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    Clinical Trial Results:
    A randomized, placebo-controlled, multi-center phase I/II trial to assess the safety and efficacy of nintedanib (BIBF 1120) added to low-dose cytarabine in elderly patients with AML unfit for an intensive induction therapy

    Summary
    EudraCT number
    		 2011-001086-41
    Trial protocol
    		 DE  
    Global end of trial date
    27 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Aug 2022
    First version publication date
    09 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UKM10_0014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01488344
    WHO universal trial number (UTN)
    		 U1111-1122-6147
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Münster
    Sponsor organisation address
    Albert-Schweitzer-Campus 1, Münster, Germany, 48149
    Public contact
    Medizinische Klinik A, Universitätsklinikum Münster, christoph.schliemann@ukmuenster.de
    Scientific contact
    Medizinische Klinik A, Universitätsklinikum Münster, christoph.schliemann@ukmuenster.de
    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
    14 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jul 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective was to evaluate the safety and efficacy of nintedanib added to low-dose cytarabine (LDAC) in a phase 1/2 study in patients 60 years or older with newly diagnosed or relapsed/refractory (r/r) acute myeloid leukemia (AML) ineligible for intensive chemotherapy.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and the ICH Guidelines in Good Clinical Practice. The study was not started before the competent ethics committee had given a favorable opinion. Written informed consent was obtained from all patients and the study was only conducted as approved by the ethics committee and the competent authority. Amendments were only implemented after approval.
    Background therapy
    		 LDAC is used as standard treatment in elderly patients with newly diagnosed or relapsed/refractory AML ineligible for intensive chemotherapy. Patients in this study received the investigational drug nintedanib or placebo in addition to LDAC.
    Evidence for comparator
    		 In phase II, placebo plus LDAC treatment was used as a control to assess the treatment effect of nintedanib plus LDAC.
    Actual start date of recruitment
    02 Apr 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 44
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    4
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited for Phase I of the study between April 2012 and October 2013 at the University Hospital Münster (UKM). For phase II, patients were recruited from eight hospitals throughout Germany between May 2017 and September 2019.

    Pre-assignment
    Screening details
    		 The study included patients 60 years or older with newly diagnosed or relapsed/refractory AML ineligible for intensive chemotherapy.

    Period 1
    Period 1 title
    Overall trial (Phase I and Phase II) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase I - 100 mg Nintedanib (DL 1)
    Arm description
    		 Phase I patients in dose level (DL) 1 received 100 mg nintedanib plus LDAC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    BIBF1120
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    The patients in DL 1 reveived 100 mg Nintedanib (BIBF1120) orally twice daily for 28 days of a 28-day cycle in combination with low-dose cytarabine (LDAC). LDAC was administered from days 1-10 of of a 28-day cycle at 20 mg twice daily by subcutaneous injection.

    Arm title
    		 Phase I - 150 mg Nintedanib (DL 2)
    Arm description
    		 Phase I patients in DL 2 received 150 mg nintedanib plus LDAC.
    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
    The patients in DL 2 reveived 150 mg Nintedanib (BIBF1120) orally twice daily for 28 days of a 28-day cycle in combination with LDAC. LDAC was administered from days 1-10 of of a 28-day cycle at 20 mg twice daily by subcutaneous injection.

    Arm title
    		 Phase I - 200 mg Nintedanib (DL 3)
    Arm description
    		 Phase I patients in DL 3 received 200 mg nintedanib plus LDAC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    BIBF1120
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    The patients in DL 3 reveived 200 mg Nintedanib (BIBF1120) orally twice daily for 28 days of a 28-day cycle in combination with LDAC. LDAC was administered from days 1-10 of of a 28-day cycle at 20 mg twice daily by subcutaneous injection.

    Arm title
    		 Phase II - 200 mg Nintedanib
    Arm description
    		 Phase II patients in the experimental arm received 200 mg nintedanib plus LDAC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    BIBF1120
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    The patients in this arm received 200 mg Nintedanib (BIBF1120) orally twice daily for 28 days of a 28- day cycle in combination with low-dose cytarabine (LDAC). LDAC was administered from days 1-10 of of a 28-day cycle at 20 mg twice daily by subcutaneous injection.

