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    Clinical Trial Results:
    A Randomised Phase II Study of Nintedanib (BIBF1120) Compared to Chemotherapy in Patients with Recurrent Clear Cell Carcinoma of the Ovary or Endometrium

    Summary
    EudraCT number
    2013-002109-73
    Trial protocol
    GB   FR   NL   DK   FI   NO  
    Global end of trial date
    23 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Sep 2021
    First version publication date
    16 Sep 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0NiCCC2013
    Additional study identifiers
    ISRCTN number
    ISRCTN50772895
    US NCT number
    NCT02866370
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    European Network Gynaecological Oncological Trials: ENGOT-ov36, Sponsor Reference: GN12ON259
    Sponsors
    Sponsor organisation name
    NHS Greater Glasgow and Clyde
    Sponsor organisation address
    Dykebar Hospital, Grahamston Road, Paisley, Glasgow, United Kingdom, PA2 7DE
    Public contact
    Joanne McGarry, NHS Greater Glasgow and Clyde, 0044 141 3144001, joanne.mcgarry@ggc.scot.nhs.uk
    Scientific contact
    Joanne McGarry, NHS Greater Glasgow and Clyde, 0044 141 314 4001, oanne.mcgarry@ggc.scot.nhs.uk
    Sponsor organisation name
    European Organisation for Research and Treatment of Cancer
    Sponsor organisation address
    Avenue E. Mounierlaan 83/11, Brussels, Belgium, B-1200
    Public contact
    Kin Jip Cheung, European Organisation for Research and Treatment of Cancer (EORTC), 32 27741607, kin-jip.cheung@eortc.org
    Scientific contact
    Kin Jip Cheung, European Organisation for Research and Treatment of Cancer (EORTC), 32 27741607, kin-jip.cheung@eortc.org
    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
    20 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy, safety and effect on quality of life of Nintedanib compared to chemotherapy in women with relapsed clear cell carcinoma of the ovary or endometrium
    Protection of trial subjects
    Further chemotherapy is routinely given to patients who have recurrent Clear Cell Carcinoma (CCC) of the ovary or endometrium. This chemotherapy has only modest benefit as the progression free survival for these patients is only about 24 months and reported response rates are less than 10%. Although Nintedanib appears promising and well tolerated, we cannot be sure of its benefit to patients. Women randomised to Nintendanib did not receive standard chemotherapy. However all participants were assessed every 8 weeks for tumour progression with a CT scan, so if participants progressed on Nintendanib, there was an opportunity for them to change quickly to chemotherapy. There was also an early stopping rule, to limit the number of women exposed to Nintedanib alone if it appeared to be ineffective. Additional clinic visits and tests were performed to ensure participants safety. Patient's were monitored for Drug Induced Liver Injury (DILI) (Hy's Law case), although rare. A clearly defined concept was detailed in the protocol to guard participant's safety and explained the necessary steps to take to identify and manage DILI. This included monitoring of ALT/AST result, stopping Nintedanib treatment, repeating blood tests, abdominal ultrasound and reporting such cases to study Sponsor and pharmaceutical company. The IDMC monitored study data annually for toxicity and efficacy.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Apr 2015
    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
    Netherlands: 6
    Country: Number of subjects enrolled
    United Kingdom: 66
    Country: Number of subjects enrolled
    France: 30
    Worldwide total number of subjects
    102
    EEA total number of subjects
    36
    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)
    80
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Prior to commencing any study related procedures, all participants will be fully informed about the risks, benefits and procedures involved in study participation, and will sign a consent form confirming this process. Central pathology review will be performed to confirm that all basic pathology criteria are met.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OVARIAN: Experimental arm (nintedanib)
    Arm description
    Nintedanib (BIBF1120) capsules 200mg orally twice a day, continuously until disease progression. The first 6 cycles are 28 days long and from cycle 7 onwards, the cycles are 56 days long.
    Arm type
    Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    BIBF1120
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nintedanib (BIBF1120) capsules 200mg orally twice a day, continuously until disease progression. The first 6 cycles are 28 days long and from cycle 7 onwards, the cycles are 56 days long.

