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    Clinical Trial Results:
    Multicentric randomized phase III trial comparing 6-month adjuvant chemotherapy with gemcitabine versus 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFolfirinox) in patients with resected pancreatic adenocarcinoma.

    Summary
    EudraCT number
    		 2011-002026-52
    Trial protocol
    		 FR  
    Global end of trial date
    16 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Nov 2023
    First version publication date
    04 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UC 0110/1006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01526135
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France, 75013
    Public contact
    Nourredine AIT RAHMOUNE , UNICANCER, 33 0171936704, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT RAHMOUNE , UNICANCER, 33 0171936704, n.ait-rahmoune@unicancer.fr
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare disease-free survival (DFS) at 3 years between the experimental (mFOLFIRINOX) and control arms (gemcitabine).
    Protection of trial subjects
    This study was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice (GCP) Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable local regulatory requirements and laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Apr 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 400
    Country: Number of subjects enrolled
    Canada: 93
    Worldwide total number of subjects
    493
    EEA total number of subjects
    400
    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)
    306
    From 65 to 84 years
    187
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The Prodige 24 – Accord 24 study randomized 493 patients between 16-Apr-2012 and the 03-Oct-2016: 400 patients in France and 93 in Canada. Overall, 85 centers were initiated of which 77 included patients: 58 centers in France and 19 in Canada.

    Pre-assignment
    Screening details
    		 The study consisted of a screening phase before randomization to establish eligibility. The maximum duration of treatment in both study arms was 6 months, and a long-term follow-up. The endpoint evaluated (DFS, OS, specific survival, MFS, and safety according to NCI CTCAE v4.0).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Gemcitabine
    Arm description
    		 Standard treatment: Gemcitabine (1000 mg/m² ) was administered intravenously over 30 min, once weekly for three weeks followed by one week of rest (one 4-week treatment cycle = 3 weeks of gemcitabine administered weekly then one week of rest). Treatment duration was planned for 6 cycles (24 weeks).
    Arm type
    		 Standard

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Gemcitabine (1000 mg/m²) was administered intravenously over 30 min, once weekly for three weeks followed by one week of rest (one 4-week treatment cycle = 3 weeks of gemcitabine administered weekly then one week of rest). Treatment duration was planned for 6 cycles (24 weeks).

    Arm title
    		 mFOLFIRINOX
    Arm description
    		 Experimental treatment: mFOLFIRINOX administered as 2-week cycles. On day (D)1 of each cycle, oxaliplatin (85 mg/m2 ) was administered by IV infusion over 2 h. Followed by racemic folinic acid/leucovorin (400 mg/m2 ) or L-folinic acid (200 mg/m2 ) as a 2-h IV infusion. After 30 min of the folinic acid infusion, irinotecan (180 mg/m2 ) was infused intravenously, via a Y-connector, over 90 min. This was followed by a continuous infusion over 46 h of 5-FU (2400 mg/m2). The starting dose of irinotecan was reduced to 150 mg/m2 during after a planned safety analysis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin (Eloxatin®) 85 mg/m² D1 over 2 hours.

    Investigational medicinal product name
    rinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Irinotecan (Campto®) 180 mg/m²/150 mg/m² (on D1 over 90 min to begin 30 min after starting the folinic acid infusion.). The initial irinotecan dose was reduced from 180 mg/m2 to 150 mg/m² following the IDMC held on the 12-Mar-2014. The protocol was modified by amendment N°7

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-FU 2.4 g/m² IV continuous infusion over 48 hours (1200 mg/m²/ day).

    Investigational medicinal product name
    Folinic acid (racemate) or Lfolinic acid (enantiomer)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    400 mg/m2 (racemate) or 200 mg/m2 (enantiomer) (IV infusion over 2 h).

    Number of subjects in period 1
    		Gemcitabine mFOLFIRINOX
    Started
    246
    247
    Completed
    192
    158
    Not completed
    54
    89
         Relapse
    26
    15
         Physician decision
    2
    7
         Patient decision
    2
    13
         Toxicity
    11
    21
         Intercurrent disease
    2
    1
         Wrongly inclusion
    -
    2
         Missing data
    8
    21
         Patients randomized but not treated
    3
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Gemcitabine
    Reporting group description
    		 Standard treatment: Gemcitabine (1000 mg/m² ) was administered intravenously over 30 min, once weekly for three weeks followed by one week of rest (one 4-week treatment cycle = 3 weeks of gemcitabine administered weekly then one week of rest). Treatment duration was planned for 6 cycles (24 weeks).

