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    Clinical Trial Results:
    Multicentre, randomised, double-blind, Phase III trial to investigate the efficacy and safety of oral BIBF 1120 plus standard docetaxel therapy compared to placebo plus standard docetaxel therapy in patients with stage IIIB/IV or recurrent non small cell lung cancer after failure of first line chemotherapy (LUME Lung 1).

    Summary
    EudraCT number
    		 2007-004803-36
    Trial protocol
    		 DE   BE   CZ   AT   DK   LT   ES   SK   GB   FR   PT   BG   IT   GR  
    Global end of trial date
    13 Nov 2017

    Results information
    Results version number
    		 v1
    This version publication date
    25 Nov 2018
    First version publication date
    25 Nov 2018
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    1199.13
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Nov 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of nintedanib as compared to matching placebo in patients with stage IIIB/IV or recurrent non small cell lung cancer (NSCLC) treated with standard therapy of docetaxel after failure of first line chemotherapy
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2008
    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
    China: 224
    Country: Number of subjects enrolled
    Korea, Republic of: 24
    Country: Number of subjects enrolled
    India: 158
    Country: Number of subjects enrolled
    South Africa: 43
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Bulgaria: 37
    Country: Number of subjects enrolled
    Belarus: 53
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    Germany: 204
    Country: Number of subjects enrolled
    Denmark: 22
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    France: 60
    Country: Number of subjects enrolled
    Georgia: 35
    Country: Number of subjects enrolled
    Greece: 35
    Country: Number of subjects enrolled
    Croatia: 12
    Country: Number of subjects enrolled
    Italy: 42
    Country: Number of subjects enrolled
    Israel: 48
    Country: Number of subjects enrolled
    Lithuania: 20
    Country: Number of subjects enrolled
    Portugal: 44
    Country: Number of subjects enrolled
    Poland: 149
    Country: Number of subjects enrolled
    Russian Federation: 176
    Country: Number of subjects enrolled
    Romania: 105
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Ukraine: 177
    Country: Number of subjects enrolled
    United Kingdom: 19
    Worldwide total number of subjects
    1773
    EEA total number of subjects
    830
    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)
    1229
    From 65 to 84 years
    543
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Two-arm, randomised, double-blind, placebo-controlled, parallel-group comparison of nintedanib versus matching placebo. In this study,1773 subjects were enrolled, 1314 subjects were randomised and entered and 1307 subjects were treated.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial drug if any of the specific entry criteria was violated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The trial had a parallel-group, double-blind, placebo-controlled design.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nintedanib plus docetaxel
    Arm description
    		 Nintedanib 200 mg twice daily administered orally in the form of a soft gelatin capsule plus docetaxel 75 milligram (mg)/square meter (m2) once every 3 weeks administered via intravenous infusion over 1 hour (h).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nintedanib 200 mg twice daily administered orally in the form of a soft gelatin capsule with dose reduction to 150 mg b.i.d. or 100 mg twice daily (b.i.d.) (according to the protocol-defined dose reduction scheme) if required. No dose increase was allowed after a dose reduction.

    Investigational medicinal product name
    docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h) with dose reduction to 60 mg/m2 if required.

    Arm title
    		 Placebo plus docetaxel
    Arm description
    		 Placebo soft gelatin capsule matching that of nintedanib 2 times daily plus docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h).
    Arm type
    		 Placebo

    Investigational medicinal product name
    docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h) with dose reduction to 60 mg/m2 if required.

    Investigational medicinal product name
    matching placebo to nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo to nintedanib twice daily administered orally in a form of a soft gelatin capsule.

    Number of subjects in period 1 [1]
    		Nintedanib plus docetaxel Placebo plus docetaxel
    Started
    655
    659
    Completed
    6
    5
    Not completed
    649
    654
         Other AE - Non−Fatal event
    54
    50
         Progressive disease (modified RECIST)
    404
    435
         Consent withdrawn by subject
    60
    42
         Other AE - Fatal event
    30
    23
         Worsening or AE of underlying disease
    64
    70
         Lost to follow-up
    5
    5
         Protocol deviation
    9
    9
         Reasons other than stated above
    20
    16
         Not treated
    3
    4
    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 the patients who were randomised after successfully completing the screening period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nintedanib plus docetaxel
    Reporting group description
    		 Nintedanib 200 mg twice daily administered orally in the form of a soft gelatin capsule plus docetaxel 75 milligram (mg)/square meter (m2) once every 3 weeks administered via intravenous infusion over 1 hour (h).

