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    Clinical Trial Results:
    Phase III study comparing the efficacy of paclitaxel-bevacizumab with docetaxel in 2nd or 3rd line of treatment of non squamous Non Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2012-004524-38
    Trial protocol
    		 FR  
    Global end of trial date
    12 Apr 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Feb 2022
    First version publication date
    08 Apr 2021
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    SAEs update

    Trial information

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    Trial identification
    Sponsor protocol code
    IFCT-1103 Ultimate
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01763671
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IFCT
    Sponsor organisation address
    10 rue de la Grange-Batelière, PARIS, France, 75009
    Public contact
    Responsable communication, IFCT, 33 156811046, contact@ifct.fr
    Scientific contact
    Responsable communication, IFCT, 33 156811046, contact@ifct.fr
    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
    29 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Progression free survival
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 166
    Worldwide total number of subjects
    166
    EEA total number of subjects
    166
    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)
    117
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 166 randomised patients [Paclitaxel-Bevacizumab group: 111 (67%), Docetaxel group: 55 (33%)] was included between May 31, 2013 and August 13, 2014.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 166
    Number of subjects completed
    		 166

    Period 1
    Period 1 title
    Sequence 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - Docetaxel (DOC)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m² every 21 days

    Arm title
    		 Arm B - Paclitaxel plus bevacizumab (wPAC-BEV)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    paclitaxel 90 mg/m² D1, D8, D15 every 28 days

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    bevacizumab 10 mg/kg D1, D15 every 28 days

    Number of subjects in period 1
    		Arm A - Docetaxel (DOC) Arm B - Paclitaxel plus bevacizumab (wPAC-BEV)
    Started
    55
    111
    Completed
    55
    109
    Not completed
    0
    2
         Physician decision
    -
    1
         Disease progression
    -
    1
    Period 2
    Period 2 title
    Sequence 2 (Cross-Over)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm B1 - Paclitaxel plus bevacizumab (cross-over)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    paclitaxel 90 mg/m² D1, D8, D15 every 28 days

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    bevacizumab 10 mg/kg D1, D15 every 28 days

    Arm title
    		 Arm A1 - Docetaxel (cross-over)
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m² every 21 days

    Number of subjects in period 2 [1]
    		Arm B1 - Paclitaxel plus bevacizumab (cross-over) Arm A1 - Docetaxel (cross-over)
    Started
    21
    9
    Completed
    21
    9
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The cross-over was optional

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - Docetaxel (DOC)
    Reporting group description
    		 -

    Reporting group title
    Arm B - Paclitaxel plus bevacizumab (wPAC-BEV)
    Reporting group description
    		 -

    Reporting group values
    		 Arm A - Docetaxel (DOC) Arm B - Paclitaxel plus bevacizumab (wPAC-BEV) Total
    Number of subjects
    		 55 111 166
    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
        arithmetic mean (standard deviation)
    		 60.74 ± 9.44 59.57 ± 9.38 -
    Gender categorical
    Units: Subjects
        Female
    		 13 78 91
        Male
    		 42 33 75
    Smoking
    Units: Subjects
        No
    		 9 9 18
        Yes
    		 46 102 148
    PS
    Units: Subjects
        PS 0
    		 20 47 67
        PS 1
    		 31 56 87
        PS 2
    		 4 8 12
    Histology
    Units: Subjects
        Adenocarcinoma
    		 51 100 151
        Large cells/No
    		 4 11 15
    Previous exposure to bevacizumab
    Units: Subjects
        No
    		 38 77 115
        Yes
    		 17 34 51
    Number of previous lines
    Units: Subjects
        1 line
    		 39 76 115
        2 lines
    		 14 34 48
        3 lines
    		 2 1 3
    Time between the diagnostic of cancer and inclusion
    Units: Subjects
        < 9 months
    		 20 52 72
        > 9 months
    		 35 59 94
    Age class
    Units: Subjects
        < 70 years old
    		 45 101 146
        > 70 years old
    		 10 10 20
    Weight loss
    Units: Subjects
        < 0 kg
    		 12 20 32
        0 - 5 kg
    		 42 85 127
        5 - 10 kg
    		 1 4 5
        missing
    		 0 2 2
    EGFR
    Units: Subjects
        Activating mutation
    		 2 4 6
        Resistance mutation
    		 1 0 1
        Other mutation
    		 0 1 1
        Wild-type
    		 44 87 131
        Inderminate
    		 5 9 14
        Not done
    		 3 10 13
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 69.18 ± 12.47 69.05 ± 13.72 -
    Number of pack-year
    Units: pack-years
        arithmetic mean (standard deviation)
    		 44.11 ± 23.54 37.38 ± 21.40 -