    Arm title
    OVARIAN: Control arm (chemotherapy)
    Arm description
    Physicians' choice of chemotherapy from list below: Paclitaxel 80mg/m2 intravenously on days 1, 8 and 15 of a 28 day cycle OR Pegylated Liposomal Doxorubicin (PLD) 40mg/m2 intravenously on day 1 of a 28 day cycle OR Topotecan 4mg/m2 intravenously on days 1, 8 and 15 of a 28 day cycle Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.
    Arm type
    Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80mg/m2 intravenously on Days 1, 8 and 15 of a 28 day cycle. Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.

    Investigational medicinal product name
    Pegylated Liposomal Doxorubicin
    Investigational medicinal product code
    Other name
    PLD, Caelyx
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated Liposomal Doxorubicin 40mg/m2 intravenously on Day 1 of a 28 day cycle. Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient. The maximum lifetime cumulative dose is 450mg/m2.

    Investigational medicinal product name
    Topotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Topotecan 4mg/m2 intravenously on Days 1, 8 and 15 of a 28 day cycle. Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.

    Arm title
    ENDOMETRIAL: Experimental arm (nintedanib)
    Arm description
    Nintedanib (BIBF1120) capsules 200mg orally twice a day, continuously until disease progression. The first 6 cycles are 28 days long and from cycle 7 onwards, the cycles are 56 days long.
    Arm type
    Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    BIBF1120
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Nintedanib (BIBF1120) capsules 200mg orally twice a day, continuously until disease progression. The first 6 cycles are 28 days long and from cycle 7 onwards, the cycles are 56 days long.

    Arm title
    ENDOMETRIAL: Control arm (chemotherapy)
    Arm description
    Physicians' choice of chemotherapy from list below: Carboplatin AUC 5 and Paclitaxel 175mg/m2 intravenously on day 1 of a 21 day cycle OR Doxorubicin 60mg/m2 intravenously on day 1 of a 21 day cycle. Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.
    Arm type
    Active comparator

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin AUC 5 (given along with Paclitaxel 175mg/m2) intravenously on day 1 of a 21 day cycle Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 175mg/m2 (given along with Carboplatin AUC 5) intravenously on day 1 of a 21 day cycle Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 60mg/m2 intravenously on day 1 of a 21 day cycle. Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient. The maximum lifetime cumulative dose is 450mg/m2.

    Number of subjects in period 1 [1]
    OVARIAN: Experimental arm (nintedanib) OVARIAN: Control arm (chemotherapy) ENDOMETRIAL: Experimental arm (nintedanib) ENDOMETRIAL: Control arm (chemotherapy)
    Started
    47
    44
    4
    5
    Completed
    47
    44
    4
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of patients in the baseline period are those in the ITT population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OVARIAN: Experimental arm (nintedanib)
    Reporting group description
    Nintedanib (BIBF1120) capsules 200mg orally twice a day, continuously until disease progression. The first 6 cycles are 28 days long and from cycle 7 onwards, the cycles are 56 days long.

    Reporting group title
    OVARIAN: Control arm (chemotherapy)
    Reporting group description
    Physicians' choice of chemotherapy from list below: Paclitaxel 80mg/m2 intravenously on days 1, 8 and 15 of a 28 day cycle OR Pegylated Liposomal Doxorubicin (PLD) 40mg/m2 intravenously on day 1 of a 28 day cycle OR Topotecan 4mg/m2 intravenously on days 1, 8 and 15 of a 28 day cycle Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.

    Reporting group title
    ENDOMETRIAL: Experimental arm (nintedanib)
    Reporting group description
    Nintedanib (BIBF1120) capsules 200mg orally twice a day, continuously until disease progression. The first 6 cycles are 28 days long and from cycle 7 onwards, the cycles are 56 days long.

    Reporting group title
    ENDOMETRIAL: Control arm (chemotherapy)
    Reporting group description
    Physicians' choice of chemotherapy from list below: Carboplatin AUC 5 and Paclitaxel 175mg/m2 intravenously on day 1 of a 21 day cycle OR Doxorubicin 60mg/m2 intravenously on day 1 of a 21 day cycle. Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.