    Reporting group title
    Placebo plus docetaxel
    Reporting group description
    		 Placebo soft gelatin capsule matching that of nintedanib 2 times daily plus docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h).

    Reporting group values
    		 Nintedanib plus docetaxel Placebo plus docetaxel Total
    Number of subjects
    		 655 659 1314
    Age categorical
    Units: Subjects
    Age Continuous
    Randomised Set (RS)- Includes all randomised patients, whether patients had received study treatment or not
    Units: years
        arithmetic mean (standard deviation)
    		 59.7 ( 9.7 ) 59.8 ( 9.0 ) -
    Sex: Female, Male
    Randomised Set
    Units: Subjects
        Female
    		 179 180 359
        Male
    		 476 479 955
    Tumour histology
    Randomised Set
    Units: Subjects
        Adenocarcinoma
    		 322 336 658
        Squamous cell carcinoma
    		 276 279 555
        Other
    		 57 44 101
    Number of patients with adenocarcinoma and time since first line therapy in categories
    Randomised Set
    Units: Subjects
        <9 month
    		 206 199 405
        >=9 month
    		 112 134 246
        Missing
    		 4 3 7
        No tumour histology of adenocarcinoma
    		 333 323 656

    End points

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    End points reporting groups
    Reporting group title
    Nintedanib plus docetaxel
    Reporting group description
    		 Nintedanib 200 mg twice daily administered orally in the form of a soft gelatin capsule plus docetaxel 75 milligram (mg)/square meter (m2) once every 3 weeks administered via intravenous infusion over 1 hour (h).

    Reporting group title
    Placebo plus docetaxel
    Reporting group description
    		 Placebo soft gelatin capsule matching that of nintedanib 2 times daily plus docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h).

    Subject analysis set title
    Nitedanib 200 mg bid plus docetaxel
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Nintedanib 200 mg twice daily administered orally in the form of a soft gelatin capsule plus docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h).

    Subject analysis set title
    Nintedanib 150 bid mg plus docetaxel
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Nintedanib 150 mg twice daily administered orally in the form of a soft gelatin capsule plus docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h).

    Primary: Progression Free Survival (PFS) as assessed by central independent review

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    End point title
    		 Progression Free Survival (PFS) as assessed by central independent review
    End point description
    Progression Free Survival (PFS) as assessed by central independent review according to the modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST) (version 1.0) criteria. Progression free survival (PFS) is defined as the duration of time from date of randomisation to date of progression or death (whatever occurs earlier). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
    End point type
    Primary
    End point timeframe
    From randomisation until cut-off date 2 November 2010 (when 713 PFS events were observed)
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    565 [1]
    569 [2]
    Units: months
        median (inter-quartile range (Q1-Q3))
    3.4 (1.5 to 5.7)
    2.7 (1.4 to 4.6)
    Notes
    [1] - Randomised Set
    [2] - Randomised Set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0019 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.92
    Notes
    [3] - HR below 1 favors nintedanib
    [4] - HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)

    Secondary: Overall Survival (Key secondary endpoint)

