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    Clinical Trial Results:
    A single arm study in metastatic colorectal cancer patients treated with pharmacokinetically (PK) dose adjusted weekly or biweekly 5-fluorouracil (5-FU) regimes.

    Summary
    EudraCT number
    		 2011-003553-26
    Trial protocol
    		 DE  
    Global end of trial date
    17 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2018
    First version publication date
    05 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C-II-009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CESAR Central European Society for Anticancer Drug Research-EWIV
    Sponsor organisation address
    Hanglüssgasse, 4/1-3, Vienna, Austria, 1150
    Public contact
    Sponsor, CESAR Central European Society for Anticancer Drug Research-EWIV , 0043 1522309316, max.roessler@cesar.or.at
    Scientific contact
    Sponsor, CESAR Central European Society for Anticancer Drug Research-EWIV , 0043 6765273814, max.roessler@cesar.or.at
    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
    03 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether pharmacokinetically-guided dose adjustment of 5-FU provides a stable intrapatient dose level of 20-30 mg.h /l. The primary analysis will be the comparison of the proportion of patients with AUC within 20 to 30 mg.h/L after the first 5-FU application versus the fourth application.
    Protection of trial subjects
    Patients within this trial receive pharmacokinetically adapted 5-FU infusions. Beside the individual dose adaptation, which requires additional blood draws, patients are treated according to clinical routine. In order to further reduce interventions, the needle punctures required for PK-assessments were performed in course of routine blood draws. Safety measures like regular blood analysis were performed according to clinical routine.
    Background therapy
    		 n.a.
    Evidence for comparator
    		 n.a.
    Actual start date of recruitment
    13 Jul 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
    Germany: 75
    Worldwide total number of subjects
    75
    EEA total number of subjects
    75
    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)
    32
    From 65 to 84 years
    43
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 7 study sites in Germany participated in the study. Recruitment started on 13.07.2012 and ended at 10.07.2014 as the last patient was recruited.

    Pre-assignment
    Screening details
    		 The screening criteria were defined by the inclusion and exclusion criteria as defined in the study protocol.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    n.a.

    Arms
    Arm title
    		 Experimental Treatment Arm
    Arm description
    		 Patients will be treated with AIO-regime (weekly), FUFOX-regime (weekly) or FOLFOX-6 regime (bi-weekly). Patients will be dosed for the first time in accordance to established local standard and then 5-FU will be individually adjusted before every chemotherapy application, beginning with the second application. Dose adjustments for 5-FU will be either calculated according to toxicity and/or to the results of plasma concentrations from the preceding application (see algorithm below). Patients will remain on study until a total of 6 doses of FU-treatment have been administered and the end-of-treatment visit has been performed (weekly regimen: 9 weeks and bi-weekly regimen 13 weeks) or until withdrawal of patient`s consent, or withdrawal by the treating physician for safety reasons or due tumor progression, whatever comes first. Following study completion, patients will receive further treatment according to best local practice.
    Arm type
    		 Experimental

    Investigational medicinal product name
    5-Fluoruracil
    Investigational medicinal product code
    L01BC02
    Other name
    5-Fluor-1H-pyrimidin-2,4-dion
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration according to SmPC. Individual dosing according to dosing algorithm outlined in CSP.

    Number of subjects in period 1
    		Experimental Treatment Arm
    Started
    75
    Completed
    75

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 75 75
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.06 ( 10.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 32 32
        Male
    		 43 43
    Subject analysis sets

    Subject analysis set title
    ITT-AIO Week-2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP at week 2. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-FUFOX-Week2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP (FUFOX regime) at week 2. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-FOLFOX6 Week 3
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP (FOLFOX-6 regime) at week 3. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-AIO Week-5
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP at week 5. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-FUFOX-Week5
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP (FUFOX regime) at week 5. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-FOLFOX6 Week 9
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP (FOLFOX-6 regime) at week 9. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis sets values
    		 ITT-AIO Week-2 ITT-FUFOX-Week2 ITT-FOLFOX6 Week 3 ITT-AIO Week-5 ITT-FUFOX-Week5 ITT-FOLFOX6 Week 9
    Number of subjects
    16
    33
    26
    16
    33
    26
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71,77 ( 9,84 )
    60,84 ( 10,29 )
    66,29 ( 9,5 )
    71,77 ( 9,84 )
    60,84 ( 10,29 )
    66,29 ( 9,5 )
    Gender categorical
    Units: Subjects
        Female
    32
        Male
    43