    End points

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    End points reporting groups
    Reporting group title
    Arm A - Docetaxel (DOC)
    Reporting group description
    		 -

    Reporting group title
    Arm B - Paclitaxel plus bevacizumab (wPAC-BEV)
    Reporting group description
    		 -
    Reporting group title
    Arm B1 - Paclitaxel plus bevacizumab (cross-over)
    Reporting group description
    		 -

    Reporting group title
    Arm A1 - Docetaxel (cross-over)
    Reporting group description
    		 -

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    End point type
    Primary
    End point timeframe
    Time between randomisation and disease progression (as assessed by the investigator using RECIST 1.1) or death from any cause, whatever came first.
    End point values
    		 Arm A - Docetaxel (DOC) Arm B - Paclitaxel plus bevacizumab (wPAC-BEV)
    Number of subjects analysed
    55
    109
    Units: months
        number (confidence interval 95%)
    3.9 (2.69 to 5.26)
    5.4 (4.63 to 7.13)
    Statistical analysis title
    		 Progression Free Survival
    Statistical analysis description
    Time between randomisation and disease progression (as assessed by the investigator using RECIST 1.1) or death from any cause, whatever came first.
    Comparison groups
    Arm A - Docetaxel (DOC) v Arm B - Paclitaxel plus bevacizumab (wPAC-BEV)
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.86

    Secondary: Response Rate

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    End point title
    		 Response Rate
    End point description
    End point type
    Secondary
    End point timeframe
    At 8 weeks
    End point values
    		 Arm A - Docetaxel (DOC) Arm B - Paclitaxel plus bevacizumab (wPAC-BEV)
    Number of subjects analysed
    55
    109
    Units: Pourcentage
        Not Done / Not Evaluable
    4
    10
        Progression
    19
    21
        Objective response
    3
    25
        Stable
    29
    55
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival is defined as time between date of inclusion and all-cause death
    End point values
    		 Arm A - Docetaxel (DOC) Arm B - Paclitaxel plus bevacizumab (wPAC-BEV)
    Number of subjects analysed
    55
    109
    Units: months
        number (confidence interval 95%)
    11.4 (7.85 to 13.14)
    9.9 (8.11 to 12.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events have to be reported from inclusion to 30 day following the end of administration of study treatments.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Safety population - Arm A
    Reporting group description
    		 The safety population - Arm A will be defined as all patients who received at least one dose of docetaxel.

    Reporting group title
    Safety population - Arm B
    Reporting group description
    		 The safety population - Arm B will be defined as all patients who received at least one dose of paclitaxel and bevacizumab.

    Reporting group title
    Safety population - Arm A1
    Reporting group description
    		 The safety population - Arm A1 will be defined as all patients who received at least one dose of docetaxel during cross-over.

    Reporting group title
    Safety population - Arm B1
    Reporting group description
    		 The safety population - Arm B1 will be defined as all patients who received at least one dose of paclitaxel-bevacizumab during cross-over.