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    End point title
    		 Overall Survival (Key secondary endpoint)
    End point description
    Overall Survival (OS) defined as the duration from randomisation to death (irrespective of the reason of death). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. A fixed-sequence-testing was implemented for key secondary endpoint if both the primary and the follow-up analysis showed a treatment benefit (P<0.05) of nintedanib over placebo. In this case, the OS would be tested using hierarchical testing of statistical hypotheses in (1) patients with adenocarcinoma and <9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013 (approximately 48 months or 1151 deaths among all patients )
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [5]
    659 [6]
    Units: months
    median (inter-quartile range (Q1-Q3))
        Adenocarcinoma and <9 months|
    10.9 (5.1 to 21.9)
    7.9 (4.5 to 14.5)
        Adenocarcinoma|
    12.6 (5.5 to 24.2)
    10.3 (5.5 to 19.9)
        All patients|
    10.1 (5.0 to 19.4)
    9.1 (4.8 to 17.2)
    Notes
    [5] - Randomised Set
    [6] - Randomised Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hierarchical testing was tested in a fixed sequence of statistical hypotheses in (1) patients with adenocarcinoma and <9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been rejected. Overall survival for patients with adenocarcinoma and <9 months since start of first line therapy.
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0073 [8]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.92
    Notes
    [7] - The overall alpha level followed a Lan-DeMets spending function with O’Brien-Fleming shape parameter to preserve an overall 2-sided alpha level of 0.05. HR below 1 favors nintedanib
    [8] - HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs 1 - one pat. had 2), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Hierarchical testing was tested in a fixed sequence of statistical hypotheses in (1) patients with adenocarcinoma and <9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been rejected. Overall survival for patients with adenocarcinoma.
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0359 [10]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.99
    Notes
    [9] - The overall alpha level followed a Lan-DeMets spending function with O’Brien-Fleming shape parameter to preserve an overall 2-sided alpha level of 0.05. HR below 1 favors nintedanib
    [10] - HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs 1 - one pat. had 2), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Hierarchical testing was tested in a fixed sequence of statistical hypotheses in (1) patients with adenocarcinoma and <9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been rejected. Overall survival for all patients.
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.272 [12]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.05
    Notes
    [11] - The overall alpha level followed a Lan-DeMets spending function with O’Brien-Fleming shape parameter to preserve an overall 2-sided alpha level of 0.05. HR below 1 favors nintedanib
    [12] - HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs 1 - one pat. had 2), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)

    Secondary: Follow-up analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review

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    End point title
    		 Follow-up analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review
    End point description
    Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [13]
    659 [14]
    Units: months
        median (inter-quartile range (Q1-Q3))
    3.5 (1.5 to 5.7)
    2.7 (1.4 to 5.5)
    Notes
    [13] - Randomised Set
    [14] - Randomised Set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.007 [16]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 0.96
    Notes
    [15] - HR below 1 favors nintedanib
    [16] - HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)

    Secondary: Follow-up analysis of Progression Free Survival (PFS) as Assessed by investigator

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    End point title
    		 Follow-up analysis of Progression Free Survival (PFS) as Assessed by investigator
    End point description
    Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by investigator according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [17]
    659 [18]
    Units: months
        median (inter-quartile range (Q1-Q3))
    4.2 (2.1 to 7.1)
    3.0 (1.4 to 5.7)
    Notes
    [17] - Randomised Set
    [18] - Randomised Set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0012 [20]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 0.93
    Notes
    [19] - HR below 1 favors nintedanib
    [20] - HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)

    Secondary: Objective Tumour Response

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    End point title
    		 Objective Tumour Response
    End point description
    Confirmed objective response is defined as confirmed Complete Response (CR) and Partial Response (PR) and evaluated according to the modified RECIST criteria version 1.0. As per RECIST v1.0, Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. This endpoint was analysed based on the central independent reviewer as well as the investigator.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [21]
    659 [22]
    Units: % of participants
    number (not applicable)
        central independent reviewer|
    4.4
    3.3
        investigator assessment|
    10.4
    7.6
    Notes
    [21] - Randomised Set
    [22] - Randomised Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on the central independent review
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.3067 [24]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 2.39
    Notes
    [23] - An odds ratio >1 indicates a benefit to nintedanib
    [24] - Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis based on the investigator's assessment
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.0761 [26]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 2.08
    Notes
    [25] - An odds ratio >1 indicates a benefit to nintedanib
    [26] - Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1)

    Secondary: Duration of confirmed objective tumour response

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    End point title
    		 Duration of confirmed objective tumour response
    End point description
    The duration of objective response is the time from first documented (CR) or (PR) to the time of progression or death and evaluated according to the modified RECIST criteria version 1.0. As per RECIST v1.0, Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [27]
    659 [28]
    Units: months
    median (inter-quartile range (Q1-Q3))
        central independent reviewer|
    4.3 (3.0 to 5.7)
    4.3 (2.8 to 8.5)
        investigator assessment|
    5.7 (4.1 to 10.0)
    5.5 (3.9 to 9.6)
    Notes
    [27] - Randomised Set
    [28] - Randomised Set
    No statistical analyses for this end point

