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    Clinical Trial Results:
    LUME-Meso: Double blind, randomised, multicentre, phase II/III study of nintedanib in combination with pemetrexed / cisplatin followed by continuing nintedanib monotherapy versus placebo in combination with pemetrexed / cisplatin followed by continuing placebo monotherapy for the treatment of patients with unresectable malignant pleural mesothelioma

    Summary
    EudraCT number
    2012-005201-48
    Trial protocol
    DE   IT   GB   FR   DK   ES   BE   NL   SE   PT   CZ   AT   PL   HR  
    Global end of trial date
    31 Aug 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1199.93
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01907100
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin followed by nintedanib monotherapy vs. placebo plus pemetrexed/cisplatin followed by placebo monotherapy as first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. 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
    27 Sep 2013
    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
    Egypt: 38
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Japan: 31
    Country: Number of subjects enrolled
    Australia: 56
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Croatia: 14
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    France: 49
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Italy: 84
    Country: Number of subjects enrolled
    Netherlands: 20
    Country: Number of subjects enrolled
    Norway: 11
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    Turkey: 12
    Country: Number of subjects enrolled
    United Kingdom: 64
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Mexico: 28
    Worldwide total number of subjects
    645
    EEA total number of subjects
    388
    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)
    270
    From 65 to 84 years
    373
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were initially treated with combination therapy consisting of nintedanib or placebo plus standard chemotherapy (pemetrexed/cisplatin), for a maximum of 6 cycles of 21 days duration. After completion of combination therapy, patients who had not progressed continued with nintedanib or placebo monotherapy.

    Pre-assignment
    Screening details
    All participants were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the participants) met all implemented inclusion/exclusion criteria. Participants were not to be entered to trial if any of the specific entry criteria was violated. PD: Progressive Disease; approx.: approximately

    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
    Blinding implementation details
    Double blind, randomised, multicentre, phase II/III study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo_Phase II
    Arm description
    Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (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
    Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Arm title
    Nintedanib_Phase II
    Arm description
    Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
    Arm type
    Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Arm title
    Placebo_Phase III
    Arm description
    Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (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
    Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Arm title
    Nintedanib_Phase III
    Arm description
    Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
    Arm type
    Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Number of subjects in period 1 [1]
    Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
    Started
    43
    44
    229
    229
    Treated Patients
    41
    44
    228
    227
    Completed
    0
    4
    82
    83
    Not completed
    43
    40
    147
    146
         Protocol deviation
    -
    -
    1
    1
         Adverse event, serious fatal
    -
    -
    4
    4
         Other than reasons specified
    1
    -
    10
    6
         Adverse event, non-fatal
    7
    3
    26
    27
         PD based on modified RECIST criteria
    31
    32
    95
    92
         Consent withdrawn by subject
    2
    5
    10
    13
         Lost to follow-up
    -
    -
    -
    1
         Not treated
    2
    -
    1
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo_Phase II
    Reporting group description
    Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib_Phase II
    Reporting group description
    Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Placebo_Phase III
    Reporting group description
    Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib_Phase III
    Reporting group description
    Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group values
    Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III Total
    Number of subjects
    43 44 229 229 545
    Age categorical
    Units: Subjects
    Age Continuous
    Randomised Set: This patient set included all randomized patients.
    Units: years
        arithmetic mean (standard deviation)
    65.9 ± 7.6 66.4 ± 8.6 64.3 ± 8.9 63.6 ± 9.5 -
    Gender, Male/Female
    Randomised Set: This patient set included all randomized patients.
    Units: Subjects
        Female
    8 10 60 64 142
        Male
    35 34 169 165 403
    Race (NIH/OMB)
    Race was only collected where allowed by local law. Randomised Set: This patient set included all randomized patients.