    Arm title
    		 Phase II - Placebo
    Arm description
    		 Phase II patients in the comparator arm received placebo plus LDAC.
    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
    The patients in this arm received the placebo orally twice daily for 28 days of a 28- day cycle in combination with low-dose cytarabine (LDAC). LDAC was administered from days 1-10 of of a 28-day cycle at 20 mg twice daily by subcutaneous injection.

    Number of subjects in period 1 [1]
    		Phase I - 100 mg Nintedanib (DL 1) Phase I - 150 mg Nintedanib (DL 2) Phase I - 200 mg Nintedanib (DL 3) Phase II - 200 mg Nintedanib Phase II - Placebo
    Started
    3
    3
    6
    15
    15
    Completed
    1
    2
    0
    0
    0
    Not completed
    2
    1
    6
    15
    15
         Consent withdrawn by subject
    -
    -
    3
    -
    -
         Relapse
    -
    -
    -
    1
    2
         Patient decision
    -
    -
    -
    -
    1
         Disease progression
    2
    -
    2
    -
    -
         Death
    -
    -
    -
    2
    2
         AE / AML progression / death
    -
    -
    -
    -
    1
         AE / general physical health deterioration / death
    -
    -
    -
    1
    -
         Suspected unexpected serious adverse reaction
    -
    1
    1
    -
    -
         AML progression
    -
    -
    -
    7
    7
         Consent withdrawn by patient
    -
    -
    -
    2
    1
         Adverse event (AE)
    -
    -
    -
    1
    1
         AE / consent withdrawn by patient
    -
    -
    -
    1
    -
    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: One patient in DL 2 of Phase I did not receive study medication due to death from AML progression shortly after informed consent and was replaced. One randomized patient in Phase II did not receive allocated intervention because the patient withdrew consent immediately after giving consent and before the start of the first cycle.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase I - 100 mg Nintedanib (DL 1)
    Reporting group description
    		 Phase I patients in dose level (DL) 1 received 100 mg nintedanib plus LDAC.

    Reporting group title
    Phase I - 150 mg Nintedanib (DL 2)
    Reporting group description
    		 Phase I patients in DL 2 received 150 mg nintedanib plus LDAC.

    Reporting group title
    Phase I - 200 mg Nintedanib (DL 3)
    Reporting group description
    		 Phase I patients in DL 3 received 200 mg nintedanib plus LDAC.

    Reporting group title
    Phase II - 200 mg Nintedanib
    Reporting group description
    		 Phase II patients in the experimental arm received 200 mg nintedanib plus LDAC.

    Reporting group title
    Phase II - Placebo
    Reporting group description
    		 Phase II patients in the comparator arm received placebo plus LDAC.

    Reporting group values
    		 Phase I - 100 mg Nintedanib (DL 1) Phase I - 150 mg Nintedanib (DL 2) Phase I - 200 mg Nintedanib (DL 3) Phase II - 200 mg Nintedanib Phase II - Placebo Total
    Number of subjects
    		 3 3 6 15 15 42
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 1 0 1 1 4
        From 65-84 years
    		 2 2 6 14 14 38
        85 years and over
    		 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 0 4 8 7 21
        Male
    		 1 3 2 7 8 21

    End points

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    End points reporting groups
    Reporting group title
    Phase I - 100 mg Nintedanib (DL 1)
    Reporting group description
    		 Phase I patients in dose level (DL) 1 received 100 mg nintedanib plus LDAC.

    Reporting group title
    Phase I - 150 mg Nintedanib (DL 2)
    Reporting group description
    		 Phase I patients in DL 2 received 150 mg nintedanib plus LDAC.

    Reporting group title
    Phase I - 200 mg Nintedanib (DL 3)
    Reporting group description
    		 Phase I patients in DL 3 received 200 mg nintedanib plus LDAC.

    Reporting group title
    Phase II - 200 mg Nintedanib
    Reporting group description
    		 Phase II patients in the experimental arm received 200 mg nintedanib plus LDAC.

    Reporting group title
    Phase II - Placebo
    Reporting group description
    		 Phase II patients in the comparator arm received placebo plus LDAC.

