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    Clinical Trial Results:
    A double-blind, randomised, placebo controlled Phase III study of nintedanib plus Best Supportive Care (BSC) versus placebo plus BSC in patients with colorectal cancer refractory to standard therapies

    Summary
    EudraCT number
    		 2012-000095-42
    Trial protocol
    		 LU   IT   SE   AT   DK   BE   DE   PT   NL   PL   FR  
    Global end of trial date
    15 Sep 2016

    Results information
    Results version number
    		 v1
    This version publication date
    06 Aug 2017
    First version publication date
    06 Aug 2017
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    1199.52
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02149108
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    14 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 May 2016
    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
    To evaluate efficacy and safety of Nintedanib plus BSC vs. placebo plus BSC in patients with metastatic colorectal cancer after failure of previous treatment with standard chemotherapy and biological agents.
    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. There were 2 dose reductions planned in the protocol: From 200 mg bid to 150 mg bid; then from 150 mg bid to 100 mg bid. In case a patient had these 2 dose reductions and , thereafter had an adverse event that require further dose reduction, the patient should be withdrawn as no further dose reduction was allowed. Symptomatic treatment of tumour associated symptoms were allowed throughout.
    Background therapy
    		 -
    Evidence for comparator
    		 Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course was the active comparator.
    Actual start date of recruitment
    14 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 23
    Country: Number of subjects enrolled
    Australia: 37
    Country: Number of subjects enrolled
    Austria: 27
    Country: Number of subjects enrolled
    Belgium: 61
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    Czech Republic: 33
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Hong Kong: 15
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 104
    Country: Number of subjects enrolled
    Japan: 112
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 73
    Country: Number of subjects enrolled
    Luxembourg: 3
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Portugal: 30
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Spain: 97
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Taiwan: 29
    Country: Number of subjects enrolled
    Turkey: 39
    Country: Number of subjects enrolled
    United Kingdom: 64
    Country: Number of subjects enrolled
    United States: 54
    Worldwide total number of subjects
    949
    EEA total number of subjects
    494
    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)
    542
    From 65 to 84 years
    405
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The "completed" patients were on treatment (2 patients on Placebo, 3 patients on Nintedanib) at the data cut-off date 14JUN2016. The "NOT Completed" patients were off-treatment (380 patients on Placebo, 383 patients on Nintedanib) at the data cut-off date 14JUN2016. Enrolled=949 subjects were enrolled, randomised (entered) =768 and treated=765.

    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 strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were not met.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Patients, investigators, the sponsor’s trial team, and everyone involved in the analysis or with an interest in this trial remained blinded with regard to the randomised treatment assignments until after database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Arm title
    		 Nintedanib
    Arm description
    		 Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Number of subjects in period 1 [1]
    		Placebo Nintedanib
    Started
    382
    386
    Completed
    2
    3
    Not completed
    380
    383
         Adverse event, serious fatal
    11
    12
         Other not defined above
    -
    2
         Adverse event, non-fatal
    28
    38
         Progressive Disease (PD)
    324
    318
         Refusal to continue trial medication
    15
    11
         Lost to follow-up
    1
    -
         Not treated
    1
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group values
    		 Placebo Nintedanib Total
    Number of subjects
    		 382 386 768
    Age categorical
    Units: Subjects
    Age Continuous
    Randomised Set (RS): This patient set included all patients who were randomised to receive treatment, whether treated or not.
    Units: years
        arithmetic mean (standard deviation)
    		 61.1 ± 10.8 61 ± 11.3 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 164 150 314
        Male
    		 218 236 454

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Primary: Progression-Free Survival (PFS) by Central Review Assessment

