Flag of the European Union EU Clinical Trials Register Help

Clinical trials

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

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

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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

    < Back to search results

    Download PDF

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

    Summary
    EudraCT number
    		 2008-002072-10
    Trial protocol
    		 HU   LV   NL   IE   SE   RO   PL   DE   BG   DK  
    Global end of trial date
    30 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2016
    First version publication date
    23 Dec 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1199.14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00806819
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    173 Binger Strasse, 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
    15 Feb 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jul 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2015
    Was the trial ended prematurely?
    Yes
    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 pemetrexed 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. Rescue medication was allowed for all patients as required.
    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
    Hong Kong: 9
    Country: Number of subjects enrolled
    Malaysia: 44
    Country: Number of subjects enrolled
    Taiwan: 43
    Country: Number of subjects enrolled
    Korea, Republic of: 114
    Country: Number of subjects enrolled
    Philippines: 38
    Country: Number of subjects enrolled
    Thailand: 73
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    New Zealand: 33
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 16
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Latvia: 28
    Country: Number of subjects enrolled
    Moldova, Republic of: 8
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 10
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Romania: 25
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    Turkey: 42
    Country: Number of subjects enrolled
    Ukraine: 26
    Country: Number of subjects enrolled
    Serbia: 90
    Country: Number of subjects enrolled
    Canada: 53
    Country: Number of subjects enrolled
    United States: 133
    Country: Number of subjects enrolled
    Brazil: 128
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Ecuador: 3
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Panama: 6
    Country: Number of subjects enrolled
    Peru: 49
    Country: Number of subjects enrolled
    Argentina: 22
    Country: Number of subjects enrolled
    Chile: 37
    Worldwide total number of subjects
    1116
    EEA total number of subjects
    102
    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)
    766
    From 65 to 84 years
    344
    85 years and over
    6

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 5 patients at one investigator site were excluded from the enrollment count because of site non-compliance. In the subject disposition , started are actually the randomised patients and completed patients were On-treatment at analysis DBL date (15 February 2013).

    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 an 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, Carer, Assessor
    Blinding implementation details
    This was a randomised, double-blind and placebo-controlled study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nintedanib plus pemetrexed
    Arm description
    		 Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course administered plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
    Arm type
    		 Active comparator

    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 a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course. If required the dose of nitedanib could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. No dose increase was allowed after a dose reduction.

    Investigational medicinal product name
    pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Arm title
    		 Placebo plus pemetrexed
    Arm description
    		 Placebo soft gelatin capsule matching that of nintedanib twice daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required the dose of placebo could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally. If required the dose of placebo could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d.

    Investigational medicinal product name
    pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Number of subjects in period 1 [1]
    		Nintedanib plus pemetrexed Placebo plus pemetrexed
    Started
    353
    360
    Completed
    7
    2
    Not completed
    346
    358
         Adverse event, serious fatal
    8
    9
         Adverse event, non-fatal
    30
    31
         Worsening or AE of underlying disease
    18
    25
         Refused to continue taking trial medication
    32
    29
         progressive disease (modified RECIST )
    217
    216
         Lost to follow-up
    1
    -
         Protocol deviation
    9
    4
         Not treated
    6
    3
         Reasons other than stated above
    25
    41
    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 and received at least one of the trial medication.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Nintedanib plus pemetrexed
    Reporting group description
    		 Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course administered plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Placebo plus pemetrexed
    Reporting group description
    		 Placebo soft gelatin capsule matching that of nintedanib twice daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required the dose of placebo could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed Total
    Number of subjects
    		 353 360 713
    Age categorical
    Units: Subjects
    Age Continuous
    Randomised set uncut (RS): all patients who were randomised whether patients had received study treatment or not. Patients were allocated to the treatment groups as randomised, regardless of the actual medication taken.
    Units: years
        arithmetic mean (standard deviation)
    		 59.2 ( 10.3 ) 58.7 ( 10.9 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 158 152 310
        Male
    		 195 208 403

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Nintedanib plus pemetrexed
    Reporting group description
    		 Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course administered plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Placebo plus pemetrexed
    Reporting group description
    		 Placebo soft gelatin capsule matching that of nintedanib twice daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required the dose of placebo could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Subject analysis set title
    Nintedanib 200 mg bid plus pemetrexed
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion.