    End points

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    End points reporting groups
    Reporting group title
    Experimental Treatment Arm
    Reporting group description
    		 Patients will be treated with AIO-regime (weekly), FUFOX-regime (weekly) or FOLFOX-6 regime (bi-weekly). Patients will be dosed for the first time in accordance to established local standard and then 5-FU will be individually adjusted before every chemotherapy application, beginning with the second application. Dose adjustments for 5-FU will be either calculated according to toxicity and/or to the results of plasma concentrations from the preceding application (see algorithm below). Patients will remain on study until a total of 6 doses of FU-treatment have been administered and the end-of-treatment visit has been performed (weekly regimen: 9 weeks and bi-weekly regimen 13 weeks) or until withdrawal of patient`s consent, or withdrawal by the treating physician for safety reasons or due tumor progression, whatever comes first. Following study completion, patients will receive further treatment according to best local practice.

    Subject analysis set title
    ITT-AIO Week-2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP at week 2. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-FUFOX-Week2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP (FUFOX regime) at week 2. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-FOLFOX6 Week 3
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP (FOLFOX-6 regime) at week 3. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-AIO Week-5
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP at week 5. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-FUFOX-Week5
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP (FUFOX regime) at week 5. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Subject analysis set title
    ITT-FOLFOX6 Week 9
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patient in the ITT group who reveived IMP (FOLFOX-6 regime) at week 9. The Intent-to-Treat (ITT) population was defined as all enrolled patients with at least one 5-FU treatment. It was the primary analysis population for safety and efficacy analysis.

    Primary: Primary Endpoint in AIO ITT Patients

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    End point title
    		 Primary Endpoint in AIO ITT Patients
    End point description
    To determine whether pharmacokinetically-guided dose adjustment of 5-FU provides a stable intrapatient dose level of 20-30 mg.h /l.The primary analysis will be the comparison of the proportion of patients with AUC within 20 to 30 mg.h/L after the first 5-FU application versus the fourth application.
    End point type
    Primary
    End point timeframe
    First 5-FU application till fourth 5 FU application
    End point values
    		 Experimental Treatment Arm ITT-AIO Week-2 ITT-AIO Week-5
    Number of subjects analysed
    16
    16
    16
    Units: Patients
    16
    16
    16
    Statistical analysis title
    		 McNemar’s test
    Statistical analysis description
    The primary endpoint was the comparison between the proportion of patients with an AUC in target range during the first 5-FU application versus the fourth 5-FU application. This comparison was performed with a McNemar’s test to determine whether the row and column marginal frequencies (in a 2x2 contingency table of the first vs. fourth application vs. within target range vs. not within target range) were equal.
    Comparison groups
    ITT-AIO Week-2 v ITT-AIO Week-5
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.5637
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [1] - McNemar’s test to determine whether the row and column marginal frequencies (in a 2x2 contingency table of the first vs. fourth application vs. within target range vs. not within target range) were equal.

    Primary: Primary Endpoint in FUFOX ITT Patients

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    End point title
    		 Primary Endpoint in FUFOX ITT Patients
    End point description
    End point type
    Primary
    End point timeframe
    Between 1st and Fourth study drug administration
    End point values
    		 ITT-FUFOX-Week2 ITT-FUFOX-Week5
    Number of subjects analysed
    33
    33
    Units: Patients
    28
    27
    Statistical analysis title
    		 McNemar’s test
    Comparison groups
    ITT-FUFOX-Week2 v ITT-FUFOX-Week5
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.1336
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [2] - McNemar’s test