    Secondary: Time to Confirmed Objective Tumour Response

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    End point title
    		 Time to Confirmed Objective Tumour Response
    End point description
    Time to confirmed objective response is defined as time from randomisation to the date of first documented (CR) or (PR) and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [29]
    659 [30]
    Units: months
    median (inter-quartile range (Q1-Q3))
        central independent reviewer|
    1.5 (1.4 to 3.0)
    2.9 (1.4 to 5.6)
        investigator assessment|
    2.6 (1.4 to 4.0)
    2.7 (1.4 to 4.1)
    Notes
    [29] - Randomised Set
    [30] - Randomised Set
    No statistical analyses for this end point

    Secondary: Disease Control

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    End point title
    		 Disease Control
    End point description
    Disease control was defined as a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) and evaluated according to the modified RECIST criteria version 1.0. As per RECIST v1.0 for target lesions : Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. This endpoint was analysed based on the central independent reviewer as well as the investigator.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [31]
    659 [32]
    Units: % of participants
    number (not applicable)
        central independent reviewer|
    54.0
    41.3
        investigator assessment|
    63.4
    51.4
    Notes
    [31] - Randomised Set
    [32] - Randomised Set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on the central independent review
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.0001 [34]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.35
         upper limit
    		 2.09
    Notes
    [33] - An odds ratio >1 indicates a benefit to nintedanib
    [34] - Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis based on investigator's assessment
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 [35]
    P-value
    		 < 0.0001 [36]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.31
         upper limit
    		 2.05
    Notes
    [35] - An odds ratio >1 indicates a benefit to nintedanib
    [36] - Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1)

    Secondary: Duration of Disease Control

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    End point title
    		 Duration of Disease Control
    End point description
    The duration of disease control was defined as the time from randomisation to the date of disease progression or death (which ever occurs first) for patients with disease control. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [37]
    659 [38]
    Units: months
    median (inter-quartile range (Q1-Q3))
        central independent reviewer|
    5.6 (4.1 to 7.1)
    5.6 (4.0 to 8.2)
        investigator assessment|
    5.7 (4.2 to 8.4)
    5.6 (4.1 to 8.5)
    Notes
    [37] - Randomised Set
    [38] - Randomised Set
    No statistical analyses for this end point

    Secondary: Change from baseline in tumour size

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    End point title
    		 Change from baseline in tumour size
    End point description
    Percentage change from baseline in tumour size is defined as decrease in the sum of the longest diameter of the target lesion. Presented means are in fact adjusted best means percentage changes generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) This endpoint was analysed based on the central independent reviewer as well as the investigator.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [39]
    659 [40]
    Units: percentage of change in tumor size in mm
    arithmetic mean (confidence interval 95%)
        central independent reviewer|
    -4.87 (-6.62 to -3.12)
    0.58 (-1.19 to 2.35)
        investigator assessment|
    -10.34 (-12.58 to -8.11)
    -2.14 (-4.39 to 0.10)
    Notes
    [39] - Randomised Set
    [40] - Randomised Set
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis based on the investigator's assessment
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [41]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [41] - P-value generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on the central independent review
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [42]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [42] - P-value generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)

    Secondary: Clinical improvement

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    End point title
    		 Clinical improvement
    End point description
    Clinical improvement was defined as the time from randomisation to deterioration in body weight and/or Eastern Cooperative Oncology group performance score (ECOG PS) whichever occurred first. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [43]
    659 [44]
    Units: months
        median (inter-quartile range (Q1-Q3))
    5.9 (2.1 to 22.7)
    5.2 (2.1 to 19.2)
    Notes
    [43] - Randomised set
    [44] - Randomised set
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.7282 [46]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.21
    Notes
    [45] - HR below 1 favors nintedanib
    [46] - HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs 1 - one pat.had 2), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)

    Secondary: Quality of life (QoL)