    Subject analysis set title
    Nintedanib 150 mg bid Plus pemetrexed
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Nintedanib 150 mg twice daily administered orally in a form of a soft gelatin capsule plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion.

    Primary: Progression Free Survival (PFS) as Assessed by Central Independent Review

    		 Close Top of page
    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 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. Randomised set uncut (RS): all patients who were randomised whether patients had received study treatment or not. Patients were allocated to the treatment groups as randomised, regardless of the actual medication taken.
    End point type
    Primary
    End point timeframe
    From randomisation until cut-off date 9 July 2012
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [1]
    360 [2]
    Units: months
        median (inter-quartile range (Q1-Q3))
    4.4 (2.3 to 9.5)
    3.6 (1.4 to 7.5)
    Notes
    [1] - RS
    [2] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) was used to obtain the HR, CI and p-value. HR below 1 favors nintedanib.
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0435
    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

    Secondary: Overall Survival (Key Secondary Endpoint)

    		 Close Top of page
    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.
    End point type
    Secondary
    End point timeframe
    From randomisation until data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [3]
    360 [4]
    Units: months
        median (inter-quartile range (Q1-Q3))
    12 (7 to 24.2)
    12.7 (5.4 to 24)
    Notes
    [3] - RS
    [4] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) was used to obtain HR, CI and p-value. HR below 1 favors nintedanib.
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.894
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.21

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

    		 Close Top of page
    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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [5]
    360 [6]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    4.4 (2.3 to 9.5)
    3.4 (1.4 to 7.5)
    Notes
    [5] - RS
    [6] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) to obtain HR, CI and p-value. HR below 1 favors nintedanib
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0506
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1

    Secondary: Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator

    		 Close Top of page
    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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [7]
    360 [8]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    5.3 (2.6 to 9.4)
    4.3 (1.9 to 8.3)
    Notes
    [7] - RS
    [8] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) to obtain HR, CI and p-value. HR below 1 favors nintedanib.
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0865 [9]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.02
    Notes
    [9] - HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (y vs no)

    Secondary: Objective tumor response

    		 Close Top of page
    End point title
    		 Objective tumor 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. 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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [10]
    360 [11]
    Units: % of participants
    number (not applicable)
        Central independent reviewer
    9.1
    8.3
        Investigator assessment
    15
    13.3
    Notes
    [10] - RS
    [11] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on the central independent review
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7279 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.85
    Notes
    [12] - Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1). An odds ratio >1 indicates a benefit to nintedanib.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis based on the investigator's assessment
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.518 [13]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.76
    Notes
    [13] - Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1). An odds ratio >1 indicates a benefit to nintedanib.

    Secondary: Duration of Confirmed Objective Tumour Response

    		 Close Top of page
    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. 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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [14]
    360 [15]
    Units: Months
    median (inter-quartile range (Q1-Q3))
        central independent reviewer (N=32, 30)
    6.9 (5.1 to 11.3)
    4.4 (3.3 to 8.9)
        Investigator assessment (N=53, 48)
    6.5 (4.4 to 12.7)
    7.2 (4.2 to 16.2)
    Notes
    [14] - RS
    [15] - RS
    No statistical analyses for this end point

    Secondary: Time to Confirmed Objective Tumour Response

    		 Close Top of page
    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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [16]
    360 [17]
    Units: Months
    median (inter-quartile range (Q1-Q3))
        Central independent review (N=32, 30)
    2.6 (1.4 to 4)
    2.7 (1.4 to 4.2)
        Investigator assessment (N=53, 48)
    2.6 (1.4 to 3)
    2.8 (1.4 to 3.1)
    Notes
    [16] - RS
    [17] - RS
    No statistical analyses for this end point

