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    Clinical Trial Results:
    Phase III international, randomized study of Trabectedin plus Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin plus PLD in patients with ovarian cancer progressing within 6-12 months of last platinum

    Summary
    EudraCT number
    		 2010-022949-17
    Trial protocol
    		 IT   GB   FI   BE   NL   DK   DE   ES   AT   NO  
    Global end of trial date
    09 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Sep 2022
    First version publication date
    15 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ET-D-009-10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Istituto di Ricerche Farmacologiche Mario Negri IRCCS
    Sponsor organisation address
    Via Mario Negri 2, Milan, Italy, 20156
    Public contact
    Eliana Rulli, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 0039 0239014645, eliana.rulli@marionegri.it
    Scientific contact
    Eliana Rulli, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 0039 0239014645, eliana.rulli@marionegri.it
    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
    09 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the combination of trabectedin (Yondelis®) and pegylated liposomal doxorubicin (PLD) prolongs overall survival (OS) over carboplatin and PLD in patients with relapsed ovarian cancer progressing within 6-12 months after end of last platinum.
    Protection of trial subjects
    NA
    Background therapy
    		 In both arms PLD was administered as background therapy
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2014
    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
    Netherlands: 24
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Spain: 108
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Austria: 22
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Finland: 25
    Country: Number of subjects enrolled
    Germany: 58
    Country: Number of subjects enrolled
    Italy: 283
    Country: Number of subjects enrolled
    Switzerland: 42
    Worldwide total number of subjects
    617
    EEA total number of subjects
    550
    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)
    330
    From 65 to 84 years
    285
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The randomization started in Dec2011 but had to be put onto temporary hold just a month later (with one patient randomized) due to the worldwide shortage of PLD. AIFA approved the study restart on Aug 2013 whereas the Central EC approved the study restart on Sept 2013. Patients’ accrual recommenced on Jan 8th 2014 and ended on Sept18th 2017.

    Pre-assignment
    Screening details
    		 NA

    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
    		 ARM A: Carboplatin+PLD
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    PLD 30 mg/m² i.v. as a 1-hour infusion followed by carboplatin AUC 5 i.v. as a 30 min infusion on Day 1 every 4 weeks. A 4-week schedule defines a cycle of treatment

    Arm title
    		 ARM B: Trabectedin+PLD
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    trabectedin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    PLD 30 mg/m2 i.v. infusion immediately followed by trabectedin 1.1 mg/m2 3-hour i.v. infusion on Day 1 every 3 weeks. A 3-week schedule defines a cycle of treatment.

    Number of subjects in period 1
    		ARM A: Carboplatin+PLD ARM B: Trabectedin+PLD
    Started
    306
    311
    Completed
    306
    311

    Baseline characteristics

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

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 617 617
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 330 330
        From 65-84 years
    		 285 285
        85 years and over
    		 2 2
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 64 (55 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 617 617
    Subject analysis sets

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    the ITT analysis set included all subjets who provided informed consent and were randomized to either carboplatin+PLD arm or trabectedin+PLD arm, without major deviations of the eligibility criteria. Subjects were considered in the randomization arm regardless of the treatment they received.

    Subject analysis set title
    safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    the Safety Analysis Set included all subjects of ITT analysis set who received at least one dose of treatment. Subjects were considered in the arm of the treatment they actually received.

    Subject analysis sets values
    		 Intention to treat safety analysis set
    Number of subjects
    611
    598
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    327
    317
        From 65-84 years
    282
    279
        85 years and over
    2
    2
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    64 (55 to 71)
    64 (55 to 71)
    Gender categorical
    Units: Subjects
        Female

    End points

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    End points reporting groups
    Reporting group title
    ARM A: Carboplatin+PLD
    Reporting group description
    		 -

    Reporting group title
    ARM B: Trabectedin+PLD
    Reporting group description
    		 -

    Subject analysis set title
    Intention to treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    the ITT analysis set included all subjets who provided informed consent and were randomized to either carboplatin+PLD arm or trabectedin+PLD arm, without major deviations of the eligibility criteria. Subjects were considered in the randomization arm regardless of the treatment they received.