    Primary: Primary Endpoint in FOLFOX-6 ITT Patients

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    End point title
    		 Primary Endpoint in FOLFOX-6 ITT Patients
    End point description
    End point type
    Primary
    End point timeframe
    First to fourth application
    End point values
    		 ITT-FOLFOX6 Week 3 ITT-FOLFOX6 Week 9
    Number of subjects analysed
    26
    26
    Units: Patients
    24
    22
    Statistical analysis title
    		 McNemar’s test
    Comparison groups
    ITT-FOLFOX6 Week 9 v ITT-FOLFOX6 Week 3
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0209
    Method
    		 Mcnemar
    Confidence interval
    Notes
    [3] - McNemar’s test

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs have been assessed from first study drug administration to the End of treatment visit.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    AIO (weekly)
    Reporting group description
    		 AIO-Regimen: 5-FU 2600 mg/m². Infusion for 24 hours. Leucovorin 200 mg/m² Once weekly for 6 weeks, 2 weeks off. Continuous intravenous infusion of 5-FU for 24 hours given as a continuous infusion. Additionally the regimen can contain oxaliplatin. Either bevacizumab or cetuximab may be added to the regimens, according to local medical practice at each center.

    Reporting group title
    FUFOX (weekly)
    Reporting group description
    		 FUFOX: Oxaliplatin 60mg/m² . Infusion for 2 (-6) hours. 5FU 2000 mg/m². Infusion for 24 hours. Leucovorin 200 mg/m² Once weekly for 6 weeks, 2 weeks off Continuous intravenous infusion of 5-FU for 24 hours given as a continuous infusion. Additionally the regimen can contain oxaliplatin. Either bevacizumab or cetuximab may be added to the regimens, according to local medical practice at each center.

    Reporting group title
    FOLFOX6 (bi-weekly)
    Reporting group description
    		 Modified FOLFOX6: Oxaliplatin 85 mg/m² as Infusion for 2 (-6) hours. 5-FU 400 mg/m² on day 1 as bolus (OPTIONAL) 5-FU 2400 mg/m² Infusion for 46 hours. Leucovorin 400 mg or 400mg/m2 (the same dosing scheme should consistently be used for a patient) Repeat every 2 weeks. Either bevacizumab or cetuximab may be added to the regimen, according to local medical practice at each center.