    Secondary: Disease control

    		 Close Top of page
    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. 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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [18]
    360 [19]
    Units: % of participants
    number (not applicable)
        Central independent review (N=215, 192)
    60.9
    53.3
        Investigator assessment (N=233, 217)
    66
    60.3
    Notes
    [18] - RS
    [19] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on the central independent review
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0387 [20]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.85
    Notes
    [20] - Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1). An odds ratio >1 indicates a benefit to nintedanib.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis based on investigator's assessment
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1071 [21]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.75
    Notes
    [21] - Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1). An odds ratio >1 indicates a benefit to nintedanib.

    Secondary: Duration of Disease Control

    		 Close Top of page
    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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [22]
    360 [23]
    Units: Months
    median (inter-quartile range (Q1-Q3))
        Central independent review (N=215, 192)
    7.4 (4.3 to 11.2)
    6.8 (4.2 to 12.5)
        Investigator assessment (N=233, 217)
    6.9 (4.4 to 12.5)
    6.8 (4.4 to 11.1)
    Notes
    [22] - RS
    [23] - RS
    No statistical analyses for this end point

    Secondary: Change From Baseline in Tumour Size

    		 Close Top of page
    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 (adenocarcinoma vs. non-adenocarcinoma), 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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [24]
    360 [25]
    Units: percentage of change in tumor size in mm
    arithmetic mean (confidence interval 95%)
        Central independent review (N=298, 305)
    -10.1 (-12.63 to -7.58)
    -7.53 (-10.03 to -5.04)
        Investigator assessment (N=322, 325)
    -15.6 (-18.75 to -12.46)
    -11.28 (-14.42 to -8.15)
    Notes
    [24] - RS
    [25] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis based on the central independent review
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1558 [26]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [26] - P-value generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), 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 based on the investigator's assessment
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0565 [27]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [27] - P-value generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)

    Secondary: clinical improvement.

    		 Close Top of page
    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 data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [28]
    360 [29]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    7.2 (2.8 to 21.9)
    7.5 (1.8 to 24.2)
    Notes
    [28] - RS
    [29] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio, confidence interval and p-value obtained from a proportional-hazards model stratified by baseline ECOG PS (0 vs >=1), tumor histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs. no) and prior treatment with bevacizumab (yes vs. no). HR below 1 favors nintedanib
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5068
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.16

    Secondary: Quality of Life (QoL)

    		 Close Top of page
    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. 99999: As only 43.9% of patients had a deterioration of cough by the cut-off date, the 75th percentile was not estimable.
    End point type
    Secondary
    End point timeframe
    From randomisation until data cut-off (15 February 2013), Up to 30 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    353 [30]
    360 [31]
    Units: Months
    median (inter-quartile range (Q1-Q3))
        Time to deterioration of cough
    6 (2.2 to 23.6)
    4.3 (1.4 to 99999)
        Time to deterioration of dyspnoea
    2.4 (0.9 to 6.4)
    2 (0.8 to 5.7)
        Time to deterioration of pain
    2.8 (1.2 to 7)
    2.7 (1.1 to 8)
    Notes
    [30] - RS
    [31] - RS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis evaluating the time to deterioration of cough. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >=1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no). HR below 1 favors nintedanib.
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1181
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.05
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis evaluating the time to deterioration of dyspnoea. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >=1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no). HR below 1 favors nintedanib
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4264
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.12
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Analysis evaluating the time to deterioration of pain. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >= 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no). HR below 1 favors nintedanib
    Comparison groups
    Nintedanib plus pemetrexed v Placebo plus pemetrexed
    Number of subjects included in analysis
    713
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8929
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.23

    Secondary: Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202and BIBF 1202 Glucuronide

