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    Clinical Trial Results:
    An open-label, randomised, non-comparative phase 2 study evaluating S 95005 (TAS-102) plus bevacizumab to capecitabine plus bevacizumab in patients with previously untreated metastatic colorectal cancer who are non-eligible for intensive therapy.

    Summary
    EudraCT number
    2015-004544-18
    Trial protocol
    GB   DE   DK   NL   BE   ES   FR   IT  
    Global end of trial date
    01 Sep 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Aug 2021
    First version publication date
    21 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-95005-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02743221
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, 33 155724366, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, 33 155724366, clinicaltrials@servier.com
    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
    01 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the progression-free survival (PFS) based on investigator assessment following RECIST 1.1 in patients receiving S 95005 + bevacizumab (experimental arm) or capecitabine + bevacizumab (control arm) as first-line treatment for metastatic colorectal cancer in patients non-eligible for intensive therapy.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Netherlands: 29
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 6
    Worldwide total number of subjects
    154
    EEA total number of subjects
    104
    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)
    36
    From 65 to 84 years
    111
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    Investigators were oncologists.

    Pre-assignment
    Screening details
    Male or female patients aged ≥18 years old, with histological or cytological confirmation of adenocarcinoma of the colon or rectum, RAS status determined on tumour biopsy, with at least one measurable metastatic lesion (RECIST criteria), unresectable metastatic disease diagnosed within 6 months prior to the first study drug intake.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    S95005 + bevacizumab
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    S95005
    Investigational medicinal product code
    Other name
    Trifluridine-tipiracil
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    S95005 was administered orally twice a day ( 35 mg/m²/dose), within 1 hour after completion of morning and evening meals, 5 days on/2 days off, over 2 weeks, followed by a 14-day rest; with bevacizumab (5 mg/kg, intravenously) administered every 2 weeks (Day 1 and Day 15).

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously at 5 mg/kg at Day 1 and Day 15 of each cycle in combination with S95005.

    Arm title
    Capecitabine + bevacizumab
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered orally twice daily (1250 mg/m²) on Days 1–14 of each cycle, with bevacizumab (7.5 mg/kg, IV) administered on Day 1 of each cycle. This treatment cycle was repeated every 3 weeks. The starting dose of capecitabine could be 1000mg/m² according to local clinical practice.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered intravenously at 7.5 mg/kg on Day 1 of each cycle in combination with capecitabine.

    Number of subjects in period 1
    S95005 + bevacizumab Capecitabine + bevacizumab
    Started
    77
    77
    Completed
    0
    0
    Not completed
    77
    77
         Progressive disease
    47
    50
         Protocol deviation
    1
    -
         non-medical reason
    8
    3
         Physician decision
    3
    6
         Adverse event, non-fatal
    18
    17
         Randomised (enrolled) but not treated
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    S95005 + bevacizumab
    Reporting group description
    -

    Reporting group title
    Capecitabine + bevacizumab
    Reporting group description
    -

    Reporting group values
    S95005 + bevacizumab Capecitabine + bevacizumab Total
    Number of subjects
    77 77 154
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    20 16 36
        From 65-84 years
    57 54 111
        85 years and over
    0 7 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.8 ± 10.2 72.8 ± 11.0 -
    Gender categorical
    Units: Subjects
        Female
    37 29 66
        Male
    40 48 88

    End points

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    End points reporting groups
    Reporting group title
    S95005 + bevacizumab
    Reporting group description
    -

    Reporting group title
    Capecitabine + bevacizumab
    Reporting group description
    -

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    Tumour assessments were performed by the investigator based on Response Evaluation Criteria in Solid Tumours (RECIST version 1.1, 2009) every 8 weeks until the progression of the disease, death or initiation of new anticancer treatment (whichever occurred first).
    End point type
    Primary
    End point timeframe
    PFS was defined as the time from the date of randomisation until the date of PFS event i.e. radiological disease progression or death due to any cause.
    End point values
    S95005 + bevacizumab Capecitabine + bevacizumab
    Number of subjects analysed
    77
    76
    Units: Number of PFS events
    48
    52
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    The primary analysis was conducted after having reached 100 PFS events.
    Comparison groups
    S95005 + bevacizumab v Capecitabine + bevacizumab
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.06
    Notes
    [1] - This study was a non-comparative study in order to optimize the design of the Phase 3 confirmatory study. The PFS hazard ratio was estimated using the Cox proportional hazard model adjusting for the stratification factors (RAS status, ECOG status).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred or worsened or became serious between the first or bevacizumab intake and the last IMP intake + 35 days (both included).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    S 95005 + bevacizumab
    Reporting group description
    -

    Reporting group title
    Capecitabine + bevacizumab
    Reporting group description
    -