    Reporting group values
    OVARIAN: Experimental arm (nintedanib) OVARIAN: Control arm (chemotherapy) ENDOMETRIAL: Experimental arm (nintedanib) ENDOMETRIAL: Control arm (chemotherapy) Total
    Number of subjects
    47 44 4 5 100
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (standard deviation)
    53 ( 9.8 ) 55.5 ( 7.8 ) 71 ( 2.2 ) 68 ( 5.4 ) -
    Gender categorical
    Units: Subjects
        Female
    47 44 4 5 100
        Male
    0 0 0 0 0
    Country
    Country of recruitment
    Units: Subjects
        France
    13 10 2 5 30
        Holland
    2 4 0 0 6
        United Kingdom
    32 30 2 0 64
    Previous lines of therapy
    Units: Subjects
        One
    20 21 3 3 47
        Two
    17 13 1 2 33
        Three
    6 6 0 0 12
        Four
    4 3 0 0 7
        Five
    0 0 0 0 0
        Six
    0 1 0 0 1
    Previous treatment with bevacizumab
    Units: Subjects
        Yes
    14 10 0 0 24
        No
    33 34 4 5 76
    Chemotherapy assigned at randomisation
    Units: Subjects
        Paclitaxel
    17 17 0 0 34
        PLD
    21 20 0 0 41
        Topotecan
    9 7 0 0 16
        Carboplatin & Paclitaxel
    0 0 0 2 2
        Doxorubicin
    0 0 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    OVARIAN: Experimental arm (nintedanib)
    Reporting group description
    Nintedanib (BIBF1120) capsules 200mg orally twice a day, continuously until disease progression. The first 6 cycles are 28 days long and from cycle 7 onwards, the cycles are 56 days long.

    Reporting group title
    OVARIAN: Control arm (chemotherapy)
    Reporting group description
    Physicians' choice of chemotherapy from list below: Paclitaxel 80mg/m2 intravenously on days 1, 8 and 15 of a 28 day cycle OR Pegylated Liposomal Doxorubicin (PLD) 40mg/m2 intravenously on day 1 of a 28 day cycle OR Topotecan 4mg/m2 intravenously on days 1, 8 and 15 of a 28 day cycle Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.

    Reporting group title
    ENDOMETRIAL: Experimental arm (nintedanib)
    Reporting group description
    Nintedanib (BIBF1120) capsules 200mg orally twice a day, continuously until disease progression. The first 6 cycles are 28 days long and from cycle 7 onwards, the cycles are 56 days long.

    Reporting group title
    ENDOMETRIAL: Control arm (chemotherapy)
    Reporting group description
    Physicians' choice of chemotherapy from list below: Carboplatin AUC 5 and Paclitaxel 175mg/m2 intravenously on day 1 of a 21 day cycle OR Doxorubicin 60mg/m2 intravenously on day 1 of a 21 day cycle. Patients receive up to 6 cycles of chemotherapy but it is acceptable to continue beyond this until progression or unacceptable toxicity if the Investigator deemed this to be beneficial to the patient.

    Primary: Progression-free survival

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    End point title
    Progression-free survival
    End point description
    End point type
    Primary
    End point timeframe
    Baseline: within 28 days of randomisation From randomisation until week 48 (or progressive disease): 8 weekly Week 72 Then as clinically indicated
    End point values
    OVARIAN: Experimental arm (nintedanib) OVARIAN: Control arm (chemotherapy) ENDOMETRIAL: Experimental arm (nintedanib) ENDOMETRIAL: Control arm (chemotherapy)
    Number of subjects analysed
    47 [1]
    44 [2]
    4 [3]
    5 [4]
    Units: PFS
        median (confidence interval 80%)
    2.07 (1.94 to 3.68)
    1.84 (1.84 to 1.91)
    1.95 (1.71 to 3.65)
    2.04 (2.00 to 6.04)
    Notes
    [1] - ITT
    [2] - ITT
    [3] - ITT
    [4] - ITT
    Statistical analysis title
    PFS: Grouped
    Statistical analysis description
    Progression-free survival is compared between the study arms in the context of a Cox model incorporating the baseline stratification factors. To prevent any ascertainment bias as a result of earlier detection of progression on study arms with a weekly schedule, all progressions will be allocated to the next fixed CT scanning date - a grouped survival method.
    Comparison groups
    OVARIAN: Experimental arm (nintedanib) v OVARIAN: Control arm (chemotherapy)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0419 [5]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23
    Notes
    [5] - One sided