    Subject analysis set title
    safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    the Safety Analysis Set included all subjects of ITT analysis set who received at least one dose of treatment. Subjects were considered in the arm of the treatment they actually received.

    Primary: overall survival

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    End point title
    		 overall survival
    End point description
    End point type
    Primary
    End point timeframe
    from randomization to death or end of trial
    End point values
    		 ARM A: Carboplatin+PLD ARM B: Trabectedin+PLD Intention to treat
    Number of subjects analysed
    304
    307
    611
    Units: patients
    231
    240
    471
    Statistical analysis title
    		 overall survival
    Comparison groups
    ARM A: Carboplatin+PLD v ARM B: Trabectedin+PLD
    Number of subjects included in analysis
    611
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.35
    Notes
    [1] - For the primary analysis, OS between treatment arms will be compared by the log-rank test. Cox regression will be used to calculate the risk reduction and to evaluate the influence of the randomization variables and other potential prognostic factors on the time to event endpoint.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from informed consent signature until 30 days after the last administration of study treatments
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Carboplatin + PLD

    Reporting group title
    Arm B
    Reporting group description
    		 Trabectedin + PLD

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    66 / 294 (22.45%)
    130 / 304 (42.76%)
         number of deaths (all causes)
    228
    238
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant bowel obstruction
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ascites
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites, pyrexia, pancytopenia, deep vein thrombosis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Metastasis to lung, pharyngitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         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 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 294 (0.34%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 294 (0.68%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Portacath insertion
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent placement
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (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
    Obstruction
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia, vomiting
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 294 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    1 / 294 (0.34%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue, cachexia, hepatic enzyme increased
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 294 (1.02%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflamation
         subjects affected / exposed
    1 / 294 (0.34%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 294 (0.34%)
    8 / 304 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Infusion related reaction
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia, asthenia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchospasm
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 294 (0.00%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 294 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 294 (0.68%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion, pulmonary embolism
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 294 (0.00%)
    6 / 304 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 294 (0.34%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram ST segment elevation
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting, phlebitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 294 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         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
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular systolic dysfunction
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain chest
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         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 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    1 / 294 (0.34%)
    12 / 304 (3.95%)
         occurrences causally related to treatment / all
    1 / 1
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis, pancytopenia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia, stomatitis, platelet count decreased
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia, anaemia, otitis media
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 294 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 294 (0.00%)
    6 / 304 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia, anaemia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia, thrombocytopenia
         subjects affected / exposed
    1 / 294 (0.34%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 294 (0.68%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia, pyrexia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsisClostridium difficile infection Pancytopenia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 294 (1.36%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    7 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased, febrile neutropenia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain, decreased appetite
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    6 / 294 (2.04%)
    8 / 304 (2.63%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain, ileal obstruction, constipation
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Pancreatitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 294 (0.68%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel obstruction
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowel occlusion
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 294 (0.68%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    2 / 294 (0.68%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (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
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileus
         subjects affected / exposed
    4 / 294 (1.36%)
    4 / 304 (1.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    8 / 294 (2.72%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal occlusion