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    End point title
    		 Quality of life (QoL)
    End point description
    QoL was measured by standardised questionnaires (EQ-5D, EORTC QLQ-C30, EORTC QLQ-LC13). The EORTC QLQ-C30 comprises of 30 questions, using both multi-item scales and single-item measures. EORTC LC-13 comprises of 13 questions incorporating 1 multi-item scale and a series of single items. The following were the main points of interest: Time to deterioration of cough (QLQ-LC13 question 1), Time to deterioration of dyspnoea (QLQ-LC13, composite of questions 3 to 5), Time to deterioration of pain (QLQ- C30, composite of questions 9 and 19). Time to deterioration of cough, dyspnoea and pain was defined as the time to a 10-point increase from the baseline score. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 15 February 2013
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [47]
    659 [48]
    Units: months
    median (inter-quartile range (Q1-Q3))
        Time to deterioration of cough|
    4.3 (1.6 to 11.8)
    3.5 (1.5 to 12.6)
        Time to deterioration of dyspnoea|
    2.0 (0.8 to 4.2)
    2.1 (0.8 to 4.5)
        Time to deterioration of pain|
    2.8 (1.1 to 6.5)
    2.6 (0.8 to 5.8)
    Notes
    [47] - Randomised set
    [48] - Randomised set
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis evaluating the time to deterioration of cough
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 = 0.1858 [50]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.05
    Notes
    [49] - HR below 1 favors nintedanib
    [50] - HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >=1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis evaluating the time to deterioration of dyspnoea
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.5203 [52]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.2
    Notes
    [51] - HR below 1 favors nintedanib
    [52] - HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >=1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Analysis evaluating the time to deterioration of pain
    Comparison groups
    Nintedanib plus docetaxel v Placebo plus docetaxel
    Number of subjects included in analysis
    1314
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 = 0.4373 [54]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.09
    Notes
    [53] - HR below 1 favors nintedanib
    [54] - HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >= 1), tumour histology (squamous vs non-squamous), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)

    Secondary: Dose normalised predose plasma concentration at steady state (Cpre,ss,norm) of nintedanib and of its metabolites BIBF 1202 and BIBF 1202 glucuronide

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    End point title
    		 Dose normalised predose plasma concentration at steady state (Cpre,ss,norm) of nintedanib and of its metabolites BIBF 1202 and BIBF 1202 glucuronide
    End point description
    Geometric mean of dose normalised predose plasma concentration (Cpre,ss,norm) of nintedanib and of its metabolites BIBF 1202 and BIBF 1202 glucuronide evaluated at steady state based on course 2 and 3. If only one value was available and valid, then this value was used for calculation of Cpre,ss,norm.
    End point type
    Secondary
    End point timeframe
    Before the administration of nintedanib or placebo and between a window of 30 mins to an hour after administration of trial drug during Course 2 and between 1 and 3 hours after administration of trial drug during Course 3
    End point values
    		 Nitedanib 200 mg bid plus docetaxel Nintedanib 150 bid mg plus docetaxel
    Number of subjects analysed
    454
    38
    Units: ng/mL/mg
    geometric mean (geometric coefficient of variation)
        nintedanib|
    0.0707 ( 77.7 )
    0.106 ( 52.6 )
        metabolite BIBF 1202|
    0.0907 ( 127 )
    0.190 ( 152 )
        metabolite BIBF 1202 glucuronide|
    1.04 ( 153 )
    1.94 ( 135 )
    No statistical analyses for this end point

    Secondary: Incidence and intensity of adverse events

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    End point title
    		 Incidence and intensity of adverse events
    End point description
    Incidence and intensity of adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The worst CTCAE grade per patient is reported and MedDRA version 15.1 used. Serious signs and symptoms of progressive disease were reported as an adverse event in analysis of this endpoint. Treated set- all randomised patients who were documented to have taken at least 1 dose of study medication . Patients were allocated to the treatment groups according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    From the first drug administration until 28 days after the last drug administration, up to 42 months
    End point values
    		 Nintedanib plus docetaxel Placebo plus docetaxel
    Number of subjects analysed
    655 [55]
    659 [56]
    Units: % of participants
    number (not applicable)
        Grade 1
    5.7
    8.2
        Grade 2
    16.6
    20.5
        Grade 3
    21.2
    21.2
        Grade 4
    33.7
    31.3
        Grade 5
    16.4
    11.8
    Notes
    [55] - Treated set
    [56] - Treated set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after the last drug administration, up to 42 months
    Adverse event reporting additional description
    Number of participants at risk corresponds to all randomised patients who were documented to have taken at least 1 dose of study medication . Patients were allocated to the treatment groups according to the treatment actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo plus docetaxel
    Reporting group description
    		 Placebo soft gelatin capsule matching that of nintedanib 2 times daily plus docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h).