    Reporting group title
    mFOLFIRINOX
    Reporting group description
    		 Experimental treatment: mFOLFIRINOX administered as 2-week cycles. On day (D)1 of each cycle, oxaliplatin (85 mg/m2 ) was administered by IV infusion over 2 h. Followed by racemic folinic acid/leucovorin (400 mg/m2 ) or L-folinic acid (200 mg/m2 ) as a 2-h IV infusion. After 30 min of the folinic acid infusion, irinotecan (180 mg/m2 ) was infused intravenously, via a Y-connector, over 90 min. This was followed by a continuous infusion over 46 h of 5-FU (2400 mg/m2). The starting dose of irinotecan was reduced to 150 mg/m2 during after a planned safety analysis.

    Reporting group values
    		 Gemcitabine mFOLFIRINOX Total
    Number of subjects
    		 246 247 493
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 147 159 306
        From 65-84 years
    		 99 88 187
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (30 to 81) 63 (30 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 111 105 216
        Male
    		 135 142 277
    ECOG PS
    Units: Subjects
        ECOG 0
    		 127 122 249
        ECOG 1
    		 115 123 238
        Missing data
    		 4 2 6
    Tumor location
    Units: Subjects
        Head
    		 166 188 354
        Head except hook
    		 9 5 14
        Hook
    		 5 3 8
        Isthmus
    		 5 5 10
        Body
    		 15 13 28
        Tail
    		 29 21 50
        Other
    		 13 11 24
        Missing
    		 4 1 5
    Dealy from primary tumour diagnosis to randomisation
    Units: Months
        median (full range (min-max))
    		 1.6 (0.3 to 6.1) 1.6 (0.1 to 2.9) -
    Time between surgery and inclusion
    Units: Months
        median (full range (min-max))
    		 1.8 (0.7 to 3.1) 1.8 (0.8 to 2.9) -

    End points

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    End points reporting groups
    Reporting group title
    Gemcitabine
    Reporting group description
    		 Standard treatment: Gemcitabine (1000 mg/m² ) was administered intravenously over 30 min, once weekly for three weeks followed by one week of rest (one 4-week treatment cycle = 3 weeks of gemcitabine administered weekly then one week of rest). Treatment duration was planned for 6 cycles (24 weeks).

    Reporting group title
    mFOLFIRINOX
    Reporting group description
    		 Experimental treatment: mFOLFIRINOX administered as 2-week cycles. On day (D)1 of each cycle, oxaliplatin (85 mg/m2 ) was administered by IV infusion over 2 h. Followed by racemic folinic acid/leucovorin (400 mg/m2 ) or L-folinic acid (200 mg/m2 ) as a 2-h IV infusion. After 30 min of the folinic acid infusion, irinotecan (180 mg/m2 ) was infused intravenously, via a Y-connector, over 90 min. This was followed by a continuous infusion over 46 h of 5-FU (2400 mg/m2). The starting dose of irinotecan was reduced to 150 mg/m2 during after a planned safety analysis.

    Primary: Disease-free survival (DFS)

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    End point title
    		 Disease-free survival (DFS)
    End point description
    Disease free survival (DFS) is defined as the interval between randomization and the occurrence of the first observed oncologic event, such as, local, metastatic recurrence, second cancer, or death from any cause. Patients without event at the time of analysis will be censored on the date of the last informative follow-up.
    End point type
    Primary
    End point timeframe
    3 years after randomization.
    End point values
    		 Gemcitabine mFOLFIRINOX
    Number of subjects analysed
    246
    247
    Units: Months
        median (confidence interval 95%)
    12.8 (11.7 to 15.2)
    21.6 (17.7 to 27.6)
    Statistical analysis title
    		 DFS analysis
    Comparison groups
    mFOLFIRINOX v Gemcitabine
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.73

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival is the time delay between the date of randomization and the patient’s death, irrespective of its cause. Patients who are still living at the time of analysis will be censored at the date of last follow-up visit.
    End point type
    Secondary
    End point timeframe
    From randomisation to death, up to 5 years.
    End point values
    		 Gemcitabine mFOLFIRINOX
    Number of subjects analysed
    246
    247
    Units: Months
        median (confidence interval 95%)
    35.5 (30.1 to 40.3)
    53.5 (43.5 to 58.4)
    Statistical analysis title
    		 OS analysis
    Comparison groups
    Gemcitabine v mFOLFIRINOX
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.85
    Variability estimate
    Standard deviation