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    End point title
    		 Progression-Free Survival (PFS) by Central Review Assessment
    End point description
    PFS by central review assessment was defined as the time from the date of randomisation to the date of disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 or death from any cause, whichever occurred first. Median, 95% Confidence Interval were calculated from an unadjusted Kaplan−Meier curve for each treatment arm. Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Primary
    End point timeframe
    From randomisation until cut-off date 14JUN2016.
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    382 [1]
    386 [2]
    Units: Months
        median (confidence interval 95%)
    1.38 (1.38 to 1.41)
    1.51 (1.45 to 2.17)
    Notes
    [1] - RS
    [2] - RS
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.69
    Notes
    [3] - Hazard ratio <1 favors Nintedanib.
    [4] - Hazard ratio, confidence interval and p−value obtained from log−rank test stratified by regorafenib pre−treatment (yes vs no), time from onset metastatic disease until randomisation (less than 24 months vs 24 months or more ) and region.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomisation to the time of death from any cause. Median, 95% Confidence Interval were calculated from an unadjusted Kaplan−Meier curve for each treatment arm. Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Primary
    End point timeframe
    From randomisation until cut-off date 14JUN2016.
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    382 [5]
    386 [6]
    Units: Months
        median (confidence interval 95%)
    6.05 (5.22 to 6.97)
    6.44 (5.98 to 7.1)
    Notes
    [5] - RS
    [6] - RS
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.8659 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.19
    Notes
    [7] - Hazard ratio below 1 favors Nintedanib.
    [8] - Hazard ratio, confidence interval and p−value obtained from log−rank test stratified by regorafenib pre−treatment (yes vs no), time from onset metastatic disease until randomisation (less than 24 months vs 24 months or more ) and region.

    Secondary: Objective Tumour Response (Complete Response (CR)) + Partial Response (PR) by Central Review Assessment

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    End point title
    		 Objective Tumour Response (Complete Response (CR)) + Partial Response (PR) by Central Review Assessment
    End point description
    Objective tumour response was defined as best overall response of CR or PR determined by central review assessment. Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 14JUN2016.
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    382 [9]
    386 [10]
    Units: Percentage of participants
        CR
    0
    0
        PR
    0
    0
    Notes
    [9] - RS
    [10] - RS
    No statistical analyses for this end point

    Secondary: Disease Control (Complete Response + Partial Response + Stable Disease) by Central Review Assessment

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    End point title
    		 Disease Control (Complete Response + Partial Response + Stable Disease) by Central Review Assessment
    End point description
    Disease control was defined as best overall response of CR, PR, or Stable Disease (SD). Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Secondary
    End point timeframe
    From randomisation until cut-off date 14JUN2016.
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    382 [11]
    386 [12]
    Units: Percentage of participants
        number (not applicable)
    10.5
    25.6
    Notes
    [11] - RS
    [12] - RS
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 4.47
    Notes
    [13] - An odds ratio >1 indicates benefit to Nintedanib.
    [14] - Odds ratio and p−value are obtained from logistic regression model adjusted for regorafenib pre−treatment (yes vs no), time from onset metastatic disease until randomization in the trial (less than 24 months vs. 24 months or more) and region.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug administration until 28 days after last drug administration, up to 22.7 months.
    Adverse event reporting additional description
    1 patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2 patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only 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
    		 Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

