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    Clinical Trial Results:
    Multicentre, randomised, double-blind Phase III trial to investigate the efficacy and safety of BIBF 1120 in combination with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in patients with advanced ovarian cancer

    Summary
    EudraCT number
    		 2008-006831-10
    Trial protocol
    		 DE   FR   SE   BE   PT   SK   DK   AT   NL   FI   PL   IT   GR   CZ   ES   GB  
    Global end of trial date
    15 Sep 2016

    Results information
    Results version number
    		 v3(current)
    This version publication date
    13 Dec 2021
    First version publication date
    22 Mar 2015
    Other versions
    		 v1 , v2
    Version creation reason
    Summary report(s)
    		 1199.15

    Trial information

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    Trial identification
    Sponsor protocol code
    1199.15
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01015118
    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
    26 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to evaluate whether nintedanib (BIBF1120), added to standard chemotherapy with paclitaxel and carboplatin for 6 courses and subsequently in monotherapy, is more effective in prolonging progression-free survival (PFS) than placebo in combination with standard chemotherapy of carboplatin/paclitaxel in patients with advanced epithelial ovarian cancer, defined as Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stages IIB-IV, after primary debulking surgery.
    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. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Dec 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Austria: 36
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    Czechia: 25
    Country: Number of subjects enrolled
    Germany: 340
    Country: Number of subjects enrolled
    Denmark: 43
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    France: 125
    Country: Number of subjects enrolled
    Greece: 33
    Country: Number of subjects enrolled
    Italy: 146
    Country: Number of subjects enrolled
    Norway: 80
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Portugal: 18
    Country: Number of subjects enrolled
    Poland: 62
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Sweden: 52
    Country: Number of subjects enrolled
    Finland: 24
    Country: Number of subjects enrolled
    Slovakia: 77
    Country: Number of subjects enrolled
    Ukraine: 26
    Country: Number of subjects enrolled
    United Kingdom: 56
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    United States: 215
    Worldwide total number of subjects
    1504
    EEA total number of subjects
    1131
    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)
    1081
    From 65 to 84 years
    423
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 1366 patients were randomised for this study.

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

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nintedanib
    Arm description
    		 Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
    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
    Patients to receive Nintedanib 200 mg soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.

    Arm title
    		 Placebo
    Arm description
    		 Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
    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
    Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.

    Number of subjects in period 1 [1]
    		Nintedanib Placebo
    Started
    911
    455
    Completed
    242
    128
    Not completed
    669
    327
         Adverse event, serious fatal
    9
    5
         Consent withdrawn by subject
    103
    27
         Other than stated below
    42
    23
         Adverse event, non-fatal
    132
    28
         Worsening or AE of underlying disease
    5
    4
         Progressive disease
    364
    229
         Protocol deviation
    5
    6
         Not treated
    9
    5
    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 of the trial medication. No Statistical analysis

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.

    Reporting group values
    		 Nintedanib Placebo Total
    Number of subjects
    		 911 455 1366
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    Randomised Set (RS): included all randomised patients, regardless of whether or not they had received treatment. Patients were assigned to nintedanib or placebo as randomised.
    Units: years
        arithmetic mean (standard deviation)
    		 57.5 ( 11.0 ) 56.9 ( 11.1 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 911 455 1366
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.

    Primary: PFS based on Investigator Assessment according to modified Response Evaluation Criteria in Solid Tumors, version 1.1 (mRECIST), and additional clinical criteria.

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    End point title
    		 PFS based on Investigator Assessment according to modified Response Evaluation Criteria in Solid Tumors, version 1.1 (mRECIST), and additional clinical criteria.
    End point description
    Progression free survival (PFS) is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first according to the Investigator assessment. The primary PFS analysis of this trial was performed when approximately 753 patients had experienced a PFS event Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
    End point type
    Primary
    End point timeframe
    First drug administration to date of disease progression or death whichever occurs first , upto 29 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911 [1]
    455 [2]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    17.2 (11.1 to 32.5)
    16.6 (10.8 to 30.4)
    Notes
    [1] - Randomised Set (RS)
    [2] - Randomised Set (RS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Hazard ratio (HR), Confidence Interval (CI) and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level Area under curve 5 (AUC5) vs. Area under curve 6 (AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0239
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.98

    Primary: PFS based on Investigator Assessment according to modified Response Evaluation Criteria in Solid Tumors, version 1.1 (mRECIST), and additional clinical criteria (follow up analysis).