    Serious adverse events
    		 AIO (weekly) FUFOX (weekly) FOLFOX6 (bi-weekly)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 16 (25.00%)
    13 / 33 (39.39%)
    5 / 26 (19.23%)
         number of deaths (all causes)
    2
    1
    1
         number of deaths resulting from adverse events
    2
    1
    1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Abdominal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Ulcerative keratitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 16 (0.00%)
    5 / 33 (15.15%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal fistula
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 33 (3.03%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 33 (9.09%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Device related infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic encephalopathy
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 33 (9.09%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 AIO (weekly) FUFOX (weekly) FOLFOX6 (bi-weekly)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 16 (87.50%)
    32 / 33 (96.97%)
    26 / 26 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Phlebitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Thrombosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Venous thrombosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 33 (9.09%)
    1 / 26 (3.85%)
         occurrences all number
    1
    3
    1
    Catheter site pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Chest discomfort
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Chills
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 33 (6.06%)
    1 / 26 (3.85%)
         occurrences all number
    1
    2
    1
    Discomfort
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    4 / 16 (25.00%)
    10 / 33 (30.30%)
    9 / 26 (34.62%)
         occurrences all number
    4
    10
    9
    Mucosal dryness
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Impaired healing
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    5 / 26 (19.23%)
         occurrences all number
    0
    2
    5
    Needle issue
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Oedema
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 33 (12.12%)
    5 / 26 (19.23%)
         occurrences all number
    0
    4
    6
    Swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Temperature intolerance
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Drug hypersensitivity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    2
    Dyspnoea
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    1
    Epistaxis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    5 / 26 (19.23%)
         occurrences all number
    0
    1
    5
    Oropharyngeal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Sleep disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Blood magnesium increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    Blood urine present
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet count increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Protein total decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Dysgeusia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 33 (3.03%)
    2 / 26 (7.69%)
         occurrences all number
    1
    1
    2
    Headache
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 33 (3.03%)
    3 / 26 (11.54%)
         occurrences all number
    1
    1
    3
    Mononeuropathy
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Paraesthesia
         subjects affected / exposed
    0 / 16 (0.00%)
    9 / 33 (27.27%)
    5 / 26 (19.23%)
         occurrences all number
    0
    9
    5
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 16 (0.00%)
    6 / 33 (18.18%)
    4 / 26 (15.38%)
         occurrences all number
    0
    6
    4
    Polyneuropathy
         subjects affected / exposed
    0 / 16 (0.00%)
    10 / 33 (30.30%)
    5 / 26 (19.23%)
         occurrences all number
    0
    10
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 33 (3.03%)
    2 / 26 (7.69%)
         occurrences all number
    2
    1
    2
    Granulocytopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Neutropenia
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 33 (9.09%)
    2 / 26 (7.69%)
         occurrences all number
    0
    3
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Intraocular haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 33 (6.06%)
    3 / 26 (11.54%)
         occurrences all number
    1
    2
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 33 (6.06%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    2
    chapped lips
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Cheilitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 16 (0.00%)
    9 / 33 (27.27%)
    6 / 26 (23.08%)
         occurrences all number
    0
    9
    6
    Diarrhoea
         subjects affected / exposed
    8 / 16 (50.00%)
    17 / 33 (51.52%)
    6 / 26 (23.08%)
         occurrences all number
    11
    24
    7
    Dyspepsia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    3 / 26 (11.54%)
         occurrences all number
    0
    1
    3
    Dysphagia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Eructation
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    7 / 16 (43.75%)
    21 / 33 (63.64%)
    9 / 26 (34.62%)
         occurrences all number
    9
    29
    10
    Oesophagitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 16 (6.25%)
    5 / 33 (15.15%)
    2 / 26 (7.69%)
         occurrences all number
    1
    5
    2
    Vomiting
         subjects affected / exposed
    5 / 16 (31.25%)
    12 / 33 (36.36%)
    7 / 26 (26.92%)
         occurrences all number
    6
    16
    7
    Abdominal distension
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal rigidity
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Colitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Glossodynia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    5 / 26 (19.23%)
         occurrences all number
    0
    0
    5
    Dermatitis acneiform
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    Dry skin
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    2
    Night sweats
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Papule
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    2
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
    5 / 33 (15.15%)
    3 / 26 (11.54%)
         occurrences all number
    1
    5
    4
    Urticaria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Postrenal failure
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Back pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    1
    Muscle spasms
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Candida infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    1
    Erysipelas
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Fungal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 33 (12.12%)
    0 / 26 (0.00%)
         occurrences all number
    0
    4
    0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Oral herpes
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    1
    Paronychia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Purulence
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 33 (3.03%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    2
    Neutrophil count decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 33 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 16 (18.75%)
    11 / 33 (33.33%)
    6 / 26 (23.08%)
         occurrences all number
    4
    11
    6
    Dehydration
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 33 (6.06%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 33 (12.12%)
    3 / 26 (11.54%)
         occurrences all number
    0
    6
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2012
    Changes to better reflect patient populations in clinical routine and corrective changes: 1) Inclusion criteria 10 and 12 were changed into: Patients show a sufficient hepatic and renal function to undergo 5-FU or 5-FU combination treatment, based on the investigators’ discretion and in accordance to the recommendation outlined in the SmPCs. 2) New inclusion criteria: Patients being naïve to 5-FU treatment or having received a maximum of only one treatment cycle of 5-FU without experiencing any AEs/SAEs related to the study drug. 3) The AUC limits were corrected in the tables of sections 1.4.2 and 5.1.2. 4) Wording of Primary objective was amended to take into account the changed inclusion criteria: To determine whether pharmacokinetically-guided dose adjustment of 5-FU provides a stable intrapatient dose level of 20-30 mg.h /l. The primary analysis will be the comparison of the proportion of patients with AUC within 20 to 30 mg.h/L after the first 5-FU application within the study versus the fourth application within the study. 5) The use of Leucovorin in the dosage 400mg/m² was allowed. 6) In case no 5-FU plasma concentration has been measured or no valid result has been obtained by the 5-FU measurement, the 5-FU dose in the subsequent cycle will be adapted only according to toxicity. 7) To make better use of the collected patient data and specimens, an additional purpose of use by the university of Bonn was specified.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27256667
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