    Units: Subjects
        American Indian or Alaska Native
    0 0 14 12 26
        Asian
    0 0 16 14 30
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0
        Black or African American
    0 0 0 2 2
        White
    38 38 180 185 441
        More than one race
    0 0 0 0 0
        Unknown or Not Reported
    5 6 19 16 46

    End points

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    End points reporting groups
    Reporting group title
    Placebo_Phase II
    Reporting group description
    Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib_Phase II
    Reporting group description
    Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Placebo_Phase III
    Reporting group description
    Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib_Phase III
    Reporting group description
    Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Primary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    This outcome measure presents progression-free survival. Disease progression was defined according to the modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Progression-free survival time was calculated as the duration from the date of randomization to the date of disease progression or death, whichever occurred first. For patients with known date of progression (or death): PFS (days) = min (date of progression, date of death) - date of randomization + 1 day. For patients without progression or death, PFS was censored at the last imaging date that showed no disease progression: PFS (days, censored) = date of last imaging showing no progression - date randomization + 1 day. Randomised Set (RS) : This patient set included all randomized patients.
    End point type
    Primary
    End point timeframe
    From (Fr.) randomization (randomiz.) until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months (mth))
    End point values
    Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
    Number of subjects analysed
    43 [1]
    44 [2]
    229 [3]
    229 [4]
    Units: Months
    median (inter-quartile range (Q1-Q3))
        Phase II
    5.72 (5.19 to 8.18)
    9.36 (5.55 to 12.65)
    6.97 (5.42 to 9.00)
    6.77 (5.36 to 9.07)
    Notes
    [1] - RS
    [2] - RS
    [3] - RS
    [4] - RS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Phase II Part:A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo). If the hazard ratio is below 1 then it favours nintedanib.
    Comparison groups
    Placebo_Phase II v Nintedanib_Phase II
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.0174
    Method
    Proportional hazards mode
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.555
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    0.907
    Notes
    [5] - Hazard ratio, confidence interval and p−value obtained from proportional hazards model stratified by tumour histology (epithelioid vs. biphasic).
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Phase III part: A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo). If the hazard ratio is below 1 then it favours nintedanib.
    Comparison groups
    Placebo_Phase III v Nintedanib_Phase III
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    [6]
    P-value
    = 0.543 [7]
    Method
    Proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.3
    Notes
    [6] - Hazard ratio, confidence interval and p−value obtained from a non-stratified proportional hazards model.
    [7] - one-sided p-value

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival was defined as the duration of time from randomization to time of death. This is the key secondary endpoint of the trial. 99999 is "Not applicable" as the 75th percentile was not reached because of insufficient number of patients with OS event thus not calculated.
    End point type
    Secondary
    End point timeframe
    From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)
    End point values
    Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
    Number of subjects analysed
    43 [8]
    44 [9]
    229 [10]
    229 [11]
    Units: Months
    median (inter-quartile range (Q1-Q3))
        Phase II
    14.46 (10.41 to 99999)
    18.30 (10.91 to 99999)
    16.07 (9.66 to 19.29)
    14.36 (9.13 to 18.69)
    Notes
    [8] - RS
    [9] - RS
    [10] - RS
    [11] - RS
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Phase II: A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo). If the hazard ratio is below 1 then it favours nintedanib.
    Comparison groups
    Placebo_Phase II v Nintedanib_Phase II
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    = 0.4132
    Method
    Proportional hazards mode
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.782
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.433
         upper limit
    1.412
    Notes
    [12] - Hazard ratio, confidence interval and p−value obtained from proportional hazards model stratified by tumour histology (epithelioid vs. biphasic).
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Phase III: A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo). If the hazard ratio is below 1 then it favours nintedanib.
    Comparison groups
    Placebo_Phase III v Nintedanib_Phase III
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    other [13]
    P-value
    = 0.7306 [14]
    Method
    Proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.58
    Notes
    [13] - Hazard ratio, confidence interval and p−value obtained from a non-stratified proportional hazards model.