    Reporting group title
    Nintedanib plus docetaxel
    Reporting group description
    		 Nintedanib 200 mg twice daily administered orally in the form of a soft gelatin capsule plus docetaxel 75 mg/m2 once every 3 weeks administered via intravenous infusion over 1 hour (h).

    Serious adverse events
    		 Placebo plus docetaxel Nintedanib plus docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    206 / 655 (31.45%)
    224 / 652 (34.36%)
         number of deaths (all causes)
    562
    565
         number of deaths resulting from adverse events
    6
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer metastatic
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         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
    17 / 655 (2.60%)
    25 / 652 (3.83%)
         occurrences causally related to treatment / all
    0 / 17
    1 / 25
         deaths causally related to treatment / all
    0 / 15
    1 / 25
    Metastases to central nervous system
         subjects affected / exposed
    2 / 655 (0.31%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastases to chest wall
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to kidney
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    0 / 655 (0.00%)
    3 / 652 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Metastases to skin
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 655 (0.15%)
    3 / 652 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Hypotension
         subjects affected / exposed
    1 / 655 (0.15%)
    3 / 652 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian artery thrombosis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (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
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombosis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Venous thrombosis limb
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 655 (0.61%)
    7 / 652 (1.07%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Chest discomfort
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest pain
         subjects affected / exposed
    8 / 655 (1.22%)
    7 / 652 (1.07%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Condition aggravated
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 655 (0.15%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Device occlusion
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (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
    1 / 655 (0.15%)
    7 / 652 (1.07%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Extravasation
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeling abnormal
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    8 / 655 (1.22%)
    11 / 652 (1.69%)
         occurrences causally related to treatment / all
    2 / 8
    4 / 12
         deaths causally related to treatment / all
    0 / 6
    0 / 8
    Malaise
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 655 (0.15%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Oedema peripheral
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organ failure
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pain
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    9 / 655 (1.37%)
    7 / 652 (1.07%)
         occurrences causally related to treatment / all
    3 / 11
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 655 (0.31%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    3 / 655 (0.46%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 655 (0.15%)
    3 / 652 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Alveolitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 655 (0.15%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    2 / 655 (0.31%)
    3 / 652 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dysphonia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    30 / 655 (4.58%)
    24 / 652 (3.68%)
         occurrences causally related to treatment / all
    2 / 33
    1 / 25
         deaths causally related to treatment / all
    1 / 12
    0 / 15
    Haemoptysis
         subjects affected / exposed
    7 / 655 (1.07%)
    6 / 652 (0.92%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Hypoxia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    8 / 655 (1.22%)
    8 / 652 (1.23%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pleuritic pain
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 655 (0.15%)
    3 / 652 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 655 (0.92%)
    4 / 652 (0.61%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 4
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    3 / 655 (0.46%)
    5 / 652 (0.77%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 5
         deaths causally related to treatment / all
    1 / 3
    0 / 3
    Respiratory failure
         subjects affected / exposed
    2 / 655 (0.31%)
    8 / 652 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 8
    Respiratory depression
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (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
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal stenosis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depression
         subjects affected / exposed
    0 / 655 (0.00%)
    4 / 652 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    3 / 655 (0.46%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mental disorder due to a general medical condition
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Panic attack
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    2 / 655 (0.31%)
    3 / 652 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 655 (0.46%)
    6 / 652 (0.92%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    2 / 655 (0.31%)
    3 / 652 (0.46%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         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
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 655 (0.31%)
    5 / 652 (0.77%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 655 (0.46%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 655 (0.00%)
    4 / 652 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericarditis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    0 / 655 (0.00%)
    4 / 652 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diplegia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiduritis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lethargy
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Monoparesis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restless legs syndrome
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 655 (0.92%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    19 / 655 (2.90%)
    30 / 652 (4.60%)
         occurrences causally related to treatment / all
    12 / 20
    27 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    21 / 655 (3.21%)
    21 / 652 (3.22%)
         occurrences causally related to treatment / all
    20 / 24
    18 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 655 (0.61%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    13 / 655 (1.98%)
    16 / 652 (2.45%)
         occurrences causally related to treatment / all
    11 / 13
    13 / 16
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Diverticulum intestinal
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Nausea
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         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 / 655 (0.46%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 655 (1.07%)
    8 / 652 (1.23%)
         occurrences causally related to treatment / all
    3 / 7
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystocholangitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 655 (0.15%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         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 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder perforation
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess rupture
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 655 (0.61%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Empyema
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Folliculitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (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
    2 / 655 (0.31%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 655 (0.15%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 655 (0.46%)
    4 / 652 (0.61%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Lung abscess
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infection
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenic sepsis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Opportunistic infection
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    26 / 655 (3.97%)
    17 / 652 (2.61%)
         occurrences causally related to treatment / all
    8 / 28
    2 / 17
         deaths causally related to treatment / all
    2 / 8
    0 / 3
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 655 (0.46%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 655 (0.46%)
    7 / 652 (1.07%)
         occurrences causally related to treatment / all
    0 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 1
    3 / 5
    Septic shock
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 652 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Streptococcal infection
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 652 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 655 (0.46%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 655 (0.15%)
    5 / 652 (0.77%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypercalcaemia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 655 (0.31%)
    1 / 652 (0.15%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 655 (0.00%)
    4 / 652 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo plus docetaxel Nintedanib plus docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    547 / 655 (83.51%)
    569 / 652 (87.27%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    55 / 655 (8.40%)
    186 / 652 (28.53%)
         occurrences all number
    76
    320
    Aspartate aminotransferase increased
         subjects affected / exposed
    43 / 655 (6.56%)
    146 / 652 (22.39%)
         occurrences all number
    53
    242
    Blood alkaline phosphatase increased
         subjects affected / exposed
    9 / 655 (1.37%)
    38 / 652 (5.83%)
         occurrences all number
    9
    43
    Haemoglobin decreased
         subjects affected / exposed
    79 / 655 (12.06%)
    71 / 652 (10.89%)
         occurrences all number
    103
    99
    Neutrophil count decreased
         subjects affected / exposed
    234 / 655 (35.73%)
    237 / 652 (36.35%)
         occurrences all number
    574
    682
    White blood cell count decreased
         subjects affected / exposed
    160 / 655 (24.43%)
    158 / 652 (24.23%)
         occurrences all number
    402
    476
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    35 / 655 (5.34%)
    31 / 652 (4.75%)
         occurrences all number
    38
    34
    Dysgeusia
         subjects affected / exposed
    34 / 655 (5.19%)
    31 / 652 (4.75%)
         occurrences all number
    43
    35
    Headache
         subjects affected / exposed
    42 / 655 (6.41%)
    39 / 652 (5.98%)
         occurrences all number
    44
    41
    Peripheral sensory neuropathy
         subjects affected / exposed
    47 / 655 (7.18%)
    40 / 652 (6.13%)
         occurrences all number
    51
    45
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    43 / 655 (6.56%)
    33 / 652 (5.06%)
         occurrences all number
    49
    40
    Neutropenia
         subjects affected / exposed
    78 / 655 (11.91%)
    77 / 652 (11.81%)
         occurrences all number
    193
    142
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    61 / 655 (9.31%)
    52 / 652 (7.98%)
         occurrences all number
    77
    58
    Chest pain
         subjects affected / exposed
    57 / 655 (8.70%)
    49 / 652 (7.52%)
         occurrences all number
    71
    52
    Fatigue
         subjects affected / exposed
    175 / 655 (26.72%)
    192 / 652 (29.45%)
         occurrences all number
    231
    252
    Oedema peripheral
         subjects affected / exposed
    42 / 655 (6.41%)
    35 / 652 (5.37%)
         occurrences all number
    52
    38
    Pyrexia
         subjects affected / exposed
    92 / 655 (14.05%)
    77 / 652 (11.81%)
         occurrences all number
    129
    108
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    37 / 655 (5.65%)
    35 / 652 (5.37%)
         occurrences all number
    45
    41
    Constipation
         subjects affected / exposed
    76 / 655 (11.60%)
    35 / 652 (5.37%)
         occurrences all number
    97
    43
    Diarrhoea
         subjects affected / exposed
    134 / 655 (20.46%)
    267 / 652 (40.95%)
         occurrences all number
    196
    518
    Nausea
         subjects affected / exposed
    118 / 655 (18.02%)
    158 / 652 (24.23%)
         occurrences all number
    172
    231
    Stomatitis
         subjects affected / exposed
    56 / 655 (8.55%)
    62 / 652 (9.51%)
         occurrences all number
    67
    78
    Vomiting
         subjects affected / exposed
    56 / 655 (8.55%)
    102 / 652 (15.64%)
         occurrences all number
    96
    152
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    108 / 655 (16.49%)
    97 / 652 (14.88%)
         occurrences all number
    126
    110
    Dyspnoea
         subjects affected / exposed
    83 / 655 (12.67%)
    102 / 652 (15.64%)
         occurrences all number
    98
    111
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    119 / 655 (18.17%)
    107 / 652 (16.41%)
         occurrences all number
    121
    107
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    38 / 655 (5.80%)
    31 / 652 (4.75%)
         occurrences all number
    43
    35
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    46 / 655 (7.02%)
    40 / 652 (6.13%)
         occurrences all number
    52
    55
    Back pain
         subjects affected / exposed
    44 / 655 (6.72%)
    27 / 652 (4.14%)
         occurrences all number
    53
    34
    Myalgia
         subjects affected / exposed
    45 / 655 (6.87%)
    40 / 652 (6.13%)
         occurrences all number
    64
    53
    Pain in extremity
         subjects affected / exposed
    41 / 655 (6.26%)
    31 / 652 (4.75%)
         occurrences all number
    45
    39
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    102 / 655 (15.57%)
    145 / 652 (22.24%)
         occurrences all number
    115
    173

