992) vs Methotrexate
    Comparison groups
    Afatinib (BIBW 2992) v Methotrexate
    Number of subjects included in analysis
    483
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0268 [39]
    Method
    Stratified Log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    0.97
    Notes
    [39] - Log−rank test stratified by baseline ECOG PS (0 or 1) and prior use of EGFR−targeted antibody in the R/M setting (Yes or No).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of study medication (afatinib or methotrexate) and within 28 days after the last administration of study medication (data cut-off 17 January 2017); Up to 61 months.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Afatinib (BIBW 2992)
    Reporting group description
    Oral administration of Afatinib (film-coated tablets). Starting dose 40 mg once daily; escalation to 50 mg/day and / or dose reduction to 40 mg/day (if applicable), 30 mg/day, or 20 mg/day (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Reporting group title
    Methotrexate
    Reporting group description
    Intravenous bolus injection of Methotrexate Starting dose 40 mg/m² weekly; escalation to 50 mg/m² and / or dose reduction to 40 mg/m² (if applicable), 30 mg/m², and 20 mg/m² (according to the protocol-defined dose escalation and dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Serious adverse events
    Afatinib (BIBW 2992) Methotrexate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    168 / 320 (52.50%)
    73 / 160 (45.63%)
         number of deaths (all causes)
    299
    150
         number of deaths resulting from adverse events
    70
    31
    Vascular disorders
    Angiopathy
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 320 (0.00%)
    4 / 160 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Hypotension
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Gastrostomy
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    40 / 320 (12.50%)
    9 / 160 (5.63%)
         occurrences causally related to treatment / all
    0 / 40
    0 / 9
         deaths causally related to treatment / all
    0 / 35
    0 / 9
    Metastases to liver
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    11 / 320 (3.44%)
    4 / 160 (2.50%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Tumour pain
         subjects affected / exposed
    3 / 320 (0.94%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour ulceration
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 320 (1.88%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Face oedema
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 320 (0.94%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    27 / 320 (8.44%)
    8 / 160 (5.00%)
         occurrences causally related to treatment / all
    1 / 29
    1 / 8
         deaths causally related to treatment / all
    0 / 16
    1 / 3
    Hyperpyrexia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal haemorrhage
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    3 / 320 (0.94%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pain
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 320 (2.19%)
    5 / 160 (3.13%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatomegaly
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body aspiration
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poisoning deliberate
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    3 / 320 (0.94%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure orthostatic decreased
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    False positive investigation result
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 320 (0.63%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    3 / 320 (0.94%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Bronchial obstruction
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    15 / 320 (4.69%)
    4 / 160 (2.50%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 320 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    4 / 320 (1.25%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Increased bronchial secretion
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal obstruction
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 320 (0.31%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung disorder
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pharyngeal stenosis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 320 (1.25%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 320 (0.94%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 320 (0.63%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    4 / 320 (1.25%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 320 (1.88%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    Respiratory tract haemorrhage
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stridor
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 320 (0.94%)
    8 / 160 (5.00%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 320 (0.63%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 320 (0.31%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 320 (0.00%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Thrombocytopenia
         subjects affected / exposed
    3 / 320 (0.94%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    5 / 320 (1.56%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paralysis recurrent laryngeal nerve
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    16 / 320 (5.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    17 / 17
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    9 / 320 (2.81%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    5 / 320 (1.56%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 320 (1.56%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    3 / 320 (0.94%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 320 (3.13%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    8 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 320 (0.94%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    6 / 320 (1.88%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Renal impairment
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device leakage
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin haemorrhage
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin reaction
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 320 (0.31%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    7 / 320 (2.19%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    5 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    9 / 320 (2.81%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    6 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food aversion
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    3 / 320 (0.94%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    3 / 320 (0.94%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    6 / 320 (1.88%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    5 / 320 (1.56%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess oral
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    4 / 320 (1.25%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 320 (1.25%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oral infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 320 (4.06%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Pulmonary sepsis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    4 / 320 (1.25%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 320 (0.94%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Septic shock
         subjects affected / exposed
    2 / 320 (0.63%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Skin infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    3 / 320 (0.94%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Afatinib (BIBW 2992) Methotrexate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    309 / 320 (96.56%)