    [14] - one-sided p-value

    Secondary: Objective response according to modified RECIST− investigator assessment

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    End point title
    Objective response according to modified RECIST− investigator assessment [15]
    End point description
    Objective response (best overall tumour response of confirmed complete response [CR] or confirmed partial response [PR]). Complete Response: disappearance of all target lesions Partial Response: at least a 30 % decrease in the total tumour measurement of target lesions, taking as reference the baseline total tumour measurement. Percentage of Patients with confirmed objective response is presented. This endpoint was only evaluated for Phase III part.
    End point type
    Secondary
    End point timeframe
    Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Placebo_Phase III Nintedanib_Phase III
    Number of subjects analysed
    229 [16]
    229 [17]
    Units: Percentage of participants
        number (confidence interval 95%)
    42.8 (36.3 to 49.5)
    45.0 (38.4 to 51.7)
    Notes
    [16] - RS
    [17] - RS
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Odds ratio and one−sided p−value are obtained from an un−adjusted logistic regression model (Nintedanib vs Placebo).
    Comparison groups
    Placebo_Phase III v Nintedanib_Phase III
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    other [18]
    P-value
    = 0.3189 [19]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.58
    Notes
    [18] - Odds ratio above 1 favours nintedanib.
    [19] - one-sided p-value

    Secondary: Disease control according to modified RECIST− investigator assessment

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    End point title
    Disease control according to modified RECIST− investigator assessment [20]
    End point description
    Disease control (best overall response of confirmed CR or PR, or Stable Disease (SD) that lasted ≥36 days) according to modified RECIST. Percentage of Patients with Disease control is presented. This endpoint was only evaluated for Phase III part.
    End point type
    Secondary
    End point timeframe
    Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Placebo_Phase III Nintedanib_Phase III
    Number of subjects analysed
    229 [21]
    229 [22]
    Units: Percentage of participants
        number (confidence interval 95%)
    92.6 (88.4 to 95.6)
    90.8 (86.3 to 94.2)
    Notes
    [21] - RS
    [22] - RS
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Odds ratio and one−sided p−value are obtained from an un−adjusted logistic regression model (Nintedanib vs Placebo).
    Comparison groups
    Placebo_Phase III v Nintedanib_Phase III
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    = 0.7512 [24]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    1.55
    Notes
    [23] - Odds ratio above 1 favours nintedanib.
    [24] - one-sided p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAE & Non SAE:Fr. 1st dose until 28days(Phase II) or 30days(Phase III) after last dose,up to approx. 30mth(Phase II) &approx. 32mth(Phase III).All-cause mortality: Fr. randomiz until end of follow-up,up to approx. 30mth(Phase II) &approx. 32mth(Phase III)
    Adverse event reporting additional description
    All-cause mortality numbers are based on randomized set whereas Serious Adverse Events (SAE) and non-SAE are based on treated set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo_Phase II
    Reporting group description
    Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocoldefined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib_Phase II
    Reporting group description
    Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Placebo_Phase III
    Reporting group description
    Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocoldefined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib_Phase III
    Reporting group description
    Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Serious adverse events
    Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 41 (41.46%)
    16 / 44 (36.36%)
    89 / 228 (39.04%)
    99 / 227 (43.61%)
         number of deaths (all causes)
    25
    22
    63
    64
         number of deaths resulting from adverse events
    0
    1
    4
    3