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    End point title
    		 PFS based on Investigator Assessment according to modified Response Evaluation Criteria in Solid Tumors, version 1.1 (mRECIST), and additional clinical criteria (follow up analysis).
    End point description
    Follow-up analysis was conducted at the time of overall survival analysis. Progression free survival (PFS) is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first according to the Investigator assessment. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
    End point type
    Primary
    End point timeframe
    First drug administration to date of disease progression or death whichever occurs first until final Data Base Lock (DBL) 26September16, upto 62 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911 [3]
    455 [4]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    17.6 (11.1 to 38.0)
    16.6 (10.8 to 37.3)
    Notes
    [3] - Randomised Set (RS)
    [4] - Randomised Set (RS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Hazard ratio (HR), Confidence Interval (CI) and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0286
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 0.98

    Secondary: PFS based on Investigator Assessment according to mRECIST version 1.1 (Key secondary endpoint).

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    End point title
    		 PFS based on Investigator Assessment according to mRECIST version 1.1 (Key secondary endpoint).
    End point description
    Progression free survival is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first based on the Investigator assessment according to Modified Response Evaluation Criteria (mRECIST), version 1.1. The primary PFS analysis of this trial was performed when approximately 753 patients had experienced a PFS event. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
    End point type
    Secondary
    End point timeframe
    First drug administration to date of disease progression or death whichever occurs first , upto 29 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911
    455
    Units: Months
        median (inter-quartile range (Q1-Q3))
    18.3 (11.1 to 32.5)
    16.6 (10.8 to 30.4)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 0.97

    Secondary: PFS based on Investigator Assessment according to mRECIST version 1.1 (Key secondary endpoint - follow up analysis).

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    End point title
    		 PFS based on Investigator Assessment according to mRECIST version 1.1 (Key secondary endpoint - follow up analysis).
    End point description
    Follow-up analysis was conducted at the time of overall survival analysis. Progression free survival is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first based on the Investigator assessment according to Modified Response Evaluation Criteria (mRECIST), version 1.1. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
    End point type
    Secondary
    End point timeframe
    First drug administration to date of disease progression or death whichever occurs first until final Data Base Lock (DBL) 26September16, upto 62 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911 [5]
    455 [6]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    18.4 (11.1 to 38.5)
    16.6 (10.8 to 37.3)
    Notes
    [5] - Randomised Set (RS)
    [6] - Randomised Set (RS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0256
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 0.98

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival is defined as time from randomization to date of death (irrespective of reason). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm. 99999: Not calculable because of insufficient number of participants with events
    End point type
    Secondary
    End point timeframe
    First drug administration to date of death until final DBL 26September16, upto 62 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911 [7]
    455 [8]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    62.0 (30.0 to 99999)
    62.8 (30.6 to 99999)
    Notes
    [7] - Randomised Set (RS)
    [8] - Randomised Set (RS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8653
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.17

    Secondary: Time to CA-125 tumour marker progression

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    End point title
    		 Time to CA-125 tumour marker progression
    End point description
    Time to tumour-marker progression was defined as the time from randomisation until the date when Carbohydrate (cancer) antigen (CA-125) values increased to higher than twice the nadir value. CA-125 >=2 x nadir in case nadir value > Upper limit of normal (ULN) or CA-125 >=2 x ULN in case nadir value <= ULN.
    End point type
    Secondary
    End point timeframe
    First drug administration until final DBL 26September16, upto 62 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911 [9]
    455 [10]
    Units: Months
        median (inter-quartile range (Q1-Q3))
    16.6 (10.6 to 47.0)
    14.1 (8.6 to 42.6)
    Notes
    [9] - Randomised Set (RS)
    [10] - Randomised Set (RS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0749
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.01