    		 Close Top of page
    End point title
    		 Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202and 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. Pharmacokinetic set (PKS): All patients in the treated set who were documented to have received at least 1 dose of nintedanib and who had at least 1 valid drug plasma concentration available.
    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
    		 Nintedanib 200 mg bid plus pemetrexed Nintedanib 150 mg bid Plus pemetrexed
    Number of subjects analysed
    188 [32]
    40 [33]
    Units: ng/mL/mg
    geometric mean (geometric coefficient of variation)
        Nintedanib BIBF 1120 (N=188, 39)
    0.0883 ( 66.4 )
    0.103 ( 72.9 )
        Nintedanib BIBF 1202 (N=188, 40)
    0.131 ( 123 )
    0.151 ( 125 )
        Nintedanib BIBF 1202 glucuronide (N=184, 39)
    1.4 ( 169 )
    1.72 ( 185 )
    Notes
    [32] - PKS
    [33] - PKS
    No statistical analyses for this end point

    Secondary: Incidence and Intensity of Adverse Events

    		 Close Top of page
    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 uncut - 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 36 months
    End point values
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Number of subjects analysed
    347 [34]
    357 [35]
    Units: % of participants
    number (not applicable)
        CTCAE grade 1
    4.9
    9.2
        CTCAE grade 2
    22.2
    30.5
        CTCAE grade 3
    46.1
    34.5
        CTCAE grade 4
    12.4
    7.8
        CTCAE grade 5
    9.8
    12
    Notes
    [34] - Treated set uncut
    [35] - Treated set uncut
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after the last drug administration, up to 36 months
    Adverse event reporting additional description
    One patient in the nintedanib plus pemetrexed treatment arm reported a serious adverse event for which the preferred term was not yet coded until data cut-off (15 February 2013).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Nintedanib plus pemetrexed
    Reporting group description
    		 Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Placebo plus pemetrexed
    Reporting group description
    		 Placebo soft gelatin capsule matching that of nintedanib twice daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required the dose of placebo could be reduced to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Serious adverse events
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Total subjects affected by serious adverse events
         subjects affected / exposed
    104 / 347 (29.97%)
    117 / 357 (32.77%)
         number of deaths (all causes)
    255
    266
         number of deaths resulting from adverse events
    6
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         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
    2 / 347 (0.58%)
    4 / 357 (1.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Malignant pleural effusion
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to bone
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (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
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour ulceration
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 347 (0.00%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 347 (0.00%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Disease progression
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 347 (0.58%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 347 (1.15%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Mass
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 347 (0.86%)
    4 / 357 (1.12%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 347 (0.58%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    9 / 347 (2.59%)
    11 / 357 (3.08%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 13
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Epistaxis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemoptysis
         subjects affected / exposed
    4 / 347 (1.15%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    2 / 2
    0 / 1
    Hypoxia
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (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
    5 / 347 (1.44%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 347 (0.86%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 347 (0.86%)
    4 / 357 (1.12%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary oedema
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Respiratory distress
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    5 / 347 (1.44%)
    6 / 357 (1.68%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 5
    0 / 6
    Throat irritation