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline until end of study
    End point values
    OVARIAN: Experimental arm (nintedanib) OVARIAN: Control arm (chemotherapy) ENDOMETRIAL: Experimental arm (nintedanib) ENDOMETRIAL: Control arm (chemotherapy)
    Number of subjects analysed
    47 [6]
    44 [7]
    4 [8]
    5 [9]
    Units: Survival
        median (confidence interval 80%)
    9.69 (7.62 to 10.41)
    4.99 (3.98 to 5.85)
    5.63 (1.71 to 8.02)
    6.04 (4.34 to 14.13)
    Notes
    [6] - ITT
    [7] - ITT
    [8] - ITT
    [9] - ITT
    Statistical analysis title
    OS
    Statistical analysis description
    Overall survival will be compared between the study arms in the context of a Cox model incorporating the baseline stratification factors.
    Comparison groups
    OVARIAN: Experimental arm (nintedanib) v OVARIAN: Control arm (chemotherapy)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0496 [10]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    0.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [10] - One sided

    Secondary: Response rate

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    End point title
    Response rate
    End point description
    Best response rate will be determined according to combined GCIG criteria (http://www.gcig.igcs.org/CA125/respdef_nov2005.pdf) for ovarian cancer patients and RECIST criteria Version 1.1 (http://www.eortc.be/recist/documents/RECISTGuidelines.pdf) for endometrial cancer patients.
    End point type
    Secondary
    End point timeframe
    Baseline: within 28 days of randomisation From randomisation until week 48 (or progressive disease): 8 weekly Week 72 Then as clinically indicated
    End point values
    OVARIAN: Experimental arm (nintedanib) OVARIAN: Control arm (chemotherapy) ENDOMETRIAL: Experimental arm (nintedanib) ENDOMETRIAL: Control arm (chemotherapy)
    Number of subjects analysed
    47 [11]
    44 [12]
    4 [13]
    5 [14]
    Units: Best response
        Partial response
    2
    2
    0
    1
        Stable disease
    16
    8
    1
    1
        Progressive disease
    27
    28
    3
    3
        Unevaluable, no baseline target lesions
    1
    1
    0
    0
        Unevaluable, no assessments made
    1
    1
    0
    0
        Unevaluable, other reason
    0
    0
    0
    0
        Died prior to response evaluation timepoint
    0
    3
    0
    0
        Withdrawn consent prior to response evaluation
    0
    1
    0
    0
    Notes
    [11] - ITT
    [12] - ITT
    [13] - ITT
    [14] - ITT
    No statistical analyses for this end point

    Secondary: Disease control rate

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    End point title
    Disease control rate
    End point description
    Disease status will be determined prior to starting treatment and the observed response [categorised as complete (CR), partial (PR), stable disease (SD), progressive disease (PD), unevaluable] at 16 weeks will be determined using GCIG criteria for ovarian cancer patients and RECIST 1.1 for endometrial cancer patients.
    End point type
    Secondary
    End point timeframe
    At 16 weeks
    End point values
    OVARIAN: Experimental arm (nintedanib) OVARIAN: Control arm (chemotherapy) ENDOMETRIAL: Experimental arm (nintedanib) ENDOMETRIAL: Control arm (chemotherapy)
    Number of subjects analysed
    47 [15]
    44 [16]
    4 [17]
    5 [18]
    Units: Response
        CR/PR/SD
    11
    5
    0
    1
        PD/Unevaluable
    36
    39
    4
    4
    Notes
    [15] - ITT
    [16] - ITT
    [17] - ITT
    [18] - ITT
    Statistical analysis title
    Logistic regression of disease control rate
    Comparison groups
    OVARIAN: Experimental arm (nintedanib) v OVARIAN: Control arm (chemotherapy)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1078 [19]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.19
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    1.14
         upper limit
    8.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Notes
    [19] - One sided