    146 / 160 (91.25%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    9 / 320 (2.81%)
    10 / 160 (6.25%)
         occurrences all number
    9
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    25 / 320 (7.81%)
    9 / 160 (5.63%)
         occurrences all number
    28
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    66 / 320 (20.63%)
    41 / 160 (25.63%)
         occurrences all number
    77
    57
    Fatigue
         subjects affected / exposed
    72 / 320 (22.50%)
    42 / 160 (26.25%)
         occurrences all number
    88
    57
    Mucosal inflammation
         subjects affected / exposed
    74 / 320 (23.13%)
    42 / 160 (26.25%)
         occurrences all number
    98
    55
    Pyrexia
         subjects affected / exposed
    38 / 320 (11.88%)
    27 / 160 (16.88%)
         occurrences all number
    44
    34
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    21 / 320 (6.56%)
    7 / 160 (4.38%)
         occurrences all number
    21
    7
    Insomnia
         subjects affected / exposed
    27 / 320 (8.44%)
    8 / 160 (5.00%)
         occurrences all number
    29
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 320 (1.25%)
    19 / 160 (11.88%)
         occurrences all number
    4
    21
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 320 (1.88%)
    20 / 160 (12.50%)
         occurrences all number
    7
    25
    Weight decreased
         subjects affected / exposed
    69 / 320 (21.56%)
    25 / 160 (15.63%)
         occurrences all number
    80
    27
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    61 / 320 (19.06%)
    42 / 160 (26.25%)
         occurrences all number
    75
    55
    Leukopenia
         subjects affected / exposed
    3 / 320 (0.94%)
    13 / 160 (8.13%)
         occurrences all number
    4
    21
    Neutropenia
         subjects affected / exposed
    1 / 320 (0.31%)
    30 / 160 (18.75%)
         occurrences all number
    1
    41
    Thrombocytopenia
         subjects affected / exposed
    2 / 320 (0.63%)
    10 / 160 (6.25%)
         occurrences all number
    2
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    41 / 320 (12.81%)
    23 / 160 (14.38%)
         occurrences all number
    53
    27
    Dyspnoea
         subjects affected / exposed
    45 / 320 (14.06%)
    21 / 160 (13.13%)
         occurrences all number
    55
    21
    Epistaxis
         subjects affected / exposed
    32 / 320 (10.00%)
    5 / 160 (3.13%)
         occurrences all number
    40
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 320 (8.13%)
    16 / 160 (10.00%)
         occurrences all number
    54
    21
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    27 / 320 (8.44%)
    5 / 160 (3.13%)
         occurrences all number
    64
    5
    Constipation
         subjects affected / exposed
    39 / 320 (12.19%)
    28 / 160 (17.50%)
         occurrences all number
    56
    33
    Diarrhoea
         subjects affected / exposed
    239 / 320 (74.69%)
    28 / 160 (17.50%)
         occurrences all number
    629
    36
    Dyspepsia
         subjects affected / exposed
    31 / 320 (9.69%)
    4 / 160 (2.50%)
         occurrences all number
    41
    6
    Dysphagia
         subjects affected / exposed
    42 / 320 (13.13%)
    12 / 160 (7.50%)
         occurrences all number
    44
    12
    Nausea
         subjects affected / exposed
    89 / 320 (27.81%)
    43 / 160 (26.88%)
         occurrences all number
    120
    70
    Stomatitis
         subjects affected / exposed
    73 / 320 (22.81%)
    28 / 160 (17.50%)
         occurrences all number
    79
    47
    Vomiting
         subjects affected / exposed
    63 / 320 (19.69%)
    26 / 160 (16.25%)
         occurrences all number
    95
    39
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    28 / 320 (8.75%)
    2 / 160 (1.25%)
         occurrences all number
    36
    2
    Dermatitis acneiform
         subjects affected / exposed
    68 / 320 (21.25%)
    4 / 160 (2.50%)
         occurrences all number
    93
    5
    Dry skin
         subjects affected / exposed
    47 / 320 (14.69%)
    5 / 160 (3.13%)
         occurrences all number
    48
    6
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    19 / 320 (5.94%)
    3 / 160 (1.88%)
         occurrences all number
    22
    3
    Pruritus
         subjects affected / exposed
    29 / 320 (9.06%)
    1 / 160 (0.63%)
         occurrences all number
    49
    1
    Rash
         subjects affected / exposed
    134 / 320 (41.88%)
    11 / 160 (6.88%)
         occurrences all number
    188
    12
    Skin fissures
         subjects affected / exposed
    40 / 320 (12.50%)
    0 / 160 (0.00%)
         occurrences all number
    51
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 320 (5.31%)
    5 / 160 (3.13%)
         occurrences all number
    17
    5
    Neck pain
         subjects affected / exposed
    17 / 320 (5.31%)
    9 / 160 (5.63%)
         occurrences all number
    18
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    60 / 320 (18.75%)
    39 / 160 (24.38%)
         occurrences all number
    69
    41
    Hypokalaemia
         subjects affected / exposed
    20 / 320 (6.25%)
    10 / 160 (6.25%)
         occurrences all number
    26
    10
    Hyponatraemia
         subjects affected / exposed
    17 / 320 (5.31%)
    4 / 160 (2.50%)
         occurrences all number
    22
    4
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    25 / 320 (7.81%)
    4 / 160 (2.50%)
         occurrences all number
    29
    4
    Folliculitis
         subjects affected / exposed
    24 / 320 (7.50%)
    1 / 160 (0.63%)
         occurrences all number
    31
    1
    Paronychia
         subjects affected / exposed
    51 / 320 (15.94%)
    0 / 160 (0.00%)
         occurrences all number
    58
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2011
    -A conversion factor was introduced in order to check the total sum of platinum dose administered for patients who were switched from cisplatin to carboplatin (or vice versa) in the first-line R/M setting. -The exclusion criterion on patients with known HIV, active hepatitis B and/or hepatitis C infection was expanded by "other known severe infections, including but not limited to tuberculosis, as judged by the investigator" -The exclusion criteria regarding the use of adequate contraception was changed from ‘three months after end of treatment’ to ‘six months after end of treatment’, in order to follow the most stringent criteria regarding pregnancy after end of treatment. -The criterion for methotrexate dose continuation and escalation was changed to ‘mucositis common terminology criteria for adverse events (CTCAE) grade ≤1’ and for methotrexate dose reduction to ‘mucositis CTCAE grade >1’.
    23 Jul 2012
    - For the inclusion criteria, it was clarified that platinum based therapy can be a combination therapy. - The handling of patients that were screened but the screening images did not show progression according to Response Evaluation Criteria in Solid Tumours (RECIST) after platinum based therapy was clarified.
    15 Apr 2014
    Amendment 3 to the clinical trial protocol only involved logistical and administrative aspects of the trial.
    25 Mar 2015
    - The option to continue treatment beyond disease progression was removed because only a small fraction of the patients continued randomised treatment beyond disease progression - Visit frequency during the treatment period was reduced from weekly visits to visits every 4 weeks. - With the implementation of the amendment, tumour assessment frequency was to be according to site local standard, but not less frequently than every 16 weeks. - With the implementation of the amendment, the trial was to be considered completed after all patients had progressed and/or permanently ended study medication and the required number of death events had occurred.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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