    Serious adverse events
    S 95005 + bevacizumab Capecitabine + bevacizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 77 (66.23%)
    45 / 76 (59.21%)
         number of deaths (all causes)
    66
    66
         number of deaths resulting from adverse events
    2
    2
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 77 (0.00%)
    4 / 76 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    13 / 77 (16.88%)
    16 / 76 (21.05%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 16
         deaths causally related to treatment / all
    0 / 12
    0 / 16
    Metastases to peritoneum
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to spine
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    General physical health deterioration
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza like illness
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal dryness
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    0 / 77 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood calcium decreased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         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
    3 / 77 (3.90%)
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         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
    4 / 77 (5.19%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 77 (3.90%)
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 77 (5.19%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (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
    2 / 77 (2.60%)
    6 / 76 (7.89%)
         occurrences causally related to treatment / all
    2 / 2
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erosive oesophagitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal vascular malformation haemorrhagic
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 77 (3.90%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Malignant gastrointestinal obstruction
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 77 (3.90%)
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Renal failure
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 77 (3.90%)
    5 / 76 (6.58%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia toxoplasmal
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 76 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    S 95005 + bevacizumab Capecitabine + bevacizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 77 (97.40%)
    69 / 76 (90.79%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 77 (12.99%)
    9 / 76 (11.84%)
         occurrences all number
    12
    11
    Hypotension
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences all number
    5
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    7 / 77 (9.09%)
    4 / 76 (5.26%)
         occurrences all number
    7
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 77 (18.18%)
    18 / 76 (23.68%)
         occurrences all number
    20
    23
    Fatigue
         subjects affected / exposed
    30 / 77 (38.96%)
    23 / 76 (30.26%)
         occurrences all number
    51
    34
    Influenza like illness
         subjects affected / exposed
    6 / 77 (7.79%)
    3 / 76 (3.95%)
         occurrences all number
    6
    4
    Pyrexia
         subjects affected / exposed
    5 / 77 (6.49%)
    4 / 76 (5.26%)
         occurrences all number
    5
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 77 (7.79%)
    2 / 76 (2.63%)
         occurrences all number
    6
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 77 (7.79%)
    5 / 76 (6.58%)
         occurrences all number
    6
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 77 (11.69%)
    2 / 76 (2.63%)
         occurrences all number
    11
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 77 (10.39%)
    3 / 76 (3.95%)
         occurrences all number
    9
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 77 (6.49%)
    2 / 76 (2.63%)
         occurrences all number
    7
    2
    Blood bilirubin increased
         subjects affected / exposed
    6 / 77 (7.79%)
    10 / 76 (13.16%)
         occurrences all number
    21
    27
    Blood creatinine increased
         subjects affected / exposed
    5 / 77 (6.49%)
    1 / 76 (1.32%)
         occurrences all number
    6
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 76 (5.26%)
         occurrences all number
    8
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 77 (7.79%)
    1 / 76 (1.32%)
         occurrences all number
    7
    1
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 77 (6.49%)
    1 / 76 (1.32%)
         occurrences all number
    8
    2
    Neutrophil count decreased
         subjects affected / exposed
    19 / 77 (24.68%)
    1 / 76 (1.32%)
         occurrences all number
    131
    1
    Platelet count decreased
         subjects affected / exposed
    7 / 77 (9.09%)
    4 / 76 (5.26%)
         occurrences all number
    30
    6
    Weight decreased
         subjects affected / exposed
    13 / 77 (16.88%)
    7 / 76 (9.21%)
         occurrences all number
    16
    8
    White blood cell count decreased
         subjects affected / exposed
    15 / 77 (19.48%)
    1 / 76 (1.32%)
         occurrences all number
    39
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 77 (3.90%)
    8 / 76 (10.53%)
         occurrences all number
    3
    9
    Dysphonia
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences all number
    6
    1
    Dyspnoea
         subjects affected / exposed
    6 / 77 (7.79%)
    8 / 76 (10.53%)
         occurrences all number
    6
    13
    Epistaxis
         subjects affected / exposed
    4 / 77 (5.19%)
    4 / 76 (5.26%)
         occurrences all number
    7
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 77 (29.87%)
    5 / 76 (6.58%)
         occurrences all number
    36
    7
    Anaemia of malignant disease
         subjects affected / exposed