    Secondary: Specific survival

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    End point title
    		 Specific survival
    End point description
    Specific survival is the time delay between the date of randomization and the patient’s death due to the treated cancer or a treatment-related complication.
    End point type
    Secondary
    End point timeframe
    From randomisation to death, up to 5 years.
    End point values
    		 Gemcitabine mFOLFIRINOX
    Number of subjects analysed
    246
    247
    Units: Months
        median (confidence interval 95%)
    36.3 (30.5 to 43.9)
    54.7 (45.8 to 68.4)
    Statistical analysis title
    		 Specific survival analysis
    Comparison groups
    Gemcitabine v mFOLFIRINOX
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.82

    Secondary: Metastasis-free survival (MFS)

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    End point title
    		 Metastasis-free survival (MFS)
    End point description
    Metastasis-free survival is the time delay between the date of randomization and the date of the 1st distant event occurrence (peritoneal, hepatic, pulmonary, and lymph nodes). Loco-regional progression were not considered as events. Patients still living without metastasis at the time of analysis were to be censored at the date of last follow-up examination objectively assessing this type of event.
    End point type
    Secondary
    End point timeframe
    36 Months
    End point values
    		 Gemcitabine mFOLFIRINOX
    Number of subjects analysed
    246
    247
    Units: Months
        median (confidence interval 95%)
    17.7 (14.0 to 21.2)
    29.4 (21.4 to 40.1)
    Statistical analysis title
    		 MFS analysis
    Comparison groups
    Gemcitabine v mFOLFIRINOX
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.8
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion until 30 days after end of treatment (up to 5 years).
    Adverse event reporting additional description
    Only subjects affected number is available. in the table of value for non serious AE only subjects affected number is reported ( Occurences not available).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    Gemcitabine
    Reporting group description
    		 -

    Reporting group title
    mFOLFIRINOX
    Reporting group description
    		 -

    Serious adverse events
    		 Gemcitabine mFOLFIRINOX
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 246 (23.58%)
    92 / 247 (37.25%)
         number of deaths (all causes)
    114
    92
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melanoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal cancer
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary carcinoma
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    catheter thrombosis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    femoral artery thrombosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischemic stroke
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischemic attack
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Anasarca
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 246 (0.00%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug delivery system malfunction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Edema
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 246 (0.81%)
    3 / 247 (1.21%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema lower limb
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media reaction
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug allergy
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    dyspnea
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial pneumonitis
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight loss
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Biliary anastomosis complication
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site extravasation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leg injury
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perforation of anastomosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Fahr's disease
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary spasm
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non ST segment elevation myocardial infarction
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholinergic syndrome
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysesthesia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epileptic seizure
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy
         subjects affected / exposed
    0 / 246 (0.00%)
    5 / 247 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresthesia
         subjects affected / exposed
    0 / 246 (0.00%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory peripheral neuropathy
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tongue paralysis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasovagal reaction
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 246 (1.22%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplasia bone marrow
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile aplasia
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 246 (1.22%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 246 (1.63%)
    6 / 247 (2.43%)
         occurrences causally related to treatment / all
    4 / 4
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenic purpura
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    2 / 246 (0.81%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic ulcer
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel obstruction
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 246 (0.41%)
    12 / 247 (4.86%)
         occurrences causally related to treatment / all
    1 / 1
    13 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bleeding
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 246 (0.00%)
    5 / 247 (2.02%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroparesis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemorrhoidal crisis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypogastric pain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    4 / 246 (1.63%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic abscess
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein-losing gastroenteropathy
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sigmoiditis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subocclusive syndrome
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper gastrointestinal bleeding
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    hepatic function disorder
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Icterus
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute renal failure
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    calf pain
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cervical pain
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis fracture
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteremia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial translocation
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia coli infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection pseudomonas aeruginosa
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pneumonitis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nocardiosis
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis perforative
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    shock septic
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serratia infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylodiscitis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus epidermidis infection
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary infection
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pericarditis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound abscess
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 246 (0.41%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia coli bacteremia
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 246 (0.41%)
    4 / 247 (1.62%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Edema generalized
         subjects affected / exposed
    1 / 246 (0.41%)
    0 / 247 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 246 (0.00%)
    2 / 247 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of control of diabetes
         subjects affected / exposed
    0 / 246 (0.00%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    2 / 246 (0.81%)
    1 / 247 (0.40%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Gemcitabine mFOLFIRINOX
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    246 / 246 (100.00%)
    247 / 247 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other-neoplasms
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Vascular disorders
    Hypotension
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Thrombosis/embolism
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Hypertension
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-vascular disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Surgical and medical procedures
    Other-surgical procedures
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Fever
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Quincke edema
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Local reaction at the site of injection
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Edema
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Chills
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Flu-like symptoms
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Pain
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-general disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Reproductive system and breast disorders
    Other-reproductive disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Cough
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Dyspnea
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-respiratory disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Anxiety
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Depression
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-psychiatric disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-injury
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Pericarditis
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Chest pain
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-cardiac disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Dysguesia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Motor neuropathy
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Paresthesia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Sensory peripheral neuropathy
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Somnolence
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Headache
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Dysesthesia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Cholinergic syndrome
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Tremor
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-nervous disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Anaemia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hyperleucocytosis
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-blood
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Ear and labyrinth disorders
    Hearing
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Tinnitus
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-ear disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Blurry vision
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-eye disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Constipation
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Diarrhea
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Mucositis
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Nausea
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Vomiting
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Dyspepsia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Flatulence/bloating
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hemorrhoids
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Gastro-esophageal reflux
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Epigastric pain
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Stearrhea
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Dysphagia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Xerostomia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-gastrointestinal disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Cutaneous hyperpigmentation
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Hand-foot cutaneous reaction
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Pruritus
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Rash (redness)
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Rash/desquamation
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Sweating
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Folliculitis
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Erythema
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-cutaneous disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Renal and urinary disorders
    Nycturia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Proteinuria
         subjects affected / exposed
    229 / 246 (93.09%)
    219 / 247 (88.66%)
         occurrences all number
    229
    219
    Other-urinary disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Back pain
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Myalgia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Pain in extremity
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Shoulder pain
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Neck pain
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Bone pain
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-musculoskeletal disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Infections and infestations
    Fissures/ulceration
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Infection without neutropenia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Local infections
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Paronychia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Bronchitis/sinusitis/rhinitis
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Urinary infection
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Abscess
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-infections
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    241 / 246 (97.97%)
    237 / 247 (95.95%)
         occurrences all number
    241
    237
    Hyperglycemia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hypoglycemia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Diabetes
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Glucose intolerance
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hypokalemia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hyperkalemia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hypoalbuminemia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hypocalcemia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hypomagnesemia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hyponatremia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Hypernatremia
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237
    Other-metabolism disorders
         subjects affected / exposed
    242 / 246 (98.37%)
    237 / 247 (95.95%)
         occurrences all number
    242
    237