    Serious adverse events
    		 Placebo Nintedanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    133 / 381 (34.91%)
    149 / 384 (38.80%)
         number of deaths (all causes)
    51
    55
         number of deaths resulting from adverse events
    2
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant ascites
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    24 / 381 (6.30%)
    27 / 384 (7.03%)
         occurrences causally related to treatment / all
    0 / 24
    0 / 27
         deaths causally related to treatment / all
    0 / 24
    0 / 27
    Metastases to central nervous system
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (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 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    5 / 381 (1.31%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour perforation
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (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
    1 / 381 (0.26%)
    0 / 384 (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
    3 / 381 (0.79%)
    4 / 384 (1.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    4 / 381 (1.05%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Fatigue
         subjects affected / exposed
    1 / 381 (0.26%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 381 (0.79%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 381 (0.26%)
    3 / 384 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    3 / 381 (0.79%)
    5 / 384 (1.30%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    Pyrexia
         subjects affected / exposed
    4 / 381 (1.05%)
    3 / 384 (0.78%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         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
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acquired diaphragmatic eventration
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    12 / 381 (3.15%)
    12 / 384 (3.13%)
         occurrences causally related to treatment / all
    0 / 12
    1 / 12
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    Haemoptysis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    6 / 381 (1.57%)
    3 / 384 (0.78%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (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
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Delirium
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 381 (0.79%)
    7 / 384 (1.82%)
         occurrences causally related to treatment / all
    1 / 3
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 381 (1.31%)
    6 / 384 (1.56%)
         occurrences causally related to treatment / all
    1 / 5
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    6 / 381 (1.57%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Liver function test increased
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         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 / 381 (0.00%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (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
    0 / 381 (0.00%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    3 / 381 (0.79%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 381 (0.52%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    2 / 381 (0.52%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory loss
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         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
    1 / 381 (0.26%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 381 (1.05%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 381 (1.05%)
    6 / 384 (1.56%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    4 / 381 (1.05%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Constipation
         subjects affected / exposed
    1 / 381 (0.26%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 381 (0.52%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 381 (0.26%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fistula of small intestine
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 381 (0.52%)
    5 / 384 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    6 / 381 (1.57%)
    6 / 384 (1.56%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal prolapse
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         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 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 381 (1.05%)
    3 / 384 (0.78%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (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 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal obstruction
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal tenesmus
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         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
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subileus
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 381 (0.52%)
    5 / 384 (1.30%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 381 (0.26%)
    4 / 384 (1.04%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    4 / 381 (1.05%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 3
    1 / 1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Jaundice
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 381 (0.79%)
    7 / 384 (1.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Focal segmental glomerulosclerosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    5 / 381 (1.31%)
    4 / 384 (1.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Micturition disorder
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         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 / 381 (0.26%)
    3 / 384 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    5 / 381 (1.31%)
    4 / 384 (1.04%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         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
    3 / 381 (0.79%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 381 (0.00%)
    3 / 384 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oral candidiasis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 384 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 381 (1.31%)
    3 / 384 (0.78%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 381 (0.00%)
    4 / 384 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Small intestine gangrene
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 381 (0.00%)
    6 / 384 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 381 (1.31%)
    6 / 384 (1.56%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 381 (0.26%)
    4 / 384 (1.04%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 381 (0.79%)
    0 / 384 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 384 (0.26%)
         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
    309 / 381 (81.10%)
    351 / 384 (91.41%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    23 / 381 (6.04%)
    90 / 384 (23.44%)
         occurrences all number
    25
    111
    Aspartate aminotransferase increased
         subjects affected / exposed
    44 / 381 (11.55%)
    90 / 384 (23.44%)
         occurrences all number
    47
    108
    Blood alkaline phosphatase increased
         subjects affected / exposed
    22 / 381 (5.77%)
    28 / 384 (7.29%)
         occurrences all number
    22
    33
    Blood bilirubin increased
         subjects affected / exposed
    15 / 381 (3.94%)
    26 / 384 (6.77%)
         occurrences all number
    18
    27
    Weight decreased
         subjects affected / exposed
    13 / 381 (3.41%)
    35 / 384 (9.11%)
         occurrences all number
    13
    35
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 381 (3.94%)
    42 / 384 (10.94%)
         occurrences all number
    16
    43
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 381 (4.99%)
    25 / 384 (6.51%)
         occurrences all number
    24
    30
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    22 / 381 (5.77%)
    23 / 384 (5.99%)
         occurrences all number
    23
    26
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    46 / 381 (12.07%)
    54 / 384 (14.06%)
         occurrences all number
    50
    60
    Fatigue
         subjects affected / exposed
    89 / 381 (23.36%)
    113 / 384 (29.43%)
         occurrences all number
    95
    127
    Oedema peripheral
         subjects affected / exposed
    28 / 381 (7.35%)
    22 / 384 (5.73%)
         occurrences all number
    28
    25
    Pain
         subjects affected / exposed
    21 / 381 (5.51%)
    9 / 384 (2.34%)
         occurrences all number
    21
    9
    Pyrexia
         subjects affected / exposed
    45 / 381 (11.81%)
    53 / 384 (13.80%)
         occurrences all number
    58
    61
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    59 / 381 (15.49%)
    65 / 384 (16.93%)
         occurrences all number
    60
    69
    Abdominal pain upper
         subjects affected / exposed
    21 / 381 (5.51%)
    25 / 384 (6.51%)
         occurrences all number
    22
    28
    Constipation
         subjects affected / exposed
    57 / 381 (14.96%)
    65 / 384 (16.93%)
         occurrences all number
    60
    73
    Diarrhoea
         subjects affected / exposed
    57 / 381 (14.96%)
    175 / 384 (45.57%)
         occurrences all number
    76
    301
    Nausea
         subjects affected / exposed
    103 / 381 (27.03%)
    163 / 384 (42.45%)
         occurrences all number
    129
    202
    Vomiting
         subjects affected / exposed
    71 / 381 (18.64%)
    149 / 384 (38.80%)
         occurrences all number
    93
    229
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    48 / 381 (12.60%)
    42 / 384 (10.94%)
         occurrences all number
    48
    47
    Dyspnoea
         subjects affected / exposed
    40 / 381 (10.50%)
    35 / 384 (9.11%)
         occurrences all number
    43
    37
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    14 / 381 (3.67%)
    20 / 384 (5.21%)
         occurrences all number
    14
    21
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    22 / 381 (5.77%)
    30 / 384 (7.81%)
         occurrences all number
    22
    33
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    12 / 381 (3.15%)
    34 / 384 (8.85%)
         occurrences all number
    14
    38
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 381 (1.57%)
    21 / 384 (5.47%)
         occurrences all number
    6
    22
    Back pain
         subjects affected / exposed
    30 / 381 (7.87%)
    33 / 384 (8.59%)
         occurrences all number
    32
    37
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    96 / 381 (25.20%)
    128 / 384 (33.33%)
         occurrences all number
    100
    143