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    2 / 228 (0.88%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Subclavian artery thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 44 (4.55%)
    2 / 228 (0.88%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural mesothelioma malignant
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    3 / 228 (1.32%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    2 / 228 (0.88%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    1 / 1
    Pyrexia
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 44 (4.55%)
    10 / 228 (4.39%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
    4 / 13
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    5 / 228 (2.19%)
    5 / 227 (2.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    3 / 228 (1.32%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Feeling of body temperature change
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Erosive balanitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 44 (2.27%)
    1 / 228 (0.44%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 44 (4.55%)
    8 / 228 (3.51%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    5 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    3 / 228 (1.32%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    3 / 228 (1.32%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 44 (2.27%)
    7 / 228 (3.07%)
    6 / 227 (2.64%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
    7 / 7
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    4 / 228 (1.75%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow toxicity
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphatic obstruction
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 44 (4.55%)
    6 / 228 (2.63%)
    5 / 227 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Pleural effusion
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 44 (4.55%)
    6 / 228 (2.63%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 44 (9.09%)
    7 / 228 (3.07%)
    13 / 227 (5.73%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
    3 / 7
    10 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    4 / 228 (1.75%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness postural
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoacusis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 44 (0.00%)
    7 / 228 (3.07%)
    8 / 227 (3.52%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    7 / 7
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 44 (2.27%)
    4 / 228 (1.75%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    4 / 5
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 44 (2.27%)
    8 / 228 (3.51%)
    6 / 227 (2.64%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    8 / 9
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Acute abdomen
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    5 / 228 (2.19%)
    9 / 227 (3.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 5
    5 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    4 / 228 (1.75%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Stasis dermatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 44 (4.55%)
    8 / 228 (3.51%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    2 / 8
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    3 / 228 (1.32%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    2 / 227 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 44 (4.55%)
    2 / 228 (0.88%)
    4 / 227 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 44 (2.27%)
    2 / 228 (0.88%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    3 / 227 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Onychomycosis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral bacterial infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    4 / 228 (1.75%)
    6 / 227 (2.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Tooth abscess
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 41 (0.00%)
    0 / 44 (0.00%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 44 (0.00%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 41 (100.00%)
    44 / 44 (100.00%)
    219 / 228 (96.05%)
    218 / 227 (96.04%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 41 (14.63%)
    6 / 44 (13.64%)
    21 / 228 (9.21%)
    26 / 227 (11.45%)
         occurrences all number
    6
    6
    26
    30
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    12 / 41 (29.27%)
    14 / 44 (31.82%)
    46 / 228 (20.18%)
    53 / 227 (23.35%)
         occurrences all number
    26
    25
    62
    79
    Chest pain
         subjects affected / exposed
    9 / 41 (21.95%)
    7 / 44 (15.91%)
    23 / 228 (10.09%)
    23 / 227 (10.13%)
         occurrences all number
    14
    8
    24
    24
    Fatigue
         subjects affected / exposed
    15 / 41 (36.59%)
    18 / 44 (40.91%)
    62 / 228 (27.19%)
    60 / 227 (26.43%)
         occurrences all number
    34
    38
    85
    81
    Mucosal inflammation
         subjects affected / exposed
    4 / 41 (9.76%)
    7 / 44 (15.91%)
    22 / 228 (9.65%)
    16 / 227 (7.05%)
         occurrences all number
    7
    9
    25
    21
    Oedema peripheral
         subjects affected / exposed
    5 / 41 (12.20%)
    5 / 44 (11.36%)
    16 / 228 (7.02%)
    16 / 227 (7.05%)
         occurrences all number
    5
    8
    19
    18
    Pyrexia
         subjects affected / exposed
    4 / 41 (9.76%)
    7 / 44 (15.91%)
    22 / 228 (9.65%)
    17 / 227 (7.49%)
         occurrences all number
    6
    13
    29
    19
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 41 (9.76%)
    8 / 44 (18.18%)
    12 / 228 (5.26%)
    11 / 227 (4.85%)
         occurrences all number
    4
    8
    12
    15
    Depression
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 44 (2.27%)
    2 / 228 (0.88%)
    6 / 227 (2.64%)
         occurrences all number
    3
    1
    2
    6
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    17 / 44 (38.64%)
    10 / 228 (4.39%)
    35 / 227 (15.42%)
         occurrences all number
    2
    39
    11
    50
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    13 / 44 (29.55%)
    9 / 228 (3.95%)
    32 / 227 (14.10%)
         occurrences all number
    1
    26
    14
    49
    Blood creatinine increased
         subjects affected / exposed
    4 / 41 (9.76%)
    6 / 44 (13.64%)
    26 / 228 (11.40%)
    21 / 227 (9.25%)
         occurrences all number
    13
    13
    39
    33
    Blood magnesium decreased
         subjects affected / exposed
    6 / 41 (14.63%)
    10 / 44 (22.73%)
    12 / 228 (5.26%)
    17 / 227 (7.49%)
         occurrences all number
    14
    22
    14
    19
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    10 / 44 (22.73%)
    13 / 228 (5.70%)
    25 / 227 (11.01%)
         occurrences all number
    1
    41
    15
    31
    Neutrophil count decreased
         subjects affected / exposed
    3 / 41 (7.32%)
    8 / 44 (18.18%)
    26 / 228 (11.40%)
    28 / 227 (12.33%)
         occurrences all number
    5
    20
    47
    45
    Weight decreased
         subjects affected / exposed
    9 / 41 (21.95%)
    8 / 44 (18.18%)
    23 / 228 (10.09%)
    20 / 227 (8.81%)
         occurrences all number
    9
    11
    24
    20
    White blood cell count decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 44 (4.55%)
    15 / 228 (6.58%)
    18 / 227 (7.93%)
         occurrences all number
    1
    2
    26
    29
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 41 (2.44%)
    9 / 44 (20.45%)
    6 / 228 (2.63%)
    7 / 227 (3.08%)
         occurrences all number
    1
    9
    6
    7
    Blood glucose increased
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 44 (11.36%)
    1 / 228 (0.44%)
    0 / 227 (0.00%)
         occurrences all number
    1
    5
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 44 (6.82%)
    1 / 228 (0.44%)
    1 / 227 (0.44%)
         occurrences all number
    0
    3
    1
    1
    Blood potassium decreased
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 44 (9.09%)
    0 / 228 (0.00%)
    0 / 227 (0.00%)
         occurrences all number
    2
    4
    0
    0
    Blood urea increased
         subjects affected / exposed
    3 / 41 (7.32%)
    8 / 44 (18.18%)
    10 / 228 (4.39%)
    9 / 227 (3.96%)
         occurrences all number
    3
    8
    10
    9
    Haemoglobin decreased
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 44 (9.09%)
    2 / 228 (0.88%)
    1 / 227 (0.44%)
         occurrences all number
    2
    4
    2
    1
    Platelet count decreased
         subjects affected / exposed
    4 / 41 (9.76%)
    8 / 44 (18.18%)
    7 / 228 (3.07%)
    9 / 227 (3.96%)
         occurrences all number
    8
    22
    12
    20
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    5 / 41 (12.20%)
    2 / 44 (4.55%)
    28 / 228 (12.28%)
    20 / 227 (8.81%)
         occurrences all number
    5
    2
    58
    50
    Anaemia
         subjects affected / exposed
    9 / 41 (21.95%)
    16 / 44 (36.36%)
    94 / 228 (41.23%)
    76 / 227 (33.48%)
         occurrences all number
    15
    28
    123
    96
    Neutropenia
         subjects affected / exposed
    9 / 41 (21.95%)
    22 / 44 (50.00%)
    82 / 228 (35.96%)
    83 / 227 (36.56%)
         occurrences all number
    22
    53
    170
    185
    Thrombocytopenia
         subjects affected / exposed
    1 / 41 (2.44%)
    7 / 44 (15.91%)
    18 / 228 (7.89%)
    13 / 227 (5.73%)
         occurrences all number
    1
    11
    27
    31
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 41 (14.63%)
    15 / 44 (34.09%)
    33 / 228 (14.47%)
    29 / 227 (12.78%)
         occurrences all number
    6
    15
    40
    33
    Dyspnoea
         subjects affected / exposed
    7 / 41 (17.07%)
    7 / 44 (15.91%)
    26 / 228 (11.40%)
    34 / 227 (14.98%)
         occurrences all number
    7
    7
    29
    35
    Hiccups
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 44 (2.27%)
    20 / 228 (8.77%)
    8 / 227 (3.52%)
         occurrences all number
    3
    1
    27
    9
    Epistaxis
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 44 (2.27%)
    13 / 228 (5.70%)
    20 / 227 (8.81%)
         occurrences all number
    2
    1
    15
    38
    Dysphonia
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 44 (6.82%)
    2 / 228 (0.88%)
    4 / 227 (1.76%)
         occurrences all number
    0
    3
    2
    4
    Oropharyngeal pain
         subjects affected / exposed
    6 / 41 (14.63%)
    2 / 44 (4.55%)
    4 / 228 (1.75%)
    6 / 227 (2.64%)
         occurrences all number
    6
    2
    4
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 41 (12.20%)
    3 / 44 (6.82%)
    18 / 228 (7.89%)
    14 / 227 (6.17%)
         occurrences all number
    5
    3
    22
    15
    Dysgeusia
         subjects affected / exposed
    11 / 41 (26.83%)
    11 / 44 (25.00%)
    27 / 228 (11.84%)
    27 / 227 (11.89%)
         occurrences all number
    11
    11
    31
    32
    Headache
         subjects affected / exposed
    4 / 41 (9.76%)
    5 / 44 (11.36%)
    23 / 228 (10.09%)
    16 / 227 (7.05%)
         occurrences all number
    4
    5
    23
    17
    Lethargy
         subjects affected / exposed
    13 / 41 (31.71%)
    6 / 44 (13.64%)
    5 / 228 (2.19%)
    13 / 227 (5.73%)
         occurrences all number
    13
    6
    11
    21
    Neuropathy peripheral
         subjects affected / exposed
    6 / 41 (14.63%)
    9 / 44 (20.45%)
    18 / 228 (7.89%)
    13 / 227 (5.73%)
         occurrences all number
    6
    9
    18
    13
    Paraesthesia
         subjects affected / exposed
    4 / 41 (9.76%)
    4 / 44 (9.09%)
    19 / 228 (8.33%)
    20 / 227 (8.81%)
         occurrences all number
    4
    4
    21
    23
    Neurotoxicity
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 44 (2.27%)
    4 / 228 (1.75%)
    8 / 227 (3.52%)
         occurrences all number
    3
    1
    4
    8
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 44 (0.00%)
    4 / 228 (1.75%)
    12 / 227 (5.29%)
         occurrences all number
    3
    0
    4
    12
    Lacrimation increased
         subjects affected / exposed
    4 / 41 (9.76%)
    7 / 44 (15.91%)
    18 / 228 (7.89%)
    14 / 227 (6.17%)
         occurrences all number
    4
    7
    18
    14
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    9 / 41 (21.95%)
    4 / 44 (9.09%)
    24 / 228 (10.53%)
    15 / 227 (6.61%)
         occurrences all number
    14
    8
    27
    15
    Hypoacusis
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 44 (9.09%)
    4 / 228 (1.75%)
    7 / 227 (3.08%)
         occurrences all number
    1
    4
    4
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 41 (7.32%)
    11 / 44 (25.00%)
    10 / 228 (4.39%)
    24 / 227 (10.57%)
         occurrences all number
    5
    18
    10
    31
    Abdominal pain upper
         subjects affected / exposed
    3 / 41 (7.32%)
    9 / 44 (20.45%)
    11 / 228 (4.82%)
    14 / 227 (6.17%)
         occurrences all number
    3
    11
    11
    14
    Constipation
         subjects affected / exposed
    19 / 41 (46.34%)
    17 / 44 (38.64%)
    73 / 228 (32.02%)
    60 / 227 (26.43%)
         occurrences all number
    27
    31
    96
    81
    Diarrhoea
         subjects affected / exposed
    15 / 41 (36.59%)
    29 / 44 (65.91%)
    47 / 228 (20.61%)
    118 / 227 (51.98%)
         occurrences all number
    27
    31
    61
    239
    Dyspepsia
         subjects affected / exposed
    11 / 41 (26.83%)
    3 / 44 (6.82%)
    20 / 228 (8.77%)
    14 / 227 (6.17%)
         occurrences all number
    12
    3
    20
    14
    Nausea
         subjects affected / exposed
    34 / 41 (82.93%)
    37 / 44 (84.09%)
    134 / 228 (58.77%)
    156 / 227 (68.72%)
         occurrences all number
    101
    114
    234
    274
    Stomatitis
         subjects affected / exposed
    5 / 41 (12.20%)
    3 / 44 (6.82%)
    16 / 228 (7.02%)
    22 / 227 (9.69%)
         occurrences all number
    5
    3
    18
    26
    Vomiting
         subjects affected / exposed
    20 / 41 (48.78%)
    24 / 44 (54.55%)
    66 / 228 (28.95%)
    96 / 227 (42.29%)
         occurrences all number
    36
    55
    115
    192
    Dry mouth
         subjects affected / exposed
    4 / 41 (9.76%)
    2 / 44 (4.55%)
    2 / 228 (0.88%)
    4 / 227 (1.76%)
         occurrences all number
    4
    2
    2
    4
    Haemorrhoids
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 44 (6.82%)
    2 / 228 (0.88%)
    5 / 227 (2.20%)
         occurrences all number
    0
    3
    2
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 44 (6.82%)
    11 / 228 (4.82%)
    7 / 227 (3.08%)
         occurrences all number
    4
    3
    11
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 41 (12.20%)
    6 / 44 (13.64%)
    8 / 228 (3.51%)
    12 / 227 (5.29%)
         occurrences all number
    5
    6
    8
    12
    Rash
         subjects affected / exposed
    7 / 41 (17.07%)
    11 / 44 (25.00%)
    23 / 228 (10.09%)
    22 / 227 (9.69%)
         occurrences all number
    7
    11
    28
    26
    Dry skin
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 44 (0.00%)
    7 / 228 (3.07%)
    4 / 227 (1.76%)
         occurrences all number
    3
    0
    7
    4
    Pruritus
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 44 (6.82%)
    10 / 228 (4.39%)
    3 / 227 (1.32%)
         occurrences all number
    1
    3
    10
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 41 (39.02%)
    17 / 44 (38.64%)
    66 / 228 (28.95%)
    66 / 227 (29.07%)
         occurrences all number
    24
    26
    91
    97
    Hypokalaemia
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 44 (9.09%)
    13 / 228 (5.70%)
    12 / 227 (5.29%)
         occurrences all number
    2
    6
    18
    12
    Hypomagnesaemia
         subjects affected / exposed
    8 / 41 (19.51%)
    13 / 44 (29.55%)
    20 / 228 (8.77%)
    20 / 227 (8.81%)
         occurrences all number
    8
    13
    28
    27
    Hyperglycaemia
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 44 (4.55%)
    15 / 228 (6.58%)
    8 / 227 (3.52%)
         occurrences all number
    1
    2
    22
    9
    Hyponatraemia
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 44 (2.27%)
    14 / 228 (6.14%)
    14 / 227 (6.17%)
         occurrences all number
    2
    1
    15
    16
    Dehydration
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 44 (9.09%)
    8 / 228 (3.51%)
    4 / 227 (1.76%)
         occurrences all number
    3
    4
    8
    4
    Hypocalcaemia
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 44 (0.00%)
    2 / 228 (0.88%)
    4 / 227 (1.76%)
         occurrences all number
    3
    0
    2
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 44 (9.09%)
    12 / 228 (5.26%)
    9 / 227 (3.96%)
         occurrences all number
    1
    4
    12
    10
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 41 (12.20%)
    2 / 44 (4.55%)
    6 / 228 (2.63%)
    16 / 227 (7.05%)
         occurrences all number
    6
    3
    8
    18
    Urinary tract infection
         subjects affected / exposed
    5 / 41 (12.20%)
    0 / 44 (0.00%)
    14 / 228 (6.14%)
