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    Clinical Trial Results:
    Phase III, randomized clinical trial to evaluate FOLFOX + bebacizumab versus FOLFOXIRI + bebacizumab as first line treatment of patients with metastatic colorectal cancer not previously treated and with three or more circulating tumoral cells.

    Summary
    EudraCT number
    		 2012-000846-37
    Trial protocol
    		 ES  
    Global end of trial date
    30 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2021
    First version publication date
    04 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TTD-12-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01640405
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo de Tratamiento de los Tumores Digestivos (TTD)
    Sponsor organisation address
    Téllez 30, Madrid, Spain, 28007
    Public contact
    Grupo de Tratamiento de los Tumores Digestivos (TTD), Grupo de Tratamiento de los Tumores Digestivos (TTD), 34 913788275, ttd@ttdgroup.org
    Scientific contact
    Grupo de Tratamiento de los Tumores Digestivos (TTD), Grupo de Tratamiento de los Tumores Digestivos (TTD), 34 913788275, ttd@ttdgroup.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Progression free survival (PFS) efficacy compared between FOLFOX + Bevacizumab vs FOLFOXIRI + Bevacizumab, in mCRC first line treated patients with 3 or more Circulating tumor cells (CTC).
    Protection of trial subjects
    Any medication that patients needed for their correct clinical control (except prohibited therapies), according to investigator's criteria were allowed.
    Background therapy
    		 Sedative treatment, antiemetic treatment, antibiotics, analgesic treatment, antihistamines. antihyperpensive drugs, low doses of steroids, concentrates of erythrocytes, platelets or plasma coud be administered to contribute at treatment of pain, infection and other complications of the malignant neoplasm. In case of febrile neutropenia or documented infection, colony stimulating factors (e.g. G-CSF, GM-CSF) and antibiotics -preventive or prophilactic- could be administered according to usual rules in every institution.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 349
    Worldwide total number of subjects
    349
    EEA total number of subjects
    349
    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)
    243
    From 65 to 84 years
    106
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 349
    Number of subjects completed
    		 349

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 FOLFOX6 modified + bevacizumab
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/Kg IV, day 1 of every cycle (1cycle=2weeks)

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85mg/m2 iv administered in 2 hour period, day 1 of cycle

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400mg/m2 IV administered in 2 hour period, day 1 of each cycle

    Investigational medicinal product name
    5-flouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m2 followed by 2400 mg/m2 administered during 48 hours given as continuous infusion.

    Arm title
    		 Arm B
    Arm description
    		 FOLFOXIRI + bevacizumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/Kg iv day 1 of each cycle (1 cycle= 2weeks)

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    165 mg/m2 IV administered in a 30-90 minutes, day 1 of each cycle

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    85mg/m2 IV administered in a 2 hour period day 1 of each cycle

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m2 IV administered in a 2 hour period day 1 of each cycle

    Investigational medicinal product name
    5-fluouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3200 mg/m2 given as continuous infusion during 48 hours, day 1 of each cycle

    Number of subjects in period 1
    		Arm A Arm B
    Started
    177
    172
    Completed
    177
    172
    Period 2
    Period 2 title
    RAS mutated
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ras mutated
    Arm description
    		 -
    Arm type
    		 Ras mutated

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 RAS wild type
    Arm description
    		 -
    Arm type
    		 RAS wild type

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Ras mutated RAS wild type
    Started
    169
    180
    Completed
    169
    180
    Period 3
    Period 3 title
    BRAF mutated
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BRAF mutated
    Arm description
    		 -
    Arm type
    		 BRAF mutated

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 BRAF wild type
    Arm description
    		 -
    Arm type
    		 BRAF wild type

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		BRAF mutated BRAF wild type
    Started
    33
    316
    Completed
    33
    316
    Period 4
    Period 4 title
    PI3K mutated
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PI3K mutated
    Arm description
    		 -
    Arm type
    		 PI3K mutated

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 PI3K wild type
    Arm description
    		 -
    Arm type
    		 PI3K wild type

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		PI3K mutated PI3K wild type
    Started
    43
    306
    Completed
    43
    306

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 FOLFOX6 modified + bevacizumab

    Reporting group title
    Arm B
    Reporting group description
    		 FOLFOXIRI + bevacizumab