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2009
    With Protocol Amendment 1, Revise typing errors that were detected in the original protocol. Addition of a statement with regard to the tasks and members of the Data Monitoring Committee (DMC), addition of a statement concerning docetaxel hypersensitivity, addition of an additional safety laboratory test in case of bilirubin increase, addition of food intake on the days of and the days preceding pharmacokinetic blood sampling, clarification of one exclusion criterion, allow extension of screening period in exceptional situations
    12 Feb 2014
    Prior to the amendment, patients who had stopped active treatment were to be followed-up until death or lost to follow-up. Since the analysis of the key secondary end point OS was complete, the follow-up period for patients who had stopped active treatment was reduced to 28 days which was the reporting period for AEs (after last administration of trial medication). With Protocol Amendment 2, the end of the trial was redefined. The clinical trial was considered completed as soon as the last patient had completed the first follow-up visit which was recommended to take place at least 28 days after end of active treatment (EOT). It was clarified that data collected after the cut-off date of the final OS analysis will be reported in a revision of the CTR.
    16 Apr 2015
    The European Commission granted marketing authorisation for nintedanib (Vargatef®) in combination with docetaxel for the treatment of patients with locally advanced, metastatic or recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy on 21 November 2014. With Protocol Amendment 3, all patients still on treatment were unblinded; patients in the placebo arm were given the opportunity to be treated with BIBF1120 and patients in the active arm were allowed to continue to be treated with BIBF1120. Since the trial was complete and no further cumulative data analyses were planned, efficacy assessment were to be done according to standard practice but were no longer collected in the CRF. Safety assessments were to be done as clinically indicated. Adverse events (AEs) were still reported in the CRF. Reporting requirements for SAEs remained the same. All sections f the clinical trial protocol affected by unblinding of the remaining patients, the switch from placebo to BIBF 1120, and the new procedures regarding data collection were revised. It was clarified that only clinically significant physical examination findings were to be reported in the CRF as an AE. New packaging of BIBF 1120 and a new distribution process were described. It was clarified that placebo was no longer provided to patients. The end of the trial was redefined. The clinical trial was considered completed as soon as the last patient was transferred to another programme or had completed the first follow-up visit which was recommended to take place 28 days after end of active treatment.

    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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