    Serious adverse events
    		 Safety population - Arm A Safety population - Arm B Safety population - Arm A1 Safety population - Arm B1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 55 (16.36%)
    15 / 109 (13.76%)
    5 / 9 (55.56%)
    3 / 21 (14.29%)
         number of deaths (all causes)
    32
    94
    9
    17
         number of deaths resulting from adverse events
    3
    2
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinomatous peritonitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Meningeal carcinomatosis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (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
    Progression of bronchial carcinoma
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Esophagitis hemorrhagic
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Orthostatic hypotension
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    2 / 55 (3.64%)
    5 / 109 (4.59%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Reduced general condition
         subjects affected / exposed
    6 / 55 (10.91%)
    12 / 109 (11.01%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    2 / 6
    8 / 12
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 109 (2.75%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Death
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (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 / 2
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (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
    Pain
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Drug allergy
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (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
    Reproductive system and breast disorders
    Dyspnea
         subjects affected / exposed
    0 / 55 (0.00%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Esophagobronchial fistula
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    Interstitial pneumonitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Pneumopathy
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 109 (3.67%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 109 (2.75%)
    0 / 9 (0.00%)
    3 / 21 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 55 (0.00%)
    5 / 109 (4.59%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Exertional dyspnea
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (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
    Pleural effusion
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (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
    Respiratory distress
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemoglobin decreased
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Pericarditis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Confusion
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 55 (0.00%)
    3 / 109 (2.75%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Convulsion
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Epilepsy
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Intracranial hypertension
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (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
    Loss of consciousness
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Memory impairment
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Motor activity retarded
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Neuralgia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological disorder NOS
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (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 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aplasia bone marrow
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Febrile aplasia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (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 / 1
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Esophagitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Gastralgia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (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
    Haematemesis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Intestinal obstruction
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Hepatic cytolysis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Skin and subcutaneous tissue disorders
    Hand-and-foot syndrome
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture NOS
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Back pain
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in hip
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Shoulder pain
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Tendinitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    2 / 9 (22.22%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Catheter related infection
         subjects affected / exposed
    0 / 55 (0.00%)
    3 / 109 (2.75%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection NOS
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Oral candida
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Pneumocystosis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Bronchitis
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (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
    Catheter site infection
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (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
    Colonic abscess
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Localized infection
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (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
    Meningitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Respiratory infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Diabetes
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (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
    Hypercalcemia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Hyperglycemia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Malnutrition
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population - Arm A Safety population - Arm B Safety population - Arm A1 Safety population - Arm B1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 55 (98.18%)
    109 / 109 (100.00%)
    9 / 9 (100.00%)
    20 / 21 (95.24%)
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    2 / 55 (3.64%)
    47 / 109 (43.12%)
    0 / 9 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    5
    81
    0
    5
    Hypertension
         subjects affected / exposed
    0 / 55 (0.00%)
    24 / 109 (22.02%)
    1 / 9 (11.11%)
    6 / 21 (28.57%)
         occurrences all number
    0
    33
    1