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 177 172 349
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 126 117 243
        From 65-84 years
    		 51 55 106
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.87 ( 8.43 ) 59.47 ( 7.72 ) -
    Gender categorical
    Units: Subjects
        Female
    		 58 54 112
        Male
    		 119 118 237
    ECOG at baseline
    Units: Subjects
        ECOG 0
    		 85 81 166
        ECOG 1
    		 92 91 183
    Tumor location
    Units: Subjects
        Right
    		 39 48 87
        Left
    		 137 119 256
        Right and left
    		 1 5 6
    Histopathological grade
    Units: Subjects
        Unknown
    		 38 49 87
        Gx: not evaluable
    		 1 2 3
        G1: well-differentiated
    		 49 32 81
        G2: moderately differentiated
    		 64 72 136
        G3: poorly differentiated
    		 22 16 38
        G4: undifferentiated
    		 3 1 4
    Sincronic or metacronic
    Units: Subjects
        Sincronic
    		 167 160 327
        Metacronic
    		 10 12 22
    CEA grouped
    Units: Subjects
        CEA<=5
    		 8 16 24
        CEA>5
    		 169 156 325
    Basal surgery
    Units: Subjects
        NO
    		 118 110 228
        Yes (primary tumor)
    		 55 59 114
        Yes (not primary tumor)
    		 4 3 7
    Previous antineoplastic treatments
    Units: Subjects
        NO
    		 170 163 333
        Yes (adjuvant)
    		 4 7 11
        Yes (neoadjuvant)
    		 2 0 2
        Yes (neoadjuvant and adjuvant)
    		 1 2 3
    Previous radiotherapy
    Units: Subjects
        No
    		 173 167 340
        Yes (adjuvant)
    		 3 4 7
        Yes (antialgic)
    		 0 1 1
        Yes (neoadjuvant)
    		 1 0 1
    RAS (mutational status)
    Units: Subjects
        Mutated
    		 84 85 169
        Native
    		 88 85 173
        Unknown
    		 5 2 7
    BRAF (mutational status)
    Units: Subjects
        Mutated
    		 17 16 33
        Native
    		 160 156 316
    PI3K
    Units: Subjects
        Mutated
    		 17 26 43
        Native
    		 159 146 305
        Unknown
    		 1 0 1
    Microsatellite instability (MSI)
    Units: Subjects
        MSI-High
    		 1 2 3
        MSI-Low
    		 7 8 15
        MSS (microsatellite stable)
    		 156 156 312
        Unknown
    		 13 6 19
    CEA
    Units: ng/ml
        arithmetic mean (standard deviation)
    		 1537.16 ( 4567.79 ) 1283.31 ( 3753.41 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 FOLFOX6 modified + bevacizumab

    Reporting group title
    Arm B
    Reporting group description
    		 FOLFOXIRI + bevacizumab
    Reporting group title
    Ras mutated
    Reporting group description
    		 -

    Reporting group title
    RAS wild type
    Reporting group description
    		 -
    Reporting group title
    BRAF mutated
    Reporting group description
    		 -

    Reporting group title
    BRAF wild type
    Reporting group description
    		 -
    Reporting group title
    PI3K mutated
    Reporting group description
    		 -

    Reporting group title
    PI3K wild type
    Reporting group description
    		 -

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    Time elapsed from randomization to disease progression or death from any cause.
    End point type
    Primary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    177
    172
    Units: Months
        median (confidence interval 95%)
    9.3 (8.5 to 10.7)
    12.4 (11.1 to 14.0)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0006
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Time elapsed from randomization to death from any cause.
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    177
    172
    Units: Months
        median (confidence interval 95%)
    17.6 (15.1 to 21.2)
    22.3 (17.8 to 26.4)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2627
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall response rate

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    End point title
    		 Overall response rate
    End point description
    Percentage of patients with Complete Response or Partial Response
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    177
    172
    Units: Subjects
    92
    102
    Statistical analysis title
    		 Overall response rate
    Statistical analysis description
    Overall trial
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1685
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Confidence interval

    Secondary: Tumor resection rate (R0)