    5 / 77 (6.49%)
    1 / 76 (1.32%)
         occurrences all number
    5
    2
    Leukopenia
         subjects affected / exposed
    6 / 77 (7.79%)
    2 / 76 (2.63%)
         occurrences all number
    9
    7
    Neutropenia
         subjects affected / exposed
    41 / 77 (53.25%)
    6 / 76 (7.89%)
         occurrences all number
    253
    11
    Thrombocytopenia
         subjects affected / exposed
    12 / 77 (15.58%)
    4 / 76 (5.26%)
         occurrences all number
    25
    5
    Thrombocytosis
         subjects affected / exposed
    4 / 77 (5.19%)
    0 / 76 (0.00%)
         occurrences all number
    8
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 77 (9.09%)
    9 / 76 (11.84%)
         occurrences all number
    9
    11
    Dysgeusia
         subjects affected / exposed
    6 / 77 (7.79%)
    6 / 76 (7.89%)
         occurrences all number
    7
    6
    Headache
         subjects affected / exposed
    7 / 77 (9.09%)
    4 / 76 (5.26%)
         occurrences all number
    13
    4
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 77 (0.00%)
    4 / 76 (5.26%)
         occurrences all number
    0
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 77 (14.29%)
    6 / 76 (7.89%)
         occurrences all number
    22
    7
    Constipation
         subjects affected / exposed
    13 / 77 (16.88%)
    15 / 76 (19.74%)
         occurrences all number
    22
    17
    Diarrhoea
         subjects affected / exposed
    41 / 77 (53.25%)
    32 / 76 (42.11%)
         occurrences all number
    95
    65
    Dry mouth
         subjects affected / exposed
    2 / 77 (2.60%)
    6 / 76 (7.89%)
         occurrences all number
    2
    7
    Dyspepsia
         subjects affected / exposed
    6 / 77 (7.79%)
    2 / 76 (2.63%)
         occurrences all number
    7
    2
    Nausea
         subjects affected / exposed
    38 / 77 (49.35%)
    13 / 76 (17.11%)
         occurrences all number
    127
    23
    Proctalgia
         subjects affected / exposed
    4 / 77 (5.19%)
    4 / 76 (5.26%)
         occurrences all number
    7
    4
    Stomatitis
         subjects affected / exposed
    14 / 77 (18.18%)
    16 / 76 (21.05%)
         occurrences all number
    19
    30
    Vomiting
         subjects affected / exposed
    23 / 77 (29.87%)
    9 / 76 (11.84%)
         occurrences all number
    84
    9
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    5 / 77 (6.49%)
    7 / 76 (9.21%)
         occurrences all number
    6
    12
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 77 (2.60%)
    6 / 76 (7.89%)
         occurrences all number
    3
    11
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 77 (23.38%)
    0 / 76 (0.00%)
         occurrences all number
    18
    0
    Dry skin
         subjects affected / exposed
    4 / 77 (5.19%)
    4 / 76 (5.26%)
         occurrences all number
    4
    4
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 77 (3.90%)
    39 / 76 (51.32%)
         occurrences all number
    4
    54
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 77 (9.09%)
    3 / 76 (3.95%)
         occurrences all number
    9
    4
    Back pain
         subjects affected / exposed
    7 / 77 (9.09%)
    6 / 76 (7.89%)
         occurrences all number
    10
    6
    Myalgia
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 76 (5.26%)
         occurrences all number
    2
    5
    Pain in extremity
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences all number
    4
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 77 (37.66%)
    15 / 76 (19.74%)
         occurrences all number
    49
    23
    Hyperkalaemia
         subjects affected / exposed
    5 / 77 (6.49%)
    0 / 76 (0.00%)
         occurrences all number
    7
    0
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 77 (5.19%)
    2 / 76 (2.63%)
         occurrences all number
    4
    2
    Hypomagnesaemia
         subjects affected / exposed
    4 / 77 (5.19%)
    2 / 76 (2.63%)
         occurrences all number
    4
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 77 (10.39%)
    5 / 76 (6.58%)
         occurrences all number
    10
    5
    Oral herpes
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 76 (5.26%)
         occurrences all number
    1
    4
    Rhinitis
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 76 (1.32%)
         occurrences all number
    4
    1
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 77 (10.39%)
    3 / 76 (3.95%)
         occurrences all number
    13
    3
    Urinary tract infection
         subjects affected / exposed
    10 / 77 (12.99%)
    5 / 76 (6.58%)
         occurrences all number
    15
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2016
    ­Update of study duration: selection stopped after the primary endpoint has been reached (100 PFS event) or after the randomization of 150 patients. Update of inclusion/non-inclusion criteria. Update of prohibited medications (sorivudine or its analogues) and therapies (palliative radiotherapy allowed).
    25 Jan 2017
    The main objective of this amendment was to implement the urgent safety measures which aimed to revise the instructions given in the study protocol for the dose modifications for S95005 in case of febrile neutropenia to be in line with the European SmPCs of Lonsurf® which had been approved by the European Commission at the time of medicine registration in the European Union on 25 April 2016.
    29 Jan 2019
    The definition of end of study was revised as last treatment withdrawal visit.

    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.
    Due to the exceptional circumstances in relation to the COVID-19 pandemic, the Sponsor decided in accordance with competent regulatory authorities’ guidelines to implement some precautionary measures in order to mitigate the risk of infection.
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