    Secondary: QTWiST

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    End point title
    QTWiST [20]
    End point description
    The Q-TWiST analysis partitions overall survival into three health states: toxicity (TOX); time without symptoms of disease of progression or toxicity (TWiST); and time from progression until death (REL), and the duration of each state is calculated for every patient. All grade 2 and above toxicities are included in this analysis, apart from those that are experienced after progression. Due to the lack of data available regarding the duration of each toxicity, the TOX state is calculated on the assumption that any grade 1 or above toxicity listed on the CRF is experienced for the duration of the cycle. Patients experiencing no toxicity are assumed to have a TOX duration of 0 days. The restricted mean estimates, standard error and 95% confidence intervals are calculated by the bootstrap method.
    End point type
    Secondary
    End point timeframe
    Restricted mean health state duration, up to 26 weeks = 182 days The TOX state captures the total number of days spent with toxicity between randomisation and stopping chemotherapy.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analysis not undertaken for Endometrial patients
    End point values
    OVARIAN: Experimental arm (nintedanib) OVARIAN: Control arm (chemotherapy)
    Number of subjects analysed
    47
    44
    Units: Days
        arithmetic mean (standard error)
    44.20 ( 0.22 )
    32.58 ( 0.22 )
    Statistical analysis title
    Restricted mean health state duration comparison
    Statistical analysis description
    2-sided p-value calculated using a t-test under the normal distribution
    Comparison groups
    OVARIAN: Experimental arm (nintedanib) v OVARIAN: Control arm (chemotherapy)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    11.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11
         upper limit
    12.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs are collected from randomisation until progression or withdrawal from the trial. Number of occurences of non-serious AEs = number of patients experiencing the event due to the way that this data is collected.
    Adverse event reporting additional description
    For some AEs, grade 0 & 1 cannot be distringuished from one another due to unknown limits of normal. These are reported as grade 0: hypo/hyper-glycaemia, anaemia, WBC decrease, leukocytosis, platelets/neutrophils decreased, lymphocytes increase/decreased.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    ENDOMETRIAL: Control arm (chemotherapy)
    Reporting group description
    -

    Reporting group title
    OVARIAN: Control arm (chemotherapy)
    Reporting group description
    -

    Reporting group title
    OVARIAN: Experimental arm (nintedanib)
    Reporting group description
    -

    Reporting group title
    ENDOMETRIAL: Experimental arm (nintedanib)
    Reporting group description
    -