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    End point title
    		 Tumor resection rate (R0)
    End point description
    Percentage of patients who achieved complete resection
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    177
    172
    Units: Subjects
        No
    163
    160
        Si
    14
    12
    Statistical analysis title
    		 Chi squared test
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.74
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Confidence interval

    Secondary: Number of patients with grade >=3 treatment-related TEAEs in each arm according to CTCAE v4.0 criteria

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    End point title
    		 Number of patients with grade >=3 treatment-related TEAEs in each arm according to CTCAE v4.0 criteria
    End point description
    Number of patients with grade >=3 treatment-related TEAEs in each arm according to CTCAE v4.0 criteria
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    177
    170 [1]
    Units: Subjects
        YES
    119
    133
        NO
    58
    37
    Notes
    [1] - 2 patients don't be evaluated in Safety population because they haven't received any study treatment
    Statistical analysis title
    		 Chi-squared test
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0216
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Confidence interval

    Secondary: Number of patients with treatment-related serious TEAEs in each arm according to CTCAE v4.0 criteria

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    End point title
    		 Number of patients with treatment-related serious TEAEs in each arm according to CTCAE v4.0 criteria
    End point description
    Number of patients with treatment-related serious TEAEs in each arm according to CTCAE v4.0 criteria
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    177
    170 [2]
    Units: Subjects
        Yes
    38
    60
        No
    139
    110
    Notes
    [2] - 2 patients weren't considered safety population because they didn't received any study treatment
    Statistical analysis title
    		 Chi squared test
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0042
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Confidence interval

    Secondary: Progression free survival according to basal count of circulating tumor cells<=20 /7.5 mL blood

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    End point title
    		 Progression free survival according to basal count of circulating tumor cells<=20 /7.5 mL blood
    End point description
    Progression free survival according to basal count of circulating tumor cells<=20 /7.5 mL blood
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    149
    152
    Units: Months
        median (confidence interval 95%)
    10 (8.9 to 11.1)
    12.5 (11.2 to 14.3)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0086
    Method
    		 Regression, Cox
    Parameter type
    		 Log risk ratio
    Confidence interval

    Secondary: Progression free survival according to RAS status

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    End point title
    		 Progression free survival according to RAS status
    End point description
    Progression free survival according to RAS status
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 Ras mutated RAS wild type
    Number of subjects analysed
    169
    180
    Units: months
        median (confidence interval 95%)
    9.1 (8.3 to 11.0)
    11.4 (10.5 to 13.6)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Ras mutated v RAS wild type
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0003
    Method
    		 Logrank
    Confidence interval

    Secondary: Progression free survival according to BRAF

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    End point title
    		 Progression free survival according to BRAF
    End point description
    Progression free survival according to BRAF
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 BRAF mutated BRAF wild type
    Number of subjects analysed
    33
    316
    Units: Months
        median (confidence interval 95%)
    7.7 (3.7 to 10.6)
    11.0 (9.9 to 11.7)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    BRAF mutated v BRAF wild type
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0006
    Method
    		 Logrank
    Confidence interval

    Secondary: Progression free survival according to PI3K status

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    End point title
    		 Progression free survival according to PI3K status
    End point description
    Progression free survival according to PI3K status
    End point type
    Secondary
    End point timeframe
    Overall study
    End point values
    		 PI3K mutated PI3K wild type
    Number of subjects analysed
    43
    306
    Units: Months
        median (confidence interval 95%)
    9.1 (8.1 to 14.2)
    10.9 (9.5 to 11.4)
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    PI3K mutated v PI3K wild type
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4689
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 -