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 347 (0.58%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restlessness
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (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
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical injury
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (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
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         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 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 347 (0.58%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 347 (0.58%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 347 (0.58%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (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
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system necrosis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 347 (1.44%)
    8 / 357 (2.24%)
         occurrences causally related to treatment / all
    3 / 6
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    7 / 347 (2.02%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    5 / 7
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 347 (0.86%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 347 (0.86%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 347 (0.58%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic obstruction
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 347 (0.86%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestine perforation
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 347 (0.58%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 347 (0.86%)
    6 / 357 (1.68%)
         occurrences causally related to treatment / all
    3 / 4
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cholecystitis acute
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic function abnormal
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal injury
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 347 (0.00%)
    4 / 357 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Amoebiasis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (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
    0 / 347 (0.00%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchopneumonia
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious peritonitis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 347 (0.29%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 357 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphangitis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal candidiasis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    11 / 347 (3.17%)
    16 / 357 (4.48%)
         occurrences causally related to treatment / all
    3 / 12
    1 / 17
         deaths causally related to treatment / all
    1 / 2
    0 / 6
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 347 (0.29%)
    3 / 357 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Sepsis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 347 (0.86%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 347 (1.73%)
    4 / 357 (1.12%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 357 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 347 (0.58%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 357 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nintedanib plus pemetrexed Placebo plus pemetrexed
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    320 / 347 (92.22%)
    312 / 357 (87.39%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    149 / 347 (42.94%)
    87 / 357 (24.37%)
         occurrences all number
    268
    140
    Aspartate aminotransferase increased
         subjects affected / exposed
    129 / 347 (37.18%)
    68 / 357 (19.05%)
         occurrences all number
    242
    123
    Blood alkaline phosphatase increased
         subjects affected / exposed
    33 / 347 (9.51%)
    13 / 357 (3.64%)
         occurrences all number
    45
    17
    Haemoglobin decreased
         subjects affected / exposed
    41 / 347 (11.82%)
    44 / 357 (12.32%)
         occurrences all number
    54
    54
    Neutrophil count decreased
         subjects affected / exposed
    74 / 347 (21.33%)
    47 / 357 (13.17%)
         occurrences all number
    210
    110
    Platelet count decreased
         subjects affected / exposed
    23 / 347 (6.63%)
    13 / 357 (3.64%)
         occurrences all number
    35
    31
    Weight decreased
         subjects affected / exposed
    23 / 347 (6.63%)
    15 / 357 (4.20%)
         occurrences all number
    23
    16
    White blood cell count decreased
         subjects affected / exposed
    57 / 347 (16.43%)
    38 / 357 (10.64%)
         occurrences all number
    133