    16
    Pulmonary embolism
         subjects affected / exposed
    1 / 55 (1.82%)
    8 / 109 (7.34%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    15
    0
    0
    Haemoptysis
         subjects affected / exposed
    3 / 55 (5.45%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    7
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    30 / 55 (54.55%)
    65 / 109 (59.63%)
    2 / 9 (22.22%)
    9 / 21 (42.86%)
         occurrences all number
    70
    145
    2
    28
    Oedema peripheral
         subjects affected / exposed
    5 / 55 (9.09%)
    16 / 109 (14.68%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    8
    20
    0
    2
    Fatigue
         subjects affected / exposed
    2 / 55 (3.64%)
    5 / 109 (4.59%)
    1 / 9 (11.11%)
    4 / 21 (19.05%)
         occurrences all number
    3
    7
    1
    4
    General physical health deterioration
         subjects affected / exposed
    9 / 55 (16.36%)
    8 / 109 (7.34%)
    3 / 9 (33.33%)
    2 / 21 (9.52%)
         occurrences all number
    9
    9
    3
    2
    Oedema
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 109 (0.92%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Diarrhoea
         subjects affected / exposed
    13 / 55 (23.64%)
    26 / 109 (23.85%)
    1 / 9 (11.11%)
    4 / 21 (19.05%)
         occurrences all number
    23
    38
    1
    4
    Chest pain
         subjects affected / exposed
    7 / 55 (12.73%)
    10 / 109 (9.17%)
    1 / 9 (11.11%)
    4 / 21 (19.05%)
         occurrences all number
    13
    13
    1
    5
    Pyrexia
         subjects affected / exposed
    6 / 55 (10.91%)
    7 / 109 (6.42%)
    1 / 9 (11.11%)
    3 / 21 (14.29%)
         occurrences all number
    7
    9
    1
    3
    Face oedema
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 55 (1.82%)
    13 / 109 (11.93%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    22
    0
    0
    Dyspnoea
         subjects affected / exposed
    16 / 55 (29.09%)
    25 / 109 (22.94%)
    2 / 9 (22.22%)
    6 / 21 (28.57%)
         occurrences all number
    27
    42
    2
    10
    Lung disorder
         subjects affected / exposed
    2 / 55 (3.64%)
    3 / 109 (2.75%)
    1 / 9 (11.11%)
    2 / 21 (9.52%)
         occurrences all number
    3
    3
    1
    2
    Cough
         subjects affected / exposed
    17 / 55 (30.91%)
    31 / 109 (28.44%)
    2 / 9 (22.22%)
    4 / 21 (19.05%)
         occurrences all number
    29
    70
    2
    7
    Dyspnoea exertional
         subjects affected / exposed
    4 / 55 (7.27%)
    5 / 109 (4.59%)
    0 / 9 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    7
    8
    0
    3
    Productive cough
         subjects affected / exposed
    4 / 55 (7.27%)
    5 / 109 (4.59%)
    0 / 9 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    5
    8
    0
    6
    Pneumothorax
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 109 (2.75%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    5
    0
    3
    Pulmonary congestion
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    0
    0
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 55 (1.82%)
    7 / 109 (6.42%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    8
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    9 / 55 (16.36%)
    16 / 109 (14.68%)
    2 / 9 (22.22%)
    5 / 21 (23.81%)
         occurrences all number
    10
    18
    2
    8
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 55 (10.91%)
    13 / 109 (11.93%)
    2 / 9 (22.22%)
    1 / 21 (4.76%)
         occurrences all number
    15
    18
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 55 (3.64%)
    6 / 109 (5.50%)
    2 / 9 (22.22%)
    2 / 21 (9.52%)
         occurrences all number
    3
    8
    2
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 55 (3.64%)
    8 / 109 (7.34%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    12
    0
    0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    10 / 55 (18.18%)
    40 / 109 (36.70%)
    3 / 9 (33.33%)
    4 / 21 (19.05%)
         occurrences all number
    25
    72
    3
    5
    Neuropathy peripheral
         subjects affected / exposed
    5 / 55 (9.09%)
    22 / 109 (20.18%)
    0 / 9 (0.00%)
    8 / 21 (38.10%)
         occurrences all number
    10
    60
    0
    14
    Dysgeusia
         subjects affected / exposed
    2 / 55 (3.64%)
    8 / 109 (7.34%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    13
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Headache
         subjects affected / exposed
    6 / 55 (10.91%)
    14 / 109 (12.84%)
    1 / 9 (11.11%)
    3 / 21 (14.29%)
         occurrences all number
    6
    21
    1
    3
    Sciatica
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 109 (2.75%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    5
    4
    0
    4
    Confusional state
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 109 (0.92%)
    2 / 9 (22.22%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    2
    1
    Monoparesis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    2 / 9 (22.22%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    40 / 55 (72.73%)
    67 / 109 (61.47%)
    6 / 9 (66.67%)
    16 / 21 (76.19%)
         occurrences all number
    119
    144
    6
    30
    Neutropenia
         subjects affected / exposed
    31 / 55 (56.36%)
    50 / 109 (45.87%)
    4 / 9 (44.44%)
    7 / 21 (33.33%)
         occurrences all number
    68
    110
    6
    17
    Thrombocytopenia
         subjects affected / exposed
    13 / 55 (23.64%)
    13 / 109 (11.93%)
    1 / 9 (11.11%)
    2 / 21 (9.52%)
         occurrences all number
    19
    25
    1
    3
    Febrile neutropenia
         subjects affected / exposed
    4 / 55 (7.27%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 55 (1.82%)
    7 / 109 (6.42%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    10
    0
    0
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 109 (0.92%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    6
    3
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    13 / 55 (23.64%)
    28 / 109 (25.69%)
    1 / 9 (11.11%)
    3 / 21 (14.29%)
         occurrences all number
    15
    43
    1
    5
    Stomatitis
         subjects affected / exposed
    5 / 55 (9.09%)
    21 / 109 (19.27%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    5
    31
    1
    5
    Constipation
         subjects affected / exposed
    4 / 55 (7.27%)
    28 / 109 (25.69%)
    1 / 9 (11.11%)
    3 / 21 (14.29%)
         occurrences all number
    4
    36
    1
    5
    Vomiting
         subjects affected / exposed