    Secondary: objective response based on Investigator assessment

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    End point title
    		 objective response based on Investigator assessment
    End point description
    Objective tumour response defined as either complete response [CR] or partial response [PR] in patients with at least 1 target lesion reported at baseline
    End point type
    Secondary
    End point timeframe
    First drug administration until final DBL 26September16, upto 62 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911 [11]
    455 [12]
    Units: percentage of participants
        number (not applicable)
    74.3
    70.2
    Notes
    [11] - Randomised Set (RS) for patients with at least 1 target lesion reported at baseline
    [12] - Randomised Set (RS) for patients with at least 1 target lesion reported at baseline
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Odds ratio and p−value are obtained from logistic regression model adjusting for, macroscopic residual postoperative tumour (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB−III vs. IV) and carboplatin level (AUC5 vs. AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.349
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.82

    Secondary: Change in abdominal/gastro-intestinal symptoms over time

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    End point title
    		 Change in abdominal/gastro-intestinal symptoms over time
    End point description
    Change in abdominal/gastro-intestinal over time was calculated on symptoms (scale composite of items 31 to 37 of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Module for Ovarian Cancer 28 (EORTC QLQ OV-28). As specified in the EORTC scoring manual, for each scale or item, a linear transformation was applied to standardize the raw score to a range from 0 to 100 (high scores represent a high/severe level of symptomatology). Mean presented is Adjusted mean. Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), FIGO stage (IIB−III vs IV), and Carboplatin level (AUC5 vs. AUC6).
    End point type
    Secondary
    End point timeframe
    First drug administration until final DBL 26September16, upto 62 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911 [13]
    455 [14]
    Units: units on a scale
        arithmetic mean (standard error)
    24.63 ( 0.49 )
    19.34 ( 0.64 )
    Notes
    [13] - Randomised Set (RS) for patients with abdominal/gastro-intestinal symptoms
    [14] - Randomised Set (RS) for patients with abdominal/gastro-intestinal symptoms
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB−III vs IV), and carboplatin level (AUC5 vs. AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect growth curve model
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.88
         upper limit
    		 6.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.72

    Secondary: Change in Global Health Status/ Quality of life (QoL) scale over time.

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    End point title
    		 Change in Global Health Status/ Quality of life (QoL) scale over time.
    End point description
    Change in Global Health Status/ QoL over time was calculated on Global Health Status/QoL scale (composite of items 29 and 30 of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC QLQ-C30) as a general measure. As specified in the EORTC scoring manual, for each scale or item, a linear transformation was applied to standardize the raw score to a range from 0 to 100 (high scores represent a high/healthy level of functioning). Mean presented is Adjusted mean. Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), FIGO stage (IIB−III vs IV), and Carboplatin level (AUC5 vs. AUC6).
    End point type
    Secondary
    End point timeframe
    First drug administration until final DBL 26September16, upto 62 months
    End point values
    		 Nintedanib Placebo
    Number of subjects analysed
    911 [15]
    455 [16]
    Units: units on a scale
        arithmetic mean (standard error)
    68.79 ( 0.48 )
    70.67 ( 0.65 )
    Notes
    [15] - Randomised Set (RS) for patients with global health status/QoL
    [16] - Randomised Set (RS) for patients with global health status/QoL
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB−III vs IV), and carboplatin level (AUC5 vs. AUC6).
    Comparison groups
    Nintedanib v Placebo
    Number of subjects included in analysis
    1366
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0124
    Method
    		 Mixed effect growth curve model
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.35
         upper limit
    		 -0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after the last drug administration.
    Adverse event reporting additional description
    Adverse Events were reported for the treated patients.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses

    Serious adverse events
    		 Placebo Nintedanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    157 / 450 (34.89%)
    379 / 902 (42.02%)
         number of deaths (all causes)
    203
    402
         number of deaths resulting from adverse events
    16
    30
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal wall neoplasm
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain cancer metastatic
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer recurrent
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchioloalveolar carcinoma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar tumour
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    7 / 450 (1.56%)
    15 / 902 (1.66%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 15
         deaths causally related to treatment / all
    0 / 7
    0 / 15
    Metastases to central nervous system
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to large intestine
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to reproductive organ
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to small intestine
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian cancer
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic neoplasm
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal neoplasm
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Axillary vein thrombosis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    5 / 450 (1.11%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 450 (0.00%)
    5 / 902 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 450 (0.22%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    2 / 450 (0.44%)
    6 / 902 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 450 (0.22%)
    6 / 902 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous occlusion
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter placement
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central venous catheter removal
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemotherapy
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytoreductive surgery
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileostomy
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal resection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laparotomy
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine anastomosis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal operation
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 450 (0.44%)
    13 / 902 (1.44%)
         occurrences causally related to treatment / all
    0 / 2
    7 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site haematoma
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 450 (0.89%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Fatigue
         subjects affected / exposed
    2 / 450 (0.44%)
    10 / 902 (1.11%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    5 / 450 (1.11%)
    17 / 902 (1.88%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hernia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site erythema
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodule
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 450 (1.78%)
    23 / 902 (2.55%)
         occurrences causally related to treatment / all
    2 / 8
    1 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Surgical failure
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactoid reaction
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    3 / 450 (0.67%)
    9 / 902 (1.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine fistula
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal fistula
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal ulceration
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 450 (0.89%)
    10 / 902 (1.11%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 450 (0.22%)
    6 / 902 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 450 (1.11%)
    11 / 902 (1.22%)
         occurrences causally related to treatment / all
    3 / 6
    6 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 450 (0.22%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 450 (0.00%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biopsy vulva
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine renal clearance decreased
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 450 (0.00%)
    5 / 902 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 450 (0.22%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured coccyx
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iatrogenic injury
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    4 / 450 (0.89%)
    8 / 902 (0.89%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation of wound
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural diarrhoea
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative fever
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scar
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvovaginal injury
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cancer gene carrier
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiovascular disorder
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 450 (0.22%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asterixis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 450 (0.22%)
    5 / 902 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 450 (0.00%)
    5 / 902 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemianopia homonymous
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 450 (0.22%)
    6 / 902 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 450 (2.00%)
    36 / 902 (3.99%)
         occurrences causally related to treatment / all
    1 / 13
    5 / 43
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 450 (1.33%)
    20 / 902 (2.22%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 450 (0.22%)
    8 / 902 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathic haemolytic anaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    6 / 450 (1.33%)
    24 / 902 (2.66%)
         occurrences causally related to treatment / all
    1 / 8
    7 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 450 (0.22%)
    8 / 902 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic vein thrombosis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    6 / 450 (1.33%)
    21 / 902 (2.33%)
         occurrences causally related to treatment / all
    1 / 7
    5 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    2 / 450 (0.44%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    6 / 450 (1.33%)