    81
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 347 (8.65%)
    39 / 357 (10.92%)
         occurrences all number
    38
    46
    Headache
         subjects affected / exposed
    44 / 347 (12.68%)
    47 / 357 (13.17%)
         occurrences all number
    52
    65
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 347 (7.49%)
    23 / 357 (6.44%)
         occurrences all number
    35
    33
    Neutropenia
         subjects affected / exposed
    27 / 347 (7.78%)
    19 / 357 (5.32%)
         occurrences all number
    95
    22
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    25 / 347 (7.20%)
    31 / 357 (8.68%)
         occurrences all number
    39
    39
    Chest pain
         subjects affected / exposed
    31 / 347 (8.93%)
    29 / 357 (8.12%)
         occurrences all number
    38
    40
    Fatigue
         subjects affected / exposed
    116 / 347 (33.43%)
    127 / 357 (35.57%)
         occurrences all number
    151
    174
    Oedema peripheral
         subjects affected / exposed
    26 / 347 (7.49%)
    30 / 357 (8.40%)
         occurrences all number
    33
    45
    Pain
         subjects affected / exposed
    17 / 347 (4.90%)
    21 / 357 (5.88%)
         occurrences all number
    18
    22
    Pyrexia
         subjects affected / exposed
    36 / 347 (10.37%)
    42 / 357 (11.76%)
         occurrences all number
    55
    62
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    15 / 347 (4.32%)
    21 / 357 (5.88%)
         occurrences all number
    15
    23
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    41 / 347 (11.82%)
    27 / 357 (7.56%)
         occurrences all number
    53
    29
    Abdominal pain upper
         subjects affected / exposed
    16 / 347 (4.61%)
    22 / 357 (6.16%)
         occurrences all number
    25
    25
    Constipation
         subjects affected / exposed
    50 / 347 (14.41%)
    65 / 357 (18.21%)
         occurrences all number
    63
    73
    Diarrhoea
         subjects affected / exposed
    118 / 347 (34.01%)
    54 / 357 (15.13%)
         occurrences all number
    259
    85
    Nausea
         subjects affected / exposed
    126 / 347 (36.31%)
    118 / 357 (33.05%)
         occurrences all number
    264
    230
    Stomatitis
         subjects affected / exposed
    27 / 347 (7.78%)
    21 / 357 (5.88%)
         occurrences all number
    38
    29
    Vomiting
         subjects affected / exposed
    84 / 347 (24.21%)
    68 / 357 (19.05%)
         occurrences all number
    203
    129
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    55 / 347 (15.85%)
    60 / 357 (16.81%)
         occurrences all number
    64
    77
    Dyspnoea
         subjects affected / exposed
    45 / 347 (12.97%)
    70 / 357 (19.61%)
         occurrences all number
    50
    82
    Epistaxis
         subjects affected / exposed
    24 / 347 (6.92%)
    12 / 357 (3.36%)
         occurrences all number
    27
    14
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    29 / 347 (8.36%)
    29 / 357 (8.12%)
         occurrences all number
    39
    38
    Pruritus
         subjects affected / exposed
    26 / 347 (7.49%)
    33 / 357 (9.24%)
         occurrences all number
    35
    49
    Rash
         subjects affected / exposed
    22 / 347 (6.34%)
    28 / 357 (7.84%)
         occurrences all number
    45
    43
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 347 (8.36%)
    37 / 357 (10.36%)
         occurrences all number
    33
    37
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    23 / 347 (6.63%)
    14 / 357 (3.92%)
         occurrences all number
    24
    19
    Back pain
         subjects affected / exposed
    37 / 347 (10.66%)
    36 / 357 (10.08%)
         occurrences all number
    41
    37
    Musculoskeletal pain
         subjects affected / exposed
    16 / 347 (4.61%)
    20 / 357 (5.60%)
         occurrences all number
    21
    22
    Myalgia
         subjects affected / exposed
    12 / 347 (3.46%)
    27 / 357 (7.56%)
         occurrences all number
    17
    35
    Pain in extremity
         subjects affected / exposed
    18 / 347 (5.19%)
    16 / 357 (4.48%)
         occurrences all number
    22
    18
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 347 (6.05%)
    20 / 357 (5.60%)
         occurrences all number
    30
    36
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    97 / 347 (27.95%)
    89 / 357 (24.93%)
         occurrences all number
    143
    125
    Hyperglycaemia
         subjects affected / exposed
    24 / 347 (6.92%)
    28 / 357 (7.84%)
         occurrences all number
    45
    51
    Hypokalaemia
         subjects affected / exposed
    20 / 347 (5.76%)
    8 / 357 (2.24%)
         occurrences all number
    24
    12