    Reporting group title
    Arm B
    Reporting group description
    		 -

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    64 / 177 (36.16%)
    83 / 170 (48.82%)
         number of deaths (all causes)
    149
    136
         number of deaths resulting from adverse events
    13
    14
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 177 (4.52%)
    4 / 170 (2.35%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adverse reaction to drug
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General malaise
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    device related pain
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Physical condition impairment
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Asthenia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 177 (2.26%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory insufficiency
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Insterstitial pulmonary disease
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Dissociative disorder
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device thrombosis
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ´device dysfunction
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (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
    Anastomotic dehiscence
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedure haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chemical pneumonitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nervous system disorders
    Pre-syncope
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic-clonic seizures
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 177 (2.26%)
    15 / 170 (8.82%)
         occurrences causally related to treatment / all
    4 / 4
    15 / 15
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 177 (0.56%)
    9 / 170 (5.29%)
         occurrences causally related to treatment / all
    1 / 1
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 177 (2.82%)
    14 / 170 (8.24%)
         occurrences causally related to treatment / all
    4 / 5
    12 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    9 / 177 (5.08%)
    4 / 170 (2.35%)
         occurrences causally related to treatment / all
    7 / 9
    4 / 4
         deaths causally related to treatment / all
    3 / 4
    3 / 3
    Intestinal obstruction
         subjects affected / exposed
    2 / 177 (1.13%)
    6 / 170 (3.53%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 177 (2.26%)
    8 / 170 (4.71%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 3
    0 / 7
    Abdominal pain
         subjects affected / exposed
    4 / 177 (2.26%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 177 (0.56%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestinal perforation
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    esophagitis
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hipomotility
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal inflammation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute cholecystitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic insufficiency
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hematuria
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 177 (1.13%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 170 (1.18%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Anal abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter infection
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia per Escherichia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophageal Candidiasis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumococcal pneumonia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Herpesvirus simple encephalitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphilococcal sepsis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    incision place abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pseudomonas infection urinary tract
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 177 (0.00%)
    3 / 170 (1.76%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lysis tumor syndrome
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 170 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 170 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 177 (100.00%)
    170 / 170 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    29 / 177 (16.38%)
    34 / 170 (20.00%)
         occurrences all number
    29
    34
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    119 / 177 (67.23%)
    127 / 170 (74.71%)
         occurrences all number
    119
    127
    Mucosal inflammation
         subjects affected / exposed
    63 / 177 (35.59%)
    83 / 170 (48.82%)
         occurrences all number
    63
    83
    Pyrexia
         subjects affected / exposed
    50 / 177 (28.25%)
    54 / 170 (31.76%)
         occurrences all number
    50
    54
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    50 / 177 (28.25%)
    37 / 170 (21.76%)
         occurrences all number
    50
    37
    Cough
         subjects affected / exposed
    14 / 177 (7.91%)
    16 / 170 (9.41%)
         occurrences all number
    14
    16
    Catarrh
         subjects affected / exposed
    15 / 177 (8.47%)
    14 / 170 (8.24%)
         occurrences all number
    15
    14
    Rhinorrhoea
         subjects affected / exposed
    9 / 177 (5.08%)
    13 / 170 (7.65%)
         occurrences all number
    9
    13
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 177 (4.52%)
    15 / 170 (8.82%)
         occurrences all number
    8
    15
    Investigations
    Decreased weight
         subjects affected / exposed
    8 / 177 (4.52%)
    10 / 170 (5.88%)
         occurrences all number
    8
    10
    Nervous system disorders
    Neurotoxicity
         subjects affected / exposed
    71 / 177 (40.11%)
    54 / 170 (31.76%)
         occurrences all number
    71
    54
    Peripheral neuropathy
         subjects affected / exposed
    53 / 177 (29.94%)
    41 / 170 (24.12%)
         occurrences all number
    53
    41
    Paresthesia
         subjects affected / exposed
    53 / 177 (29.94%)
    40 / 170 (23.53%)
         occurrences all number
    53
    40
    Dysaesthesia
         subjects affected / exposed
    27 / 177 (15.25%)
    34 / 170 (20.00%)
         occurrences all number
    27
    34
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    88 / 177 (49.72%)
    104 / 170 (61.18%)
         occurrences all number
    88
    104
    Thrombocytopenia
         subjects affected / exposed
    60 / 177 (33.90%)
    51 / 170 (30.00%)
         occurrences all number
    60
    51
    Anemia
         subjects affected / exposed
    41 / 177 (23.16%)
    45 / 170 (26.47%)
         occurrences all number
    41
    45
    Leukopenia
         subjects affected / exposed
    10 / 177 (5.65%)
    13 / 170 (7.65%)
         occurrences all number
    10
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    83 / 177 (46.89%)
    130 / 170 (76.47%)
         occurrences all number
    83
    130
    Nausea
         subjects affected / exposed
    65 / 177 (36.72%)
    89 / 170 (52.35%)
         occurrences all number
    65
    89
    Vomiting
         subjects affected / exposed
    41 / 177 (23.16%)
    79 / 170 (46.47%)
         occurrences all number
    41
    79
    Constipation
         subjects affected / exposed
    47 / 177 (26.55%)
    50 / 170 (29.41%)
         occurrences all number
    47
    50
    Dysgeusia
         subjects affected / exposed
    22 / 177 (12.43%)
    30 / 170 (17.65%)
         occurrences all number
    22
    30
    Rectal haemorrhage
         subjects affected / exposed
    13 / 177 (7.34%)
    23 / 170 (13.53%)
         occurrences all number
    13
    23
    Upper abdomen pain
         subjects affected / exposed
    13 / 177 (7.34%)
    20 / 170 (11.76%)
         occurrences all number
    13
    20
    Stomatitis
         subjects affected / exposed
    8 / 177 (4.52%)
    16 / 170 (9.41%)
         occurrences all number
    8
    16
    Dry mouth
         subjects affected / exposed
    10 / 177 (5.65%)
    10 / 170 (5.88%)
         occurrences all number
    10
    10
    Proctalgia
         subjects affected / exposed
    6 / 177 (3.39%)
    13 / 170 (7.65%)
         occurrences all number
    6
    13
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    13 / 177 (7.34%)
    32 / 170 (18.82%)
         occurrences all number
    13
    32
    Palmoplantar Erythrodysesthesia Syndrome
         subjects affected / exposed
    13 / 177 (7.34%)
    8 / 170 (4.71%)
         occurrences all number
    13
    8
    Eruption
         subjects affected / exposed
    9 / 177 (5.08%)
    10 / 170 (5.88%)
         occurrences all number
    9
    10
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    10 / 177 (5.65%)
    12 / 170 (7.06%)
         occurrences all number
    10
    12
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    20 / 177 (11.30%)
    14 / 170 (8.24%)
         occurrences all number
    20
    14
    Myalgia
         subjects affected / exposed
    12 / 177 (6.78%)
    11 / 170 (6.47%)
         occurrences all number
    12
    11
    Arthralgia
         subjects affected / exposed
    10 / 177 (5.65%)
    12 / 170 (7.06%)
         occurrences all number
    10
    12
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    14 / 177 (7.91%)
    9 / 170 (5.29%)
         occurrences all number
    14
    9
    Urinary tract infection
         subjects affected / exposed
    13 / 177 (7.34%)
    9 / 170 (5.29%)
         occurrences all number
    13
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    44 / 177 (24.86%)
    56 / 170 (32.94%)
         occurrences all number
    44
    56