    30 / 902 (3.33%)
         occurrences causally related to treatment / all
    3 / 7
    7 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 450 (0.00%)
    8 / 902 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous ulcer
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    8 / 450 (1.78%)
    14 / 902 (1.55%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic fistula
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    10 / 450 (2.22%)
    13 / 902 (1.44%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    8 / 450 (1.78%)
    41 / 902 (4.55%)
         occurrences causally related to treatment / all
    3 / 8
    39 / 48
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Diverticulum intestinal
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula of small intestine
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 450 (0.44%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    8 / 450 (1.78%)
    17 / 902 (1.88%)
         occurrences causally related to treatment / all
    0 / 9
    4 / 19
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Impaired gastric emptying
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 450 (0.89%)
    7 / 902 (0.78%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 450 (0.22%)
    5 / 902 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    10 / 450 (2.22%)
    24 / 902 (2.66%)
         occurrences causally related to treatment / all
    3 / 12
    13 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    4 / 450 (0.89%)
    12 / 902 (1.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 450 (0.44%)
    8 / 902 (0.89%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Umbilical hernia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    12 / 450 (2.67%)
    33 / 902 (3.66%)
         occurrences causally related to treatment / all
    5 / 13
    16 / 37
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatomyositis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin erosion
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticarial vasculitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 450 (0.67%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bladder tamponade
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 450 (0.44%)
    7 / 902 (0.78%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incontinence
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 450 (0.22%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    0 / 450 (0.00%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder haemorrhage
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urogenital fistula
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vesicocutaneous fistula
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic nodular goitre
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 450 (0.44%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Beta haemolytic streptococcal infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 450 (0.00%)
    6 / 902 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 450 (0.67%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis bacterial
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 450 (0.67%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 450 (0.22%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pharyngeal abscess
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 450 (0.67%)
    6 / 902 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulpitis dental
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 450 (0.44%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 450 (0.22%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdiaphragmatic abscess
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 450 (0.22%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 450 (0.67%)
    17 / 902 (1.88%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 450 (0.44%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 450 (0.00%)
    4 / 902 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 450 (1.33%)
    21 / 902 (2.33%)
         occurrences causally related to treatment / all
    1 / 6
    9 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 902 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 902 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 450 (0.44%)
    6 / 902 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 902 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 902 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Nintedanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    442 / 450 (98.22%)
    891 / 902 (98.78%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    45 / 450 (10.00%)
    73 / 902 (8.09%)
         occurrences all number
    55
    86
    Hypertension
         subjects affected / exposed
    23 / 450 (5.11%)
    119 / 902 (13.19%)
         occurrences all number
    24
    138
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    65 / 450 (14.44%)
    163 / 902 (18.07%)
         occurrences all number
    99
    258
    Fatigue
         subjects affected / exposed
    201 / 450 (44.67%)
    388 / 902 (43.02%)
         occurrences all number
    313
    632
    Mucosal inflammation
         subjects affected / exposed
    30 / 450 (6.67%)
    62 / 902 (6.87%)
         occurrences all number
    38
    74
    Oedema peripheral
         subjects affected / exposed
    47 / 450 (10.44%)
    48 / 902 (5.32%)
         occurrences all number
    53
    53
    Pain
         subjects affected / exposed
    27 / 450 (6.00%)
    35 / 902 (3.88%)
         occurrences all number
    41
    45
    Pyrexia
         subjects affected / exposed
    46 / 450 (10.22%)
    64 / 902 (7.10%)
         occurrences all number
    51
    74
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    21 / 450 (4.67%)
    58 / 902 (6.43%)
         occurrences all number
    32
    70
    Hypersensitivity
         subjects affected / exposed
    32 / 450 (7.11%)
    53 / 902 (5.88%)
         occurrences all number
    42
    64
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    34 / 450 (7.56%)
    57 / 902 (6.32%)
         occurrences all number
    42
    61
    Dyspnoea
         subjects affected / exposed
    55 / 450 (12.22%)
    109 / 902 (12.08%)
         occurrences all number
    69
    129
    Epistaxis
         subjects affected / exposed
    17 / 450 (3.78%)
    72 / 902 (7.98%)
         occurrences all number
    20
    88
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    27 / 450 (6.00%)
    36 / 902 (3.99%)
         occurrences all number
    33
    38
    Depression
         subjects affected / exposed
    32 / 450 (7.11%)
    51 / 902 (5.65%)
         occurrences all number
    35
    51
    Insomnia
         subjects affected / exposed
    57 / 450 (12.67%)
    105 / 902 (11.64%)
         occurrences all number
    71
    128
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    49 / 450 (10.89%)
    259 / 902 (28.71%)
         occurrences all number
    72
    385
    Aspartate aminotransferase increased
         subjects affected / exposed
    41 / 450 (9.11%)
    219 / 902 (24.28%)
         occurrences all number
    61
    330
    Blood alkaline phosphatase increased
         subjects affected / exposed
    16 / 450 (3.56%)
    74 / 902 (8.20%)
         occurrences all number
    20
    99
    Haemoglobin decreased
         subjects affected / exposed
    24 / 450 (5.33%)
    56 / 902 (6.21%)
         occurrences all number
    38
    76
    Neutrophil count decreased
         subjects affected / exposed
    23 / 450 (5.11%)
    74 / 902 (8.20%)
         occurrences all number
    35
    117
    Platelet count decreased
         subjects affected / exposed
    17 / 450 (3.78%)
    63 / 902 (6.98%)
         occurrences all number
    34
    93
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    36 / 450 (8.00%)
    77 / 902 (8.54%)
         occurrences all number
    44
    95
    Dysgeusia
         subjects affected / exposed
    37 / 450 (8.22%)
    126 / 902 (13.97%)
         occurrences all number
    41
    146
    Headache
         subjects affected / exposed
    53 / 450 (11.78%)
    140 / 902 (15.52%)
         occurrences all number
    107
    285
    Neuropathy peripheral
         subjects affected / exposed
    85 / 450 (18.89%)
    172 / 902 (19.07%)
         occurrences all number
    101
    202
    Paraesthesia
         subjects affected / exposed
    64 / 450 (14.22%)
    100 / 902 (11.09%)
         occurrences all number
    84
    124
    Peripheral sensory neuropathy
         subjects affected / exposed
    114 / 450 (25.33%)
    214 / 902 (23.73%)
         occurrences all number
    148
    263
    Polyneuropathy
         subjects affected / exposed
    25 / 450 (5.56%)
    50 / 902 (5.54%)
         occurrences all number
    28
    54
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    129 / 450 (28.67%)
    317 / 902 (35.14%)
         occurrences all number
    191
    464
    Leukopenia
         subjects affected / exposed
    78 / 450 (17.33%)
    165 / 902 (18.29%)
         occurrences all number
    164
    318
    Neutropenia
         subjects affected / exposed
    203 / 450 (45.11%)
    419 / 902 (46.45%)
         occurrences all number
    455
    885
    Thrombocytopenia
         subjects affected / exposed
    87 / 450 (19.33%)
    301 / 902 (33.37%)
         occurrences all number
    175
    589
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    20 / 450 (4.44%)
    55 / 902 (6.10%)
         occurrences all number
    25
    61
    Abdominal pain
         subjects affected / exposed
    111 / 450 (24.67%)
    281 / 902 (31.15%)
         occurrences all number
    186
    419
    Abdominal pain upper
         subjects affected / exposed
    58 / 450 (12.89%)
    125 / 902 (13.86%)
         occurrences all number
    103
    176
    Constipation
         subjects affected / exposed
    151 / 450 (33.56%)
    254 / 902 (28.16%)
         occurrences all number
    250
    373
    Diarrhoea
         subjects affected / exposed
    114 / 450 (25.33%)
    692 / 902 (76.72%)
         occurrences all number
    248
    1900
    Dyspepsia
         subjects affected / exposed
    24 / 450 (5.33%)
    77 / 902 (8.54%)
         occurrences all number
    32
    89
    Flatulence
         subjects affected / exposed
    9 / 450 (2.00%)
    53 / 902 (5.88%)
         occurrences all number
    10
    55
    Nausea
         subjects affected / exposed
    231 / 450 (51.33%)
    583 / 902 (64.63%)
         occurrences all number
    467
    1245
    Stomatitis
         subjects affected / exposed
    24 / 450 (5.33%)
    51 / 902 (5.65%)
         occurrences all number
    30
    65
    Vomiting
         subjects affected / exposed
    119 / 450 (26.44%)
    391 / 902 (43.35%)
         occurrences all number
    187
    763
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    278 / 450 (61.78%)
    519 / 902 (57.54%)
         occurrences all number
    283
    523
    Pruritus
         subjects affected / exposed
    32 / 450 (7.11%)
    44 / 902 (4.88%)
         occurrences all number
    37
    49
    Rash
         subjects affected / exposed
    50 / 450 (11.11%)
    95 / 902 (10.53%)
         occurrences all number
    64
    131
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    137 / 450 (30.44%)
    242 / 902 (26.83%)
         occurrences all number
    241
    422
    Back pain
         subjects affected / exposed
    54 / 450 (12.00%)
    83 / 902 (9.20%)
         occurrences all number
    85
    99
    Bone pain
         subjects affected / exposed
    39 / 450 (8.67%)
    62 / 902 (6.87%)
         occurrences all number
    56
    91
    Myalgia
         subjects affected / exposed
    107 / 450 (23.78%)
    201 / 902 (22.28%)
         occurrences all number
    202
    365
    Musculoskeletal pain
         subjects affected / exposed
    29 / 450 (6.44%)
    56 / 902 (6.21%)
         occurrences all number
    49
    100
    Pain in extremity
         subjects affected / exposed
    56 / 450 (12.44%)
    95 / 902 (10.53%)
         occurrences all number
    73
    125
    Infections and infestations
    Cystitis
         subjects affected / exposed
    17 / 450 (3.78%)
    66 / 902 (7.32%)
         occurrences all number
    18
    91
    Nasopharyngitis
         subjects affected / exposed
    36 / 450 (8.00%)
    73 / 902 (8.09%)
         occurrences all number
    40
    90
    Urinary tract infection
         subjects affected / exposed
    50 / 450 (11.11%)
    131 / 902 (14.52%)
         occurrences all number
    72
    185
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    63 / 450 (14.00%)
    168 / 902 (18.63%)
         occurrences all number
    84
    227
    Hypokalaemia
         subjects affected / exposed
    25 / 450 (5.56%)
    85 / 902 (9.42%)
         occurrences all number
    31
    132
    Hypomagnesaemia
         subjects affected / exposed
    25 / 450 (5.56%)
    92 / 902 (10.20%)
         occurrences all number
    38
    133