         subjects affected / exposed
    0 / 294 (0.00%)
    4 / 304 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal perforation
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 294 (0.00%)
    6 / 304 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea, asthenia, decreased appetite
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea, vomiting
         subjects affected / exposed
    1 / 294 (0.34%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea, vomiting, constipation
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea, vomiting, constipation, abdominal pain
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea, vomiting, hyponatraemia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occlusion
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis, nausea, vomiting
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (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 / 294 (0.34%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subileus
         subjects affected / exposed
    2 / 294 (0.68%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 294 (0.34%)
    10 / 304 (3.29%)
         occurrences causally related to treatment / all
    1 / 1
    10 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting, fatigue
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders, vomiting, pyrexia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased Bilirubin, neutropenia, thrombocytopenia, anemia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea, hypertransaminasaemia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia, back pain
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc compression
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 294 (0.34%)
    5 / 304 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 294 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes simplex
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 294 (0.00%)
    6 / 304 (1.97%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 304 (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 / 294 (0.34%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Shock septic
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hyponatremia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    251 / 294 (85.37%)
    262 / 304 (86.18%)
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    10 / 294 (3.40%)
    16 / 304 (5.26%)
         occurrences all number
    16
    22
    Neuropathy
         subjects affected / exposed
    41 / 294 (13.95%)
    39 / 304 (12.83%)
         occurrences all number
    44
    45
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    84 / 294 (28.57%)
    72 / 304 (23.68%)
         occurrences all number
    136
    123
    Thrombocytopenia
         subjects affected / exposed
    72 / 294 (24.49%)
    41 / 304 (13.49%)
         occurrences all number
    152
    71
    Leukopenia
         subjects affected / exposed
    40 / 294 (13.61%)
    44 / 304 (14.47%)
         occurrences all number
    86
    102
    Neutropenia
         subjects affected / exposed
    112 / 294 (38.10%)
    156 / 304 (51.32%)
         occurrences all number
    307
    373
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    61 / 294 (20.75%)
    74 / 304 (24.34%)
         occurrences all number
    115
    136
    Fatigue
         subjects affected / exposed
    77 / 294 (26.19%)
    74 / 304 (24.34%)
         occurrences all number
    102
    124
    Mucosal inflammation
         subjects affected / exposed
    25 / 294 (8.50%)
    31 / 304 (10.20%)
         occurrences all number
    38
    54
    Oedema
         subjects affected / exposed
    9 / 294 (3.06%)
    16 / 304 (5.26%)
         occurrences all number
    11
    21
    Pain
         subjects affected / exposed
    17 / 294 (5.78%)
    33 / 304 (10.86%)
         occurrences all number
    22
    43
    Pyrexia
         subjects affected / exposed
    13 / 294 (4.42%)
    34 / 304 (11.18%)
         occurrences all number
    19
    42
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    15 / 294 (5.10%)
    8 / 304 (2.63%)
         occurrences all number
    17
    8
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    111 / 294 (37.76%)
    144 / 304 (47.37%)
         occurrences all number
    196
    281
    Stomatitis
         subjects affected / exposed
    32 / 294 (10.88%)
    41 / 304 (13.49%)
         occurrences all number
    42
    66
    Vomiting
         subjects affected / exposed
    60 / 294 (20.41%)
    94 / 304 (30.92%)
         occurrences all number
    100
    162
    Abdominal pain
         subjects affected / exposed
    31 / 294 (10.54%)
    36 / 304 (11.84%)
         occurrences all number
    36
    52
    Constipation
         subjects affected / exposed
    62 / 294 (21.09%)
    93 / 304 (30.59%)
         occurrences all number
    98
    127
    Diarrhoea
         subjects affected / exposed
    50 / 294 (17.01%)
    53 / 304 (17.43%)
         occurrences all number
    71
    65
    Dyspepsia
         subjects affected / exposed
    9 / 294 (3.06%)
    18 / 304 (5.92%)
         occurrences all number
    11
    27
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 294 (5.10%)
    17 / 304 (5.59%)
         occurrences all number
    16
    23
    Dyspnoea
         subjects affected / exposed
    18 / 294 (6.12%)
    33 / 304 (10.86%)
         occurrences all number
    20
    40
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    10 / 294 (3.40%)
    17 / 304 (5.59%)
         occurrences all number
    22
    26
    Hepatotoxicity
         subjects affected / exposed
    16 / 294 (5.44%)
    85 / 304 (27.96%)
         occurrences all number
    31
    213
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    24 / 294 (8.16%)
    36 / 304 (11.84%)
         occurrences all number
    26
    45
    Dry skin
         subjects affected / exposed
    15 / 294 (5.10%)
    10 / 304 (3.29%)
         occurrences all number
    15
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 294 (8.16%)
    29 / 304 (9.54%)
         occurrences all number
    39
    41
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    34 / 294 (11.56%)
    40 / 304 (13.16%)
         occurrences all number
    46
    53

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Jan 2012
    worldwide shortage of Pegylated Liposomal Doxorubicin (PLD - Caelyx®)
    17 Sep 2013

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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