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2009
    It was specified that the DMC represented an independent multidisciplinary group consisting of clinicians & biostatistician who, collectively, had expertise in the management of patients with NSCLC &in the conduct &monitoring of randomised clinical trials. It was added that DMC reviewed all serious adverse events in an A/B fashion (i.e. the data were presented to the DMC un-blinded per treatment group without identifying the nintedanib or placebo arm) on an ongoing basis. The dose of folic acid was clarified. In ddition, it was specified that in the USA, folic acid was supplied by the trial sites. Outside of the USA, folic acid was provided by a Contract research organisation appointed by BI. Brain metastases had to be stable for 4 weeks,therefore the exclusion criterion was modified: “Chemo-, hormone-, immunotherapy with monoclonal antibodies, treatment with tyrosine kinase inhibitors, or radiotherapy (except for extremities) within the past 4 weeks prior to treatment with the trial drug". It was clarified that investigator could access the assigned treatment of individual patient if un-blinding was medically indicated.The dose reduction scheme for pemetrexed was modified.It was specified that Quality of life was only assessed in countries where validated translations of the questionnaires were available. The laboratory analysis of bilirubin was changed. It was clarified clarified that measurement of the oral or tympanic body temperature was preferable, but that other locations were allowed if the measurements were not feasible. However, the same location was to be used at each measurement. In addition to date& time of nintedanib / placebo intake,the investigators were required to also collect the time of the most recent food /beverage intake before each dose of nintedanib / placebo for 2 days prior to and on the day of blood sampling. The screening period was extended from 14 days to 21 days for exceptional cases.
    07 Jul 2011
    It was clarified that the treatment criteria for liver enzymes is for both AST and ALT. It was clarified that patients in the treatment group pemetrexed + BIBF 1120 cannot change to the treatment group BIBF 1120 monotherapy. It was clarified that the patients and site staff will be un-blinded to patients that were on active treatment as of June 18 2011. The sponsor’s trial team involved in the later analysis of the trial remained blinded. For the primary analysis of PFS and supportive inference on OS, the trial database was locked and un-blinded. Recruitment and randomisation was held from 18 June 2011. After the ad hoc interim analysis (cut-off of 14 June 2011), the sponsor stopped recruitment on 29 July 2011. Patients who had completed active therapy by 18 June 2011 remained blinded. Patients on active therapy on 18 June 2011 were un-blinded and thus this procedure did not apply to them. Patients who entered the study after 18 June 2011 were not blinded. Patients interrupting nintedanib therapy for 14 or more consecutive days were not considered non-compliant.After 18 June 2011, Quality of Life (QoL) questionnaires were no longer completed. After 18 June 2011, information on caregiver support was no longer collected. After 18 June 2011, thyroid parameters were no longer determined. For patients entered after 18 June 2011, no PK assessment was done. For patients who were on-treatment with nintedanib before 18 June 2011 and were scheduled for PK assessment after 18 June 2011 and decided to continue combination therapy with nintedanib plus pemetrexed, the PK assessment was to be completed as originally planned. For patients entered after 18 June 2011, no pharmacogenetic blood sampling and analysis was performed.
    08 Aug 2011
    It was clarified that the treatment criteria for liver enzymes is for both AST and ALT. It was clarified that patients in the treatment group pemetrexed + BIBF 1120 cannot change to the treatment group BIBF 1120 monotherapy. It was clarified that the patients and site staff will be un-blinded to patients that were on active treatment as of June 18 2011. The sponsor’s trial team involved in the later analysis of the trial remained blinded. For the primary analysis of PFS and supportive inference on OS, the trial database was locked and un-blinded. Recruitment and randomisation was held from 18 June 2011. After the ad hoc interim analysis (cut-off of 14 June 2011), the sponsor stopped recruitment on 29 July 2011. Patients who had completed active therapy by 18 June 2011 remained blinded. Patients on active therapy on 18 June 2011 were un-blinded and thus this procedure did not apply to them. Patients who entered the study after 18 June 2011 were not blinded. Patients interrupting nintedanib therapy for 14 or more consecutive days were not considered non-compliant.After 18 June 2011, Quality of Life (QoL) questionnaires were no longer completed. After 18 June 2011, information on caregiver support was no longer collected. After 18 June 2011, thyroid parameters were no longer determined. For patients entered after 18 June 2011, no PK assessment was done. For patients who were on-treatment with nintedanib before 18 June 2011 and were scheduled for PK assessment after 18 June 2011 and decided to continue combination therapy with nintedanib plus pemetrexed, the PK assessment was to be completed as originally planned. For patients entered after 18 June 2011, no pharmacogenetic blood sampling and analysis was performed.
    12 Feb 2014
    After the final analysis of PFS and OS had been completed, Amendment 4 changed the definitions for the follow-up period and the end of the whole trial. Instead of follow-up until death or lost to follow-up, patients were now to be followed up for 28 days after the last administration of trial medication (which was the reporting period for AEs). The definition for end-of-trial was thus changed to the point when the last patient had completed his first follow-up visit. Additionally, the Amendment clarified that data on patients who were still on treatment at the time of the final PFS and OS analysis were to be added to this follow-up CTR, following the process of a CTR revision.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Jun 2011
    Recruitment for the study was stopped early based on the results of a pre defined futility analysis.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Recruitment for the study was stopped early based on the results of a pre defined futility analysis.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Thu May 02 16:07:33 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA