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    Clinical Trial Results:
    A Phase II-III Randomized Trial of Pemetrexed-Cisplatin Chemotherapy With or Without Bevacizumab (Avastin), 15 mg/kg, for Malignant Pleural Mesothelioma

    Summary
    EudraCT number
    		 2007-002574-63
    Trial protocol
    		 FR  
    Global end of trial date
    31 Jul 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    IFCT-0701
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00651456
    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, contact@ifct.fr
    Scientific contact
    Responsable communication, IFCT, 33 0156811046, 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
    15 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Overall survival
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Feb 2008
    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: 448
    Worldwide total number of subjects
    448
    EEA total number of subjects
    448
    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)
    204
    From 65 to 84 years
    244
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patients included in this study were recruited in 73 sites located in France from February 2008 until July 2016.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 448
    Number of subjects completed
    		 448

    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
    		 Standard Chemotherapy (Arm A)
    Arm description
    		 Standard Chemotherapy (Pemetrexed and Cisplatin) Pemetrexed 500 mg/m² with previous Folic acid and vitamin B12 supplementation Day 1 (D1=D22, 6 cycles) Cisplatin 75 mg/m² Day 1 (D1=D22, 6 cycles)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m² with previous Folic acid and vitamin B12 supplementation Day 1 (D1=D22, 6 cycles)

    Investigational medicinal product name
    Cisplatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 75 mg/m² Day 1 (D1=D22, 6 cycles)

    Arm title
    		 Standard Chemotherapy + bevacizumab (Arm B)
    Arm description
    		 Standard Chemotherapy (Pemetrexed and Cisplatin) + Bevacizumab Pemetrexed 500 mg/m² with previous Folic acid and vitamin B12 supplementation D1 (D1=D22, 6 cycles) Cisplatin 75 mg/m2 D1 (D1=D22, 6 cycles) Bevacizumab 15 mg/kg D1 (D1=D22, until progression)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 75 mg/m2 D1 (D1=D22, 6 cycles)

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m² with previous Folic acid and vitamin B12 supplementation D1 (D1=D22, 6 cycles)

    Investigational medicinal product name
    bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab 15 mg/kg D1 (D1=D22, until progression)

    Number of subjects in period 1
    		Standard Chemotherapy (Arm A) Standard Chemotherapy + bevacizumab (Arm B)
    Started
    225
    223
    Completed
    221
    220
    Not completed
    4
    3
         Not eligible
    -
    3
         Not eligible patient
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Chemotherapy (Arm A)
    Reporting group description
    		 Standard Chemotherapy (Pemetrexed and Cisplatin) Pemetrexed 500 mg/m² with previous Folic acid and vitamin B12 supplementation Day 1 (D1=D22, 6 cycles) Cisplatin 75 mg/m² Day 1 (D1=D22, 6 cycles)

    Reporting group title
    Standard Chemotherapy + bevacizumab (Arm B)
    Reporting group description
    		 Standard Chemotherapy (Pemetrexed and Cisplatin) + Bevacizumab Pemetrexed 500 mg/m² with previous Folic acid and vitamin B12 supplementation D1 (D1=D22, 6 cycles) Cisplatin 75 mg/m2 D1 (D1=D22, 6 cycles) Bevacizumab 15 mg/kg D1 (D1=D22, until progression)

    Reporting group values
    		 Standard Chemotherapy (Arm A) Standard Chemotherapy + bevacizumab (Arm B) Total
    Number of subjects
    		 225 223 448
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 97 107 204
        From 65-84 years
    		 128 116 244
    Age continuous
    Units: years
        median (full range (min-max))
    		 65.6 (34.7 to 75.9) 65.7 (38.5 to 75.8) -
    Gender categorical
    Units: Subjects
        Female
    		 55 55 110
        Male
    		 170 168 338
    Histology
    Units: Subjects
        Epithelioid
    		 182 179 361
        Sarcomatoid-mixed
    		 43 44 87
    ECOG PS
    Units: Subjects
        0-1
    		 217 216 433
        ≥2
    		 8 7 15
    Smoking status
    Units: Subjects
        Smoker
    		 129 125 254
        Never smoker
    		 96 98 194
    Leucocytes
    Units: Subjects
        <8·3 ×109/L
    		 124 132 256
        ≥8·3 ×109/L
    		 101 91 192
    Haemoglobin
    Units: Subjects
        >14 g/dL
    		 65 74 139
        ≤14 g/dL
    		 160 149 309
    Platelets
    Units: Subjects
        <400 ×109/L
    		 164 172 336
        ≥400 ×109/L
    		 61 51 112
    Thoracoscopy
    Units: Subjects
        Yes
    		 189 193 382
        No
    		 36 30 66
    Weight loss
    Units: percentage
        arithmetic mean (standard deviation)
    		 5.4 ± 3.1 5.4 ± 2.9 -

    End points

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    End points reporting groups
    Reporting group title
    Standard Chemotherapy (Arm A)
    Reporting group description
    		 Standard Chemotherapy (Pemetrexed and Cisplatin) Pemetrexed 500 mg/m² with previous Folic acid and vitamin B12 supplementation Day 1 (D1=D22, 6 cycles) Cisplatin 75 mg/m² Day 1 (D1=D22, 6 cycles)

    Reporting group title
    Standard Chemotherapy + bevacizumab (Arm B)
    Reporting group description
    		 Standard Chemotherapy (Pemetrexed and Cisplatin) + Bevacizumab Pemetrexed 500 mg/m² with previous Folic acid and vitamin B12 supplementation D1 (D1=D22, 6 cycles) Cisplatin 75 mg/m2 D1 (D1=D22, 6 cycles) Bevacizumab 15 mg/kg D1 (D1=D22, until progression)

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Patients who received at least one protocol treatment

    Subject analysis set title
    Eligible population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients without deviation at inclusion.

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    all population

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Primary
    End point timeframe
    The duration of overall survival is defined as the time elapsed between the date of randomization and death. If the patient does not die, survival will be censored at the given date or the date of the last results. The mediane follow-up was 39.4 months.
    End point values
    		 Standard Chemotherapy (Arm A) Standard Chemotherapy + bevacizumab (Arm B)
    Number of subjects analysed
    225
    223
    Units: months
        median (confidence interval 95%)
    16.1 (14.0 to 17.9)
    18.8 (15.9 to 22.6)
    Statistical analysis title
    		 Overall survival
    Comparison groups
    Standard Chemotherapy (Arm A) v Standard Chemotherapy + bevacizumab (Arm B)
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0167
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.95

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    End point type
    Secondary
    End point timeframe
    Progression-free survival is defined as the time elapsed between randomization until the date of the first observation of progression or death (from any cause).
    End point values
    		 Standard Chemotherapy (Arm A) Standard Chemotherapy + bevacizumab (Arm B)
    Number of subjects analysed
    225
    223
    Units: months
        median (full range (min-max))
    7.3 (6.7 to 8.0)
    9.2 (8.5 to 10.5)
    Statistical analysis title
    		 Progression-free survival
    Comparison groups
    Standard Chemotherapy (Arm A) v Standard Chemotherapy + bevacizumab (Arm B)
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.75

    Secondary: Time to Progression

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    End point title
    		 Time to Progression
    End point description
    End point type
    Secondary
    End point timeframe
    Time to progression (TTP) is a related endpoint defined as the time from randomization to tumor progression explicitly.
    End point values
    		 Standard Chemotherapy (Arm A) Standard Chemotherapy + bevacizumab (Arm B)
    Number of subjects analysed
    217
    218
    Units: months
        number (not applicable)
    189
    137
    Statistical analysis title
    		 Time to Progression
    Comparison groups
    Standard Chemotherapy (Arm A) v Standard Chemotherapy + bevacizumab (Arm B)
    Number of subjects included in analysis
    435
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Confidence interval

    Secondary: EORTC QLQ C30 quality of life scores

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    End point title
    		 EORTC QLQ C30 quality of life scores
    End point description
    End point type
    Secondary
    End point timeframe
    For QLQ-C30 scores, we qualifi ed QoL as improved when we noted a ten point increase or greater for functioning scales and a ten point reduction or greater for symptom domains or items between baseline and 9 week assessments.
    End point values
    		 Standard Chemotherapy (Arm A) Standard Chemotherapy + bevacizumab (Arm B)
    Number of subjects analysed
    151
    159
    Units: percentage
        number (not applicable)
    23
    23
    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 will be defined as all patients who received at least one dose of treatment.

    Reporting group title
    Safety Population : Arm B
    Reporting group description
    		 -

    Serious adverse events
    		 Safety Population : Arm A Safety Population : Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    78 / 224 (34.82%)
    94 / 222 (42.34%)
         number of deaths (all causes)
    178
    164
         number of deaths resulting from adverse events
    16
    14
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Extradural neoplasm
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 224 (1.34%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 224 (0.00%)
    3 / 222 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 224 (0.45%)
    10 / 222 (4.50%)
         occurrences causally related to treatment / all
    0 / 1
    17 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 224 (0.45%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 224 (0.89%)
    4 / 222 (1.80%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    8 / 224 (3.57%)
    6 / 222 (2.70%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 224 (0.89%)
    5 / 222 (2.25%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    15 / 224 (6.70%)
    11 / 222 (4.95%)
         occurrences causally related to treatment / all
    6 / 15
    5 / 12
         deaths causally related to treatment / all
    0 / 6
    0 / 5
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchial obstruction
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 224 (2.23%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 224 (0.89%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    3 / 224 (1.34%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 224 (0.89%)
    8 / 222 (3.60%)
         occurrences causally related to treatment / all
    1 / 2
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory distress
         subjects affected / exposed
    1 / 224 (0.45%)
    3 / 222 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory failure
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 224 (0.89%)
    3 / 222 (1.35%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    10 / 224 (4.46%)
    6 / 222 (2.70%)
         occurrences causally related to treatment / all
    11 / 11
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    6 / 224 (2.68%)
    4 / 222 (1.80%)
         occurrences causally related to treatment / all
    6 / 6
    5 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    9 / 224 (4.02%)
    6 / 222 (2.70%)
         occurrences causally related to treatment / all
    10 / 10
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Expired product administered
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haematoma
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 224 (0.45%)
    3 / 222 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Extrasystoles
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infractio
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Headache
         subjects affected / exposed
    0 / 224 (0.00%)
    4 / 222 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    7 / 224 (3.13%)
    3 / 222 (1.35%)
         occurrences causally related to treatment / all
    7 / 7
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histiocytosis haematophagic
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Photophobia
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 224 (1.34%)
    3 / 222 (1.35%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 224 (1.79%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 224 (2.23%)
    7 / 222 (3.15%)
         occurrences causally related to treatment / all
    5 / 6
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 224 (0.89%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subileus
         subjects affected / exposed
    1 / 224 (0.45%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 224 (0.45%)
    4 / 222 (1.80%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercreatininaemia
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 224 (0.45%)
    5 / 222 (2.25%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    3 / 224 (1.34%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate infection
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 224 (1.34%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 224 (0.00%)
    2 / 222 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 224 (1.34%)
    5 / 222 (2.25%)
         occurrences causally related to treatment / all
    5 / 6
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 224 (0.45%)
    0 / 222 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 224 (0.00%)
    1 / 222 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    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
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    224 / 224 (100.00%)
    222 / 222 (100.00%)
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    22 / 224 (9.82%)
    89 / 222 (40.09%)
         occurrences all number
    32
    216
    Hypertension
         subjects affected / exposed
    35 / 224 (15.63%)
    134 / 222 (60.36%)
         occurrences all number
    106
    477
    Thrombosis
         subjects affected / exposed
    14 / 224 (6.25%)
    10 / 222 (4.50%)
         occurrences all number
    34
    19
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    173 / 224 (77.23%)
    164 / 222 (73.87%)
         occurrences all number
    594
    675
    Edema limbs
         subjects affected / exposed
    25 / 224 (11.16%)
    30 / 222 (13.51%)
         occurrences all number
    43
    48
    Fever
         subjects affected / exposed
    39 / 224 (17.41%)
    25 / 222 (11.26%)
         occurrences all number
    55
    33
    Reduced general condition
         subjects affected / exposed
    21 / 224 (9.38%)
    12 / 222 (5.41%)
         occurrences all number
    28
    17
    Chest pain
         subjects affected / exposed
    144 / 224 (64.29%)
    136 / 222 (61.26%)
         occurrences all number
    491
    441
    Pain
         subjects affected / exposed
    22 / 224 (9.82%)
    17 / 222 (7.66%)
         occurrences all number
    43
    37
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    151 / 224 (67.41%)
    143 / 222 (64.41%)
         occurrences all number
    488
    483
    Cough
         subjects affected / exposed
    83 / 224 (37.05%)
    69 / 222 (31.08%)
         occurrences all number
    191
    174
    Dysphonia
         subjects affected / exposed
    5 / 224 (2.23%)
    12 / 222 (5.41%)
         occurrences all number
    7
    16
    Pulmonary embolism
         subjects affected / exposed
    3 / 224 (1.34%)
    11 / 222 (4.95%)
         occurrences all number
    6
    17
    Rhinorrhea
         subjects affected / exposed
    19 / 224 (8.48%)
    10 / 222 (4.50%)
         occurrences all number
    28
    25
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    15 / 224 (6.70%)
    20 / 222 (9.01%)
         occurrences all number
    34
    48
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 224 (3.57%)
    11 / 222 (4.95%)
         occurrences all number
    27
    37
    Hemoglobin decreased
         subjects affected / exposed
    192 / 224 (85.71%)
    165 / 222 (74.32%)
         occurrences all number
    1043
    827
    Neutrophil count decreased
         subjects affected / exposed
    179 / 224 (79.91%)
    173 / 222 (77.93%)
         occurrences all number
    597
    605
    Platelet count decreased
         subjects affected / exposed
    122 / 224 (54.46%)
    132 / 222 (59.46%)
         occurrences all number
    344
    440
    Weight loss
         subjects affected / exposed
    34 / 224 (15.18%)
    38 / 222 (17.12%)
         occurrences all number
    79
    103
    Creatinine increased
         subjects affected / exposed
    16 / 224 (7.14%)
    33 / 222 (14.86%)
         occurrences all number
    78
    131
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 224 (7.59%)
    50 / 222 (22.52%)
         occurrences all number
    22
    119
    Paresthesia
         subjects affected / exposed
    37 / 224 (16.52%)
    22 / 222 (9.91%)
         occurrences all number
    77
    56
    Dysgeusia
         subjects affected / exposed
    24 / 224 (10.71%)
    12 / 222 (5.41%)
         occurrences all number
    34
    13
    Neuropathy
         subjects affected / exposed
    23 / 224 (10.27%)
    25 / 222 (11.26%)
         occurrences all number
    53
    50
    Paresthesia of limbs
         subjects affected / exposed
    14 / 224 (6.25%)
    13 / 222 (5.86%)
         occurrences all number
    31
    26
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    24 / 224 (10.71%)
    15 / 222 (6.76%)
         occurrences all number
    69
    24
    Vertigo
         subjects affected / exposed
    13 / 224 (5.80%)
    10 / 222 (4.50%)
         occurrences all number
    18
    12
    Eye disorders
    Eyes tearing
         subjects affected / exposed
    13 / 224 (5.80%)
    13 / 222 (5.86%)
         occurrences all number
    22
    26
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    16 / 224 (7.14%)
    19 / 222 (8.56%)
         occurrences all number
    25
    24
    Constipation
         subjects affected / exposed
    70 / 224 (31.25%)
    70 / 222 (31.53%)
         occurrences all number
    131
    146
    Diarrhea
         subjects affected / exposed
    34 / 224 (15.18%)
    44 / 222 (19.82%)
         occurrences all number
    50
    81
    Gastralgia
         subjects affected / exposed
    20 / 224 (8.93%)
    23 / 222 (10.36%)
         occurrences all number
    38
    35
    Gastrooesophageal reflux
         subjects affected / exposed
    8 / 224 (3.57%)
    12 / 222 (5.41%)
         occurrences all number
    10
    21
    Nausea
         subjects affected / exposed
    166 / 224 (74.11%)
    168 / 222 (75.68%)
         occurrences all number
    484
    550
    Oral mucosal irritation
         subjects affected / exposed
    33 / 224 (14.73%)
    31 / 222 (13.96%)
         occurrences all number
    50
    54
    Stomatitis
         subjects affected / exposed
    10 / 224 (4.46%)
    16 / 222 (7.21%)
         occurrences all number
    17
    23
    Vomiting
         subjects affected / exposed
    84 / 224 (37.50%)
    89 / 222 (40.09%)
         occurrences all number
    172
    162
    Gingival bleeding
         subjects affected / exposed
    0 / 224 (0.00%)
    13 / 222 (5.86%)
         occurrences all number
    0
    31
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    34 / 224 (15.18%)
    29 / 222 (13.06%)
         occurrences all number
    71
    68
    Erythema
         subjects affected / exposed
    24 / 224 (10.71%)
    17 / 222 (7.66%)
         occurrences all number
    33
    24
    Skin eruption
         subjects affected / exposed
    11 / 224 (4.91%)
    16 / 222 (7.21%)
         occurrences all number
    12
    26
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 224 (0.89%)
    37 / 222 (16.67%)
         occurrences all number
    5
    162
    Renal failure
         subjects affected / exposed
    10 / 224 (4.46%)
    15 / 222 (6.76%)
         occurrences all number
    28
    33
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    20 / 224 (8.93%)
    17 / 222 (7.66%)
         occurrences all number
    29
    30
    Joint pain
         subjects affected / exposed
    12 / 224 (5.36%)
    25 / 222 (11.26%)
         occurrences all number
    16
    53
    Myalgia
         subjects affected / exposed
    8 / 224 (3.57%)
    12 / 222 (5.41%)
         occurrences all number
    8
    14
    Pain neck/shoulder
         subjects affected / exposed
    12 / 224 (5.36%)
    16 / 222 (7.21%)
         occurrences all number
    26
    29
    Rib pain
         subjects affected / exposed
    7 / 224 (3.13%)
    12 / 222 (5.41%)
         occurrences all number
    15
    29
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    18 / 224 (8.04%)
    19 / 222 (8.56%)
         occurrences all number
    38
    39
    Oral candida
         subjects affected / exposed
    16 / 224 (7.14%)
    5 / 222 (2.25%)
         occurrences all number
    21
    8
    Rhinitis
         subjects affected / exposed
    7 / 224 (3.13%)
    17 / 222 (7.66%)
         occurrences all number
    13
    25
    Bronchitis
         subjects affected / exposed
    20 / 224 (8.93%)
    30 / 222 (13.51%)
         occurrences all number
    23
    40
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    87 / 224 (38.84%)
    88 / 222 (39.64%)
         occurrences all number
    189
    181

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Oct 2007
    A first modification of the protocol was done in October 2007 in order to add maintenance by bevacizumab.
    15 Dec 2007
    A 2nd modification was done in December 2007 in order to add new sites.
    15 Apr 2008
    A 3th modification was done in April 2008 in order to add new sites.
    15 Jul 2008
    A 4th modification was done in July 2008 in order to add new sites.
    15 Jan 2009
    A 5th modification was done in January 2009 in order to modify the timing of the protocol and to add new sites.
    15 Nov 2009
    A 6th modification was done in November 2009 in order to modify the number of patients.
    15 Jun 2010
    A 7th amendment was made in June 2010 to modify the sponsor and the merger of the consent.
    15 Apr 2011
    An 8th amendment was made in April 2011 to relax the inclusion criteria on cancer history and to add new sites.
    15 Nov 2011
    A 9th modification was done in November 2011 in order to add new sites.
    15 Mar 2012
    A 10th modification was done in March 2012 in order to : add new sites, clarify what to do in case of venous thrombosis and high blood pressure and update of the bevacizumab IB, extend the duration of treatment interruption during the maintenance phase.
    15 Oct 2014
    A 11th modification was done in October 2014 in order to modify the PI for 3 sites and to extend the duration of the study.
    15 Sep 2015
    A 12th modification was done in September 2015 in order to add a second interim analysis.

    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.
    Open-label trial. Assessment of QoL could have been slightly altered by the absence of masking.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26719230
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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