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2014
    In the amendment 1 primary endpoint PFS and key secondary endpoint OS were changed to coprimary endpoints to reflect the clinical benefit for patients in this trial. As the trial was already powered for OS, no other changes in the trial design or patient number were needed. All relevant sections of the Clinical Trial Protocol (CTP) were adapted accordingly. The subgroup analysis ‘previous treatment with TAS-102 (yes vs. no)’ was added for both coprimary endpoints. The amendment 1 also clarified that analyses to describe the pattern of time to death would be described, while accounting for the extent and influence of postprogression anticancer treatments. The amendment 1 added the analysis on exposure-response relationship to the CTP.
    13 Mar 2015
    The amendment 2 clarified that previous treatment for Colo Rectal Cancer (CRC) with TAS-102, if available to the patient according to local standards, was allowed in this trial. Further clarifications regarding dose reduction in the case of diarrhoea, treatment interruption in case of haematological AEs, and the threshold for liver enzymes not being dependent on CTCAE were provided. The information about history of CRC that should be obtained and recorded in the electronic Case Report Form (eCRF) was extended by ‘reasons for not administering regorafenib’. For the HRQoL analysis, it was clarified that the main HRQoL endpoints in this trial are the changes in mean scores over the duration of the median follow-up period for the physical functioning scale and global health status (QoL scale measured on the EORTC QCL-C30 questionnaire using longitudinal models). These are mixed-effects growth curve models with the average profile over time for each HRQoL endpoint described using a piecewise linear model. A mean score per patient for each HRQoL endpoint will be calculated from the area under the estimated growth curve up to the median follow-up time. An additional responder analysis will compare the proportions of patients in each treatment group that achieved an average 10-point increase from the baseline score over the follow-up time for each HRQoL endpoint of interest.

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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