    Serious adverse events
    ENDOMETRIAL: Control arm (chemotherapy) OVARIAN: Control arm (chemotherapy) OVARIAN: Experimental arm (nintedanib) ENDOMETRIAL: Experimental arm (nintedanib)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    22 / 40 (55.00%)
    16 / 47 (34.04%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify
    Additional description: Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    11 / 40 (27.50%)
    7 / 47 (14.89%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 14
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    0 / 3
    0 / 1
    Vascular disorders
    Thromboembolic event
    Additional description: Thromboembolic event
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 40 (5.00%)
    4 / 47 (8.51%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures - Other, specify
    Additional description: Surgical and medical procedures - Other, specify
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
    Additional description: Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
    Additional description: Fever
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
    Additional description: Allergic reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylaxis
    Additional description: Anaphylaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
    Additional description: Dyspnea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
    Additional description: Pleural effusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
    Additional description: Respiratory failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
    Additional description: Confusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
    Additional description: Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alkaline phosphatase increased
    Additional description: Alkaline phosphatase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INR increased
    Additional description: INR increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations - Other, specify
    Additional description: Investigations - Other, specify
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
    Additional description: Platelet count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Lethargy
    Additional description: Lethargy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke
    Additional description: Stroke
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
    Additional description: Anemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 40 (7.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
    Additional description: Febrile neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 40 (7.50%)
    2 / 47 (4.26%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
    Additional description: Ascites
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic obstruction
    Additional description: Colonic obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
    Additional description: Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 40 (5.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhea
    Additional description: Diarrhea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
    Additional description: Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 40 (5.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
    Additional description: Small intestinal obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    Additional description: Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    3 / 47 (6.38%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hematuria
    Additional description: Hematuria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
    Additional description: Hyperparathyroidism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
    Additional description: Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
    Additional description: Bone pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorder - Other, specify
    Additional description: Musculoskeletal and connective tissue disorder - Other, specify
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 40 (5.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
    Additional description: Abdominal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 40 (0.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations - Other, specify
    Additional description: Infections and infestations - Other, specify
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    4 / 47 (8.51%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
    Additional description: Anorexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
    Additional description: Dehydration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcemia
    Additional description: Hypercalcemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 40 (5.00%)
    2 / 47 (4.26%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesemia
    Additional description: Hypomagnesemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    ENDOMETRIAL: Control arm (chemotherapy) OVARIAN: Control arm (chemotherapy) OVARIAN: Experimental arm (nintedanib) ENDOMETRIAL: Experimental arm (nintedanib)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    39 / 40 (97.50%)
    46 / 47 (97.87%)
    4 / 4 (100.00%)
    Vascular disorders
    HOT FLASHES
    Additional description: HOT FLASHES
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    HYPERTENSION
    Additional description: HYPERTENSION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    THROMBOEMBOLIC EVENT
    Additional description: THROMBOEMBOLIC EVENT
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    4 / 47 (8.51%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    4
    0
    General disorders and administration site conditions
    FATIGUE
    Additional description: FATIGUE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 5 (60.00%)
    25 / 40 (62.50%)
    19 / 47 (40.43%)
    3 / 4 (75.00%)
         occurrences all number
    3
    25
    19
    3
    FEVER
    Additional description: FEVER
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
    Additional description: GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 40 (5.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    MALAISE
    Additional description: MALAISE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    PAIN
    Additional description: PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Immune system disorders
    ALLERGIC REACTION
    Additional description: ALLERGIC REACTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 40 (7.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    ANAPHYLAXIS
    Additional description: ANAPHYLAXIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    PELVIC PAIN
    Additional description: PELVIC PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
    Additional description: COUGH
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    DYSPNEA