    7 / 55 (12.73%)
    20 / 109 (18.35%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    7
    27
    0
    1
    Abdominal pain
         subjects affected / exposed
    5 / 55 (9.09%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    8
    8
    0
    4
    Abdominal pain upper
         subjects affected / exposed
    0 / 55 (0.00%)
    9 / 109 (8.26%)
    2 / 9 (22.22%)
    0 / 21 (0.00%)
         occurrences all number
    0
    12
    2
    0
    Subileus
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    19 / 55 (34.55%)
    32 / 109 (29.36%)
    1 / 9 (11.11%)
    2 / 21 (9.52%)
         occurrences all number
    36
    57
    1
    6
    Nail disorder
         subjects affected / exposed
    1 / 55 (1.82%)
    5 / 109 (4.59%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    12
    0
    5
    Onycholysis
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 109 (3.67%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    8
    0
    4
    Dry skin
         subjects affected / exposed
    2 / 55 (3.64%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    6
    13
    0
    3
    Erythema
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 109 (3.67%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    6
    7
    0
    2
    Rash
         subjects affected / exposed
    1 / 55 (1.82%)
    4 / 109 (3.67%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    6
    0
    3
    Rash erythematous
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 55 (0.00%)
    23 / 109 (21.10%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    49
    0
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 55 (10.91%)
    19 / 109 (17.43%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    10
    36
    1
    2
    Arthralgia
         subjects affected / exposed
    6 / 55 (10.91%)
    15 / 109 (13.76%)
    1 / 9 (11.11%)
    2 / 21 (9.52%)
         occurrences all number
    14
    29
    1
    4
    Pain in extremity
         subjects affected / exposed
    5 / 55 (9.09%)
    7 / 109 (6.42%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    6
    9
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 55 (7.27%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    5
    6
    0
    2
    Bone pain
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 109 (4.59%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    3
    5
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 55 (3.64%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    8
    0
    0
    Neck pain
         subjects affected / exposed
    2 / 55 (3.64%)
    3 / 109 (2.75%)
    1 / 9 (11.11%)
    2 / 21 (9.52%)
         occurrences all number
    2
    4
    1
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    4 / 55 (7.27%)
    0 / 109 (0.00%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Amyotrophy
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 109 (0.00%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Paronychia
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 109 (3.67%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    0
    5
    1
    1
    Oral candidiasis
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 109 (3.67%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    2
    4
    1
    1
    Bronchitis
         subjects affected / exposed
    6 / 55 (10.91%)
    10 / 109 (9.17%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    6
    10
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 55 (1.82%)
    7 / 109 (6.42%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    15
    0
    0
    Rhinitis
         subjects affected / exposed
    2 / 55 (3.64%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    15
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 55 (1.82%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    6
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 55 (1.82%)
    6 / 109 (5.50%)
    0 / 9 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    7
    0
    2
    Tooth abscess
         subjects affected / exposed
    1 / 55 (1.82%)
    5 / 109 (4.59%)
    0 / 9 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    6
    0
    2
    Conjunctivitis
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 109 (1.83%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Infection
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 109 (1.83%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    3
    2
    1
    1
    Metabolism and nutrition disorders
    Myalgia
         subjects affected / exposed
    2 / 55 (3.64%)
    9 / 109 (8.26%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    20
    0
    0
    Decreased appetite
         subjects affected / exposed
    13 / 55 (23.64%)
    27 / 109 (24.77%)
    4 / 9 (44.44%)
    7 / 21 (33.33%)
         occurrences all number
    29
    41
    5
    16
    Hypercreatinaemia
         subjects affected / exposed
    11 / 55 (20.00%)
    12 / 109 (11.01%)
    1 / 9 (11.11%)
    3 / 21 (14.29%)
         occurrences all number
    46
    33
    1
    5
    Hyperkalaemia
         subjects affected / exposed
    2 / 55 (3.64%)
    8 / 109 (7.34%)
    0 / 9 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    5
    16
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 55 (0.00%)
    9 / 109 (8.26%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    0
    25
    2
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 55 (1.82%)
    7 / 109 (6.42%)
    1 / 9 (11.11%)
    1 / 21 (4.76%)
         occurrences all number
    3
    15
    2
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 55 (0.00%)
    3 / 109 (2.75%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    0
    6
    1
    0
    Malnutrition
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 109 (1.83%)
    1 / 9 (11.11%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 May 2013
    - addition of an evaluation of the quality of life - reduction of the number of sites - addition of an inclusion criteria regarding the measurability of the disease - clarification of inclusion and exclusion criteria - clarification on the use of anticoagulation during the trial - deletion of the biological study

    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.
    Patients included in the DOC arm tended to be older and to be more frequently never smokers than in the paclitaxel-bavacizumab arm. Cross-over from one arm to another prevented any definitive conclusion on OS benefit.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32276179
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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