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jan 2011
    1)Details of translational substudy included in study design. Participation was not prerequisite for participation in study as whole.A separate informed consent was required for patients wants to participate in substudy.2)Inclusion criterion6 amended to include appropriate surgical intervention in patients with stageIIIC disease by laparotomy with intention for maximum surgical effort at cytoreduction &adequate staging but no or only limited actual debulking for disease if disease was intraoperatively not considered amenable to maximal cytoreduction,& no surgery was planned prior to disease progression 3)Correction of calculation of maximal dosing of carboplatin based on creatinine clearance.4)Revision of premedication needed prior to dosing with paclitaxel. Premedication schedules vary between hospitals & were considered acceptable as long as steroid in equivalent doses was part of premedication regimen.The revised regimen presented was considered recommendation &could be adapted.5)Criteria for initiation of &re-treatment with combination therapy were revised to be consistent with exclusion criteria & to note that deviations should be iscussed & agreed with sponsor.6)With amendment,it was allowed to replace the chest X-ray to be performed at baseline by chest Computed tomography(CT)scan.7)CA-125: To allow treatment decisions based on this tumour marker,results had to be available at visit. Due to long half-life of glycoprotein,7 days was considered appropriate timeframe.8)Lipase was no longer required for routine clinical laboratory safety analyses since an elevation of lipase was clinically only relevant in conjunction with abdominal symptoms. In case new or worsening abdominal symptoms were present, criteria for malignant bowel obstruction had to be assessed. With the amendment,only 1 coagulation parameters Quick, Prothrombin time (PT) or International normalised ratio(INR) to determined & creatinine to determined during combination courses.
    15 Sep 2014
    1) Global protocol amendment 2 introduced an additional analysis to be performed in October 2014, approximately 18 months after the primary PFS analysis [c01799511-02]. An update of the trial analysis was to be conducted, focusing on overall survival, but also including other efficacy and safety endpoints. The analysis was to be performed in the pre-defined subgroups along with additional exploratory subgroups identified at the time of the primary PFS analysis. Results of this additional analysis were reported in a synoptic interim report [c03038398-01]. 2) The reason for implementing this additional analysis was that data for OS were immature at the time of the primary analysis due to a low number of OS events. The time point was chosen based on the projection of OS event accumulation allowing for a more reliable estimate of any treatment effects. Potential new information gained from this additional analysis was considered highly relevant for the planning of further study activities to confirm clinically meaningful efficacy of nintedanib in Ovarian cancer(OC).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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