    Primary: Dose limiting toxicities

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    End point title
    		 Dose limiting toxicities [1] [2]
    End point description
    Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) criteria. A dose limiting toxicity (DLT) was defined as every severe adverse reaction CTC grade IV with possible or definite relationship to nintedanib. Designated exceptions for DLT determination included therapy-related cytopenias as signs of an intended anti-leukemic activity and cytopenia-associated complications (neutropenic fever, neutropenic infections, and thrombocytopenic bleedings). However, these complications could constitute a DLT if occurring in an unexpected high frequency. Furthermore, complications such as neutropenic infections, thrombocytopenic bleedings, deterioration of the general condition, laboratory abnormalities, death, tumor lysis syndrome, or organ failure, were also excluded from DLT determination, whenever these were clearly attributable to AML progression in the judgment of the investigator.
    End point type
    Primary
    End point timeframe
    The determination of the maximum tolerated dose (MTD) was based on the occurrence of DLTs in the first treatment cycle.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No analytical statistics were performed to evaluate the safety of the study in phase I.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The DLTs were only evaluated in phase I.
    End point values
    		 Phase I - 100 mg Nintedanib (DL 1) Phase I - 150 mg Nintedanib (DL 2) Phase I - 200 mg Nintedanib (DL 3)
    Number of subjects analysed
    3
    3
    6
    Units: dose limiting toxicities (DLTs)
    0
    0
    0
    No statistical analyses for this end point

    Primary: Overall survival

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    End point title
    		 Overall survival [3]
    End point description
    Overall survival (OS) is defined as the time interval from day one of study treatment to the day of death. For a patient who was not known to have died by the end of follow-up, observation of OS was censored on the date the patient was last known to be alive.
    End point type
    Primary
    End point timeframe
    day 1 of study treatment to the day of death.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The OS was only evaluated in phase II.
    End point values
    		 Phase II - 200 mg Nintedanib Phase II - Placebo
    Number of subjects analysed
    15
    15
    Units: month
        median (confidence interval 95%)
    3.4 (2.3 to 8.8)
    3.6 (2.1 to 99999)
    Statistical analysis title
    		 primary endpoint (OS)
    Statistical analysis description
    The OS was compared between both treatment arms (ITT) by calculating a 95% confidence interval for the hazard ratio by using a Cox-regression with treatment arm and AML status (newly diagnosed vs. r/r) as independent variables. No noticeable difference in OS between the treatment arms could be detected. The corresponding HR for nintedanib vs placebo was 1.19 and the adjusted confirmatory 95% CI was 0.55-2.56.
    Comparison groups
    Phase II - 200 mg Nintedanib v Phase II - Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96 [4]
    Method
    		 Logrank
    Confidence interval
    Notes
    [4] - The non-stratified univariate comparison of OS between both treatment arms resulted in a HR of 1.02 (95% CI 0.48-2.15, univariate logrank test p=0.96).

    Secondary: Overall survival (r/r AML)

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    End point title
    		 Overall survival (r/r AML) [5]
    End point description
    Comparison of OS in patients with relapsed or refractory (r/r) AML.
    End point type
    Secondary
    End point timeframe
    day 1 of study treatment to the day of death.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The OS was only evaluated in phase II.
    End point values
    		 Phase II - 200 mg Nintedanib Phase II - Placebo
    Number of subjects analysed
    11
    11
    Units: month
        median (confidence interval 95%)
    3.0 (1.6 to 99999)
    3.6 (2.1 to 99999)
    Statistical analysis title
    		 secondary endpoint (OS - r/r AML)
    Statistical analysis description
    In the 22 patients enrolled into the phase II part of the study with r/r AML, median OS was 3.0 months in the nintedanib arm and 3.6 months in the placebo arm (HR 1.54, 95% CI, 0.61-3.86; logrank P = 0.36).
    Comparison groups
    Phase II - 200 mg Nintedanib v Phase II - Placebo
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall survival (newly diagnosed AML)