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jul 2012
    Expansion of 14 sites
    04 Oct 2012
    Change of PI in Son Llátzer Hospital
    01 Nov 2012
    Change PI in Son Espases Hospital
    01 Feb 2013
    Change PI in Puerta del Hierro Hospital
    10 May 2013
    Substantial change to the protocol (Version 4 Protocol- 10May2013- is generated), expansion of 5 sites, change PI in 12 de Octubre Hospital, change in the general Subject Information Sheet
    18 Mar 2014
    Substantial change to Protocol (Version 5-18Mar2014) is generated with adition of sub-study and Subject Sheet Information-Informed Consent for sub-study), expansion of 1 site, change of Subject Sheet Information-Informed Consent for study
    01 Apr 2015
    Change PI in Virgen del Rocío Hospital
    01 Oct 2015
    Change PI in A Coruña Hospital
    26 Jul 2016
    Modifications in annexes 8 and 10. Change in Subject Information Sheet- Informed Consent general and specific for sub-study, cahange of 2 responsibles of laboratory of the study, addition of new central laboratory
    04 Aug 2017
    Change of PI in 3 sites: Hospital of Valencia, Hospital of Elda, Hospital of Sagunto
    12 Apr 2018
    Change of PI in Central University Hospital of Asturias
    27 Nov 2018
    Change PI in Hospital of Zamora, change of laboratory of analysis of sub-study
    10 Jul 2019
    Substantial change to Protocol (Version 6-10Jul2019) is generated to extent follow up 12 more months

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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