    12 / 227 (5.29%)
         occurrences all number
    8
    0
    20
    16
    Conjunctivitis
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 44 (9.09%)
    11 / 228 (4.82%)
    11 / 227 (4.85%)
         occurrences all number
    2
    4
    11
    11
    Influenza
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 44 (6.82%)
    4 / 228 (1.75%)
    5 / 227 (2.20%)
         occurrences all number
    2
    3
    4
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2015
    - Changes in the procedures and timing of assessments in the combination therapy period and the monotherapy period (update of the flow chart, implementation of the changes listed below) - Addition of hydration as premedication regimen; clarification of study treatment interruption, stopping criteria (treatment beyond disease progression was allowed), and management of AEs; revision of timing of unblinding of patient data - Revision of efficacy endpoints (OS became key secondary endpoint; objective response and disease control secondary endpoints; and change in FVC, best overall response, time to objective response, duration of objective response, duration of disease control, and health-related quality of life [Phase III only] further endpoints); addition of healthcare resource use assessment and PK sampling; clarification of evaluation of lesions and assessment of AEs; revision of timing of laboratory and PGx sampling and required laboratory parameters; clarification of management of proteinuria; revision of collection of archived tissue and serum biomarkers (biomarker collection became optional) - Clarification of the timing of the run-in and screening period; permission of continuation of study treatment beyond disease progression; specification of procedures performed at Follow-up Visit 1 and at further follow-up visits; update of the definition of end-of-trial - Revision of the planned statistical analysis of all endpoints and of the sample size to allow for inclusion of 310 patients in the Phase III part
    22 Jun 2016
    Separation of flow charts for Phase 2 & 3;Changes in procedures and timing of assessments in combination therapy period & monotherapy period of Phase 3.Limitation of Phase 3 to patients with epithelioid tumour histology.Change of creatinine clearance limit for patients with mild to moderate renal insufficiency.Description of timing of: primary OS analysis for Phase 2,primary PFS & interim & primary OS analyses for Phase 3.Increase of sample size to 450 Phase 3 patients.Description of adaptive design with OS event number reassessment.Update of dose reduction and retreatment criteria,and of criteria for liver enzyme elevations; description of unblinding of Phase 2 & Phase 3 patients and of the sponsor's independent team with regard to primary PFS analysis/interim OS analysis of Phase 3.Update of observation period for primary & secondary endpoints; clarification of central assessment of tumour images and collection of bone scans;addition of criteria for treatment beyond disease progression;change of CTCAE version from 3.0 to 4.03 for Phase 3 patients;clarifications of procedures (AE reporting,ECG,PK [to be collected at 1 time point in the Phase 3] and biomarker sampling [to be collected at 2 time points in Phase 3 part and used for biobanking]);removal of FVC evaluation for Phase 3.Clarification of follow-up for PD & OS,separated by trial phase;update of definition for end-of-trial; clarification of reporting of different analyses (PFS, OS) for Phase 2 & Phase 3.Revised description of analyses for Phase 2 & Phase 3; change of hypotheses for Phase 3 to one-sided & alpha level to one-sided 0.025;description of analyses method for adaptive design with OS event number reassessment;description of pooled exploratory analyses for Phase 2 & Phase 3 (efficacy & safety);change of OS censoring rule if patient died with death date unknown;addition of sensitivity analysis for PFS based on EMA censoring rules;revision of sample size section for Phase 2 & Phase 3.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In accordance with the specifications in the protocol, the trial was discontinued prematurely after the primary PFS analysis not because of any safety concerns but rather due to failure to meet the efficacy target.
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