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    End point title
    		 Overall survival (newly diagnosed AML) [6]
    End point description
    Comparison of OS in patients with newly diagnosed AML.
    End point type
    Secondary
    End point timeframe
    day 1 of study treatment to the day of death.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The OS was only evaluated in phase II.
    End point values
    		 Phase II - 200 mg Nintedanib Phase II - Placebo
    Number of subjects analysed
    4
    4
    Units: month
        median (confidence interval 95%)
    8.2 (5.9 to 99999)
    5.6 (2.1 to 99999)
    Statistical analysis title
    		 secondary endpoint (OS - newly diagnosed AML)
    Statistical analysis description
    No noticeable difference in OS in the subgroup of patients with newly diagnosed AML could be detected between the two treatment arms. Median OS was 8.2 months in the nintedanib arm and 5.6 months in the placebo arm (HR 0.55, 95% CI, 0.12-2.51; logrank P = 0.44).
    Comparison groups
    Phase II - 200 mg Nintedanib v Phase II - Placebo
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall response rate

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    End point title
    		 Overall response rate [7]
    End point description
    The overall response rate (ORR) is defined as proportion of patients who achieve either a complete remission (CR), a complete remission with incomplete platelet recovery (CRp) or a complete remission with incomplete neutrophil recovery (CRi).
    End point type
    Secondary
    End point timeframe
    Any time point during study participation.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The ORR was only evaluated in phase II.
    End point values
    		 Phase II - 200 mg Nintedanib Phase II - Placebo
    Number of subjects analysed
    15
    15
    Units: Patients
    1
    2
    Statistical analysis title
    		 secondary endpoint (ORR)
    Statistical analysis description
    Three patients reached an overall response. Using a competing risk approach to compare the cumulative incidence with death to treatment discontinuation without prior overall response (nintedanib n=3, placebo n=3) as a competing event, the Gray's k-sample test p-value for ORR was p=0.743. Because of the small number of responses, the estimates of the subdistribution and cause-specific hazard ratios are not reported here, and the Gray’s k-sample p-values cannot be reasonably interpreted.
    Comparison groups
    Phase II - 200 mg Nintedanib v Phase II - Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.743
    Method
    		 Gray's k-sample test
    Confidence interval

    Secondary: Complete remission

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    End point title
    		 Complete remission [8]
    End point description
    Patients who have achieved a complete remission (CR).
    End point type
    Secondary
    End point timeframe
    Any time point during study participation.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The CR was only evaluated in phase II.
    End point values
    		 Phase II - 200 mg Nintedanib Phase II - Placebo
    Number of subjects analysed
    15
    15
    Units: Patients
    1
    2
    Statistical analysis title
    		 secondary endpoint (CR)
    Statistical analysis description
    All three responders achieved a CR. Using a competing risk approach to compare the cumulative incidence with death to treatment discontinuation without prior overall response (nintedanib n=3, placebo n=3) as a competing event, the Gray's k-sample test p-value for CR was p=0.743. Because of the small number of responses, the estimates of the subdistribution and cause-specific hazard ratios are not reported here, and the Gray’s k-sample p-values cannot be reasonably interpreted.
    Comparison groups
    Phase II - 200 mg Nintedanib v Phase II - Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.743
    Method
    		 Gray's k-sample test
    Confidence interval

    Secondary: Relapse-free survival

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    End point title
    		 Relapse-free survival [9]
    End point description
    Relapse-free survival (RFS) is defined as the time interval from the first day a patient achieved CR / CRi / CRp until relapse or death from any course, whatever occurs first. For a patient who was not known to have died or had relapsed by the end of follow-up, observation of RFS was censored on the date the patient was last known to be alive and in CR.
    End point type
    Secondary
    End point timeframe
    first day of CR / CRi / CRp until relapse or death from any course.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The RFS was only evaluated in phase II.
    End point values
    		 Phase II - 200 mg Nintedanib Phase II - Placebo
    Number of subjects analysed
    1
    2
    Units: Patients
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time of signing the informed consent until 28 days after last protocol treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Safety group: Phase I - 100 mg Nintedanib (DL 1)
    Reporting group description
    		 Study patients who received at least one dose of nintedanib in DL 1 of Phase I.

    Reporting group title
    Safety group: Phase I - 150 mg Nintedanib (DL 2)
    Reporting group description
    		 Study patients who received at least one dose of nintedanib in DL 2 of Phase I.