    Additional description: DYSPNEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    0
    EPISTAXIS
    Additional description: EPISTAXIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 40 (5.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Psychiatric disorders
    INSOMNIA
    Additional description: INSOMNIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    2 / 47 (4.26%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
    Additional description: ALANINE AMINOTRANSFERASE INCREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    7 / 40 (17.50%)
    26 / 47 (55.32%)
    3 / 4 (75.00%)
         occurrences all number
    1
    7
    32
    5
    ALKALINE PHOSPHATASE INCREASED
    Additional description: ALKALINE PHOSPHATASE INCREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 5 (80.00%)
    23 / 40 (57.50%)
    30 / 47 (63.83%)
    4 / 4 (100.00%)
         occurrences all number
    4
    23
    33
    5
    ASPARTATE AMINOTRANSFERASE INCREASED
    Additional description: ASPARTATE AMINOTRANSFERASE INCREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    9 / 40 (22.50%)
    18 / 47 (38.30%)
    3 / 4 (75.00%)
         occurrences all number
    1
    10
    22
    4
    BLOOD BILIRUBIN INCREASED
    Additional description: BLOOD BILIRUBIN INCREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    6 / 40 (15.00%)
    6 / 47 (12.77%)
    0 / 4 (0.00%)
         occurrences all number
    1
    6
    6
    0
    CREATININE INCREASED
    Additional description: CREATININE INCREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 40 (10.00%)
    11 / 47 (23.40%)
    0 / 4 (0.00%)
         occurrences all number
    2
    4
    12
    0
    GGT INCREASED
    Additional description: GGT INCREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    2 / 47 (4.26%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    1
    LYMPHOCYTE COUNT DECREASED
    Additional description: LYMPHOCYTE COUNT DECREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 5 (80.00%)
    15 / 40 (37.50%)
    4 / 47 (8.51%)
    3 / 4 (75.00%)
         occurrences all number
    4
    15
    4
    3
    LYMPHOCYTE COUNT INCREASED
    Additional description: LYMPHOCYTE COUNT INCREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 40 (7.50%)
    2 / 47 (4.26%)
    0 / 4 (0.00%)
         occurrences all number
    1
    3
    2
    0
    NEUTROPHIL COUNT DECREASED
    Additional description: NEUTROPHIL COUNT DECREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    5 / 40 (12.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    6
    0
    0
    PLATELET COUNT DECREASED
    Additional description: PLATELET COUNT DECREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    6 / 40 (15.00%)
    3 / 47 (6.38%)
    0 / 4 (0.00%)
         occurrences all number
    0
    7
    3
    0
    WEIGHT LOSS
    Additional description: WEIGHT LOSS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    WHITE BLOOD CELL DECREASED
    Additional description: WHITE BLOOD CELL DECREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    5 / 40 (12.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    6
    0
    0
    Cardiac disorders
    HEART FAILURE
    Additional description: HEART FAILURE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 40 (0.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    DIZZINESS
    Additional description: DIZZINESS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 40 (5.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    DYSGEUSIA
    Additional description: DYSGEUSIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    2 / 47 (4.26%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    0
    HEADACHE
    Additional description: HEADACHE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    ISCHEMIA CEREBROVASCULAR
    Additional description: ISCHEMIA CEREBROVASCULAR
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    LETHARGY
    Additional description: LETHARGY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
    Additional description: NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    PARESTHESIA
    Additional description: PARESTHESIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 40 (0.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    PERIPHERAL MOTOR NEUROPATHY
    Additional description: PERIPHERAL MOTOR NEUROPATHY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    PERIPHERAL SENSORY NEUROPATHY
    Additional description: PERIPHERAL SENSORY NEUROPATHY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    7 / 40 (17.50%)
    3 / 47 (6.38%)
    0 / 4 (0.00%)
         occurrences all number
    0
    7
    3
    0
    Blood and lymphatic system disorders
    ANEMIA
    Additional description: ANEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 5 (80.00%)
    26 / 40 (65.00%)
    21 / 47 (44.68%)
    2 / 4 (50.00%)
         occurrences all number
    6
    35
    25
    2
    FEBRILE NEUTROPENIA
    Additional description: FEBRILE NEUTROPENIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    LEUKOCYTOSIS
    Additional description: LEUKOCYTOSIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    3 / 47 (6.38%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Ear and labyrinth disorders
    VERTIGO
    Additional description: VERTIGO
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 40 (0.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
    Additional description: ABDOMINAL PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 40 (10.00%)
    8 / 47 (17.02%)
    1 / 4 (25.00%)
         occurrences all number
    0
    4
    8
    1
    ASCITES
    Additional description: ASCITES
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    BLOATING
    Additional description: BLOATING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    CONSTIPATION
    Additional description: CONSTIPATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 40 (10.00%)
    5 / 47 (10.64%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    5
    0
    DIARRHEA
    Additional description: DIARRHEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 40 (7.50%)
    21 / 47 (44.68%)
    2 / 4 (50.00%)
         occurrences all number
    0
    3
    21
    2
    DRY MOUTH
    Additional description: DRY MOUTH
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    DYSPEPSIA
    Additional description: DYSPEPSIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    GASTROESOPHAGEAL REFLUX DISEASE
    Additional description: GASTROESOPHAGEAL REFLUX DISEASE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    GASTROINTESTINAL DISORDERS - OTHER, SPECIFY
    Additional description: GASTROINTESTINAL DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 40 (0.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    MUCOSITIS ORAL
    Additional description: MUCOSITIS ORAL
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    9 / 40 (22.50%)
    3 / 47 (6.38%)
    0 / 4 (0.00%)