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2012
    -Change of the trial sponsor from the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) to UNICANCER.
    05 Jan 2012
    -Modification of the investigators list.
    03 Jul 2012
    -Clarification of the study protocol. -Modification of the investigators list.
    06 Nov 2012
    -Modification of the investigators list.
    06 May 2013
    -Clarification and correction of the protocol -Change in the project leader from Beata JUZYNA to Trevor STANBURY -Change in the name of the statistical unit from CRLC Val d’Aurelle Unité de Biostatistiques CTD INCa to Institut Régional Montpellier du Cancer Montpellier/Val d’Aurelle (ICM), with the subsequent change of the email address of the statistician. -Modification of the investigators list.
    08 Oct 2013
    -Modification of the investigators list.
    07 Oct 2014
    -Modification of the irinotecan dose from 180 mg/m2 to 150 mg/m2. An interim analysis after the inclusion of 30 patients in the mFOLFIRINOX. If the rate of diarrhea (grade 3-4) 5% the dose of irinotecan would be reduced to 150 mg/m2. Thus, following an IDMC held on the 12-Mar-2014, the protocol was modified to reduce the dose of irinotecan to 150 mg/m2. -Modification of the inclusion criterion N°11, concerning the allowed interval from surgery to initiation of adjuvant chemotherapy. The interval was initially 21 and 70 days and extended to between 21 and 84 days. The publication by Valle et al. showed that the interval from surgery had no impact on the efficacy of adjuvant chemotherapy for treating patients with pancreatic cancer. -Removal of the recommendation for the use of calcium gluconate and magnesium sulfate to prevent oxaliplatin-induced neurotoxicity. A publication by Loprinzi et al. reported that these treatments were not effective in preventing neurotoxicity in colon cancer patients receiving oxaliplatin . -Modification of the contact details. -Modification of the investigators list.
    07 Apr 2015
    -Prolongation of the inclusion period by two years (from 3 years to 5 years). -Correction of errors in the protocol. -Modification of the investigators list.
    02 Feb 2016
    -Modification of the investigators list.

    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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