    Reporting group title
    Safety group: Phase I - 200 mg Nintedanib (DL 3)
    Reporting group description
    		 Study patients who received at least one dose of nintedanib in DL 3 of Phase I.

    Reporting group title
    Safety group: Phase II - 200 mg Nintedanib
    Reporting group description
    		 Study patients who received at least one dose of nintedanib in Phase II.

    Reporting group title
    Safety group: Phase II - Placebo
    Reporting group description
    		 Study patients who received at least one dose of placebo in Phase II.

    Serious adverse events
    		 Safety group: Phase I - 100 mg Nintedanib (DL 1) Safety group: Phase I - 150 mg Nintedanib (DL 2) Safety group: Phase I - 200 mg Nintedanib (DL 3) Safety group: Phase II - 200 mg Nintedanib Safety group: Phase II - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    5 / 6 (83.33%)
    9 / 15 (60.00%)
    12 / 15 (80.00%)
         number of deaths (all causes)
    3
    3
    6
    14
    14
         number of deaths resulting from adverse events
    0
    1
    2
    3
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    General physical condition decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Refractoriness to platelet transfusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transfusion related complication
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    5 / 15 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 5
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Febrile infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Lung infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety group: Phase I - 100 mg Nintedanib (DL 1) Safety group: Phase I - 150 mg Nintedanib (DL 2) Safety group: Phase I - 200 mg Nintedanib (DL 3) Safety group: Phase II - 200 mg Nintedanib Safety group: Phase II - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    14 / 15 (93.33%)
    14 / 15 (93.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone neoplasm
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Peripheral coldness
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    4 / 15 (26.67%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    5
    4
    Injection site reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    2
    1
    2
    1
    3
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    2
    5
    2
    Immune system disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Breast swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pelvic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blister
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    1
    1
    3
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    3 / 15 (20.00%)
         occurrences all number
    2
    1
    0
    1
    3
    Haemoptysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Pharyngeal erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Dry skin
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    1
    0
    0
    2
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Restlessness
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Heart rate irregular
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Liver function test increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Periorbital haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    1
    0
    7
    Hypotonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Lymphadenitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Lymph node pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Atrial flutter
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    1
    Vestibular disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    1
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Anal fissure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Constipation
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    3
    0
    1
    2
    1
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    5 / 6 (83.33%)
    7 / 15 (46.67%)
    5 / 15 (33.33%)
         occurrences all number
    0
    5
    8
    39
    8
    Dry mouth
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Eructation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Faeces hard
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Gingival bleeding
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Haematochezia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Mouth haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    6 / 15 (40.00%)
    4 / 15 (26.67%)
         occurrences all number
    3
    1
    5
    29
    8
    Oral mucosal erythema
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    8 / 15 (53.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    3
    5
    10
    0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Purpura
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    3
    1
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Skin ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    2
    1
    0
    Chest wall haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    1
    0
    0
    3
    Infections and infestations
    Abscess soft tissue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Bacterial disease carrier
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    Enterococcal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Herpes simplex
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Lip infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Lung infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pathogen resistance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pelvic infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Soft tissue infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    1
    2
    Vaginal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    3
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2013
    Protocol amendment 1 was done in response to a new IB for nintedanib from Boehringer Ingelheim (version 12). Changes were made to the inclusion/exclusion criteria to take into account the risk for hollow organ perforation upon therapy with nintedanib, among other minor changes to the protocol and clarifications.
    28 Sep 2016
    After the completion of Phase I and before the start of Phase II, the protocol was amended. The study design for phase II was changed to a double-blind, placebo-controlled study part. Patients should be randomized 1:1 to receive either LDAC plus nintedanib or LDAC plus placebo with overall survival rather than CR rate as the primary endpoint. Prof. Utz Krug was in phase I the coordinating investigator of the study. He was replaced by Prof. Christoph Schliemann before the start of phase II.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In total, only 30 randomized patients were analyzed in the full-analysis set. The initial sample size of 100 patients was not reached due to discontinuation of recruitment due to new drugs for this disease and slow recruitment.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27716819
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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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