         occurrences all number
    1
    9
    3
    0
    NAUSEA
    Additional description: NAUSEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 5 (40.00%)
    15 / 40 (37.50%)
    25 / 47 (53.19%)
    3 / 4 (75.00%)
         occurrences all number
    2
    15
    25
    3
    VOMITING
    Additional description: VOMITING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    5 / 40 (12.50%)
    12 / 47 (25.53%)
    2 / 4 (50.00%)
         occurrences all number
    0
    5
    12
    2
    Skin and subcutaneous tissue disorders
    ALOPECIA
    Additional description: ALOPECIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 40 (7.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    DRY SKIN
    Additional description: DRY SKIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 40 (0.00%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    ERYTHEMA MULTIFORME
    Additional description: ERYTHEMA MULTIFORME
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    NAIL RIDGING
    Additional description: NAIL RIDGING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
    Additional description: PALMAR-PLANTAR ERYTHRODYSESTHESIA SYNDROME
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 40 (7.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    1
    0
    PRURITUS
    Additional description: PRURITUS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    RASH MACULO-PAPULAR
    Additional description: RASH MACULO-PAPULAR
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 40 (7.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    1
    0
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY
    Additional description: SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    2 / 47 (4.26%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    SKIN HYPERPIGMENTATION
    Additional description: SKIN HYPERPIGMENTATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    HEMATURIA
    Additional description: HEMATURIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
    Additional description: ARTHRALGIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    2 / 47 (4.26%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    2
    0
    MUSCLE WEAKNESS LOWER LIMB
    Additional description: MUSCLE WEAKNESS LOWER LIMB
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    MYALGIA
    Additional description: MYALGIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Infections and infestations
    INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
    Additional description: INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Metabolism and nutrition disorders
    ANOREXIA
    Additional description: ANOREXIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 5 (60.00%)
    7 / 40 (17.50%)
    9 / 47 (19.15%)
    2 / 4 (50.00%)
         occurrences all number
    3
    7
    9
    2
    DEHYDRATION
    Additional description: DEHYDRATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    HYPERCALCEMIA
    Additional description: HYPERCALCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    10 / 40 (25.00%)
    11 / 47 (23.40%)
    1 / 4 (25.00%)
         occurrences all number
    0
    11
    11
    1
    HYPERGLYCEMIA
    Additional description: HYPERGLYCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    6 / 40 (15.00%)
    6 / 47 (12.77%)
    0 / 4 (0.00%)
         occurrences all number
    0
    6
    6
    0
    HYPERKALEMIA
    Additional description: HYPERKALEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 40 (7.50%)
    9 / 47 (19.15%)
    1 / 4 (25.00%)
         occurrences all number
    1
    3
    9
    1
    HYPERMAGNESEMIA
    Additional description: HYPERMAGNESEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 40 (2.50%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    1
    0
    HYPERNATREMIA
    Additional description: HYPERNATREMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 40 (2.50%)
    0 / 47 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    HYPOALBUMINEMIA
    Additional description: HYPOALBUMINEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 5 (60.00%)
    21 / 40 (52.50%)
    22 / 47 (46.81%)
    1 / 4 (25.00%)
         occurrences all number
    3
    21
    22
    1
    HYPOCALCEMIA
    Additional description: HYPOCALCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 5 (40.00%)
    9 / 40 (22.50%)
    8 / 47 (17.02%)
    0 / 4 (0.00%)
         occurrences all number
    2
    10
    8
    0
    HYPOGLYCEMIA
    Additional description: HYPOGLYCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    0 / 47 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    HYPOKALEMIA
    Additional description: HYPOKALEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 40 (10.00%)
    12 / 47 (25.53%)
    1 / 4 (25.00%)
         occurrences all number
    2
    4
    12
    1
    HYPONATREMIA
    Additional description: HYPONATREMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 5 (80.00%)
    36 / 40 (90.00%)
    46 / 47 (97.87%)
    4 / 4 (100.00%)
         occurrences all number
    4
    36
    46
    4
    HYPOMAGNESEMIA
    Additional description: HYPOMAGNESEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 5 (40.00%)
    10 / 40 (25.00%)
    18 / 47 (38.30%)
    1 / 4 (25.00%)
         occurrences all number
    2
    10
    18
    1
    HYPOPHOSPHATEMIA
    Additional description: HYPOPHOSPHATEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 40 (0.00%)
    1 / 47 (2.13%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2015
    (UK only - Amendment No 02): In order to meet the reporting requirements of all the participating countries, SUSARS were reported on Eudravigilance. It was discovered that only the Marketing Authorisation Holder can report SUSARS on unlicensed drugs on Eudravigilance. As a result this responsibility had to be delegated by study Sponsor to Boehringer Ingelheim. This required a Vendor Assessment by Sponsor, a Variation to BI/Sponsor Contract to be put in place and the protocol to be updated and submitted as a substantial amendment.
    29 Mar 2016
    (UK Ref - Amendment No 4) : Protocol update following feedback received from the French Health Authority. The majority of changes were in accordance with the addition of information contained in the Summary of Product Characteristics for the chemotherapy agents and the updated Investigator’s Brochure for Nintedanib. Eligibility criteria were updated and in addition, the treatment duration on the standard chemotherapy arm was extended (if, in the opinion of the investigator, the patient would benefit from continuing chemotherapy beyond 6 cycles).
    25 Sep 2019
    (UK Ref - Amendment 09): In preparation of BREXIT, the EORTC became the EU Sponsor for trial. NHS Greater Glasgow & Clyde remain as UK Sponsor and Lead Co-ordinator of trial. Protocol upated.

    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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