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    Clinical Trial Results:
    A multicenter, randomized, double-blind, parallel group study to evaluate the efficacy and safety of two different doses of palonosetron compared to ondansetron in the prevention of CINV in pediatric patients undergoing single and repeated cycles of MEC or HEC

    Summary
    EudraCT number
    		 2010-022872-30
    Trial protocol
    		 GB   HU   AT   BG   EE   DE   FR   CZ  
    Global end of trial date
    26 Oct 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Apr 2016
    First version publication date
    17 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PALO-10-20
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01442376
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Helsinn Healthcare SA
    Sponsor organisation address
    Via Pian Scairolo 9 , Lugano/Pazzallo, Switzerland, 6912
    Public contact
    Spinelli Tulla, Helsinn Healthcare SA, +41 91 985 21 21, tulla.spinelli@helsinn.com
    Scientific contact
    Spinelli Tulla, Helsinn Healthcare SA, +41 91 985 21 21, tulla.spinelli@helsinn.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
    24 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objectives of the trial: - The primary objective is to evaluate the efficacy of two different doses of IV palonosetron in the prevention of chemotherapy induced nausea and vomiting in moderately emetogenic (MEC) or highly emetogenic (HEC) patients through 120 hours after start of chemotherapy in single and repeated chemotherapy cycles.
    Protection of trial subjects
    For all patients, written informed consent signed by the parent(s)/legal guardian(s) was obtained prior to enrollment. For patients of appropriate age and intellectual maturity, the signed assent form was obtained in compliance with local laws and regulations.
    Background therapy
    		 NA
    Evidence for comparator
    		 Ondansetron (Zofran®), another 5-HT3 receptor antagonist, was chosen as the active comparator in this study because it is one of the most frequently prescribed antiemetic agents and is approved for intravenous (IV) and oral use in adults and children for CINV in many countries.
    Actual start date of recruitment
    12 Sep 2011
    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
    Chile: 29
    Country: Number of subjects enrolled
    Peru: 19
    Country: Number of subjects enrolled
    Romania: 58
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Russian Federation: 50
    Country: Number of subjects enrolled
    Serbia: 27
    Country: Number of subjects enrolled
    Ukraine: 27
    Country: Number of subjects enrolled
    United States: 27
    Country: Number of subjects enrolled
    Poland: 65
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Czech Republic: 63
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 65
    Worldwide total number of subjects
    493
    EEA total number of subjects
    310
    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)
    45
    Children (2-11 years)
    298
    Adolescents (12-17 years)
    150
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The target population was pediatric patients aged from full-term neonates to <17 years scheduled to receive at least one moderately or highly emetogenic chemotherapeutic agent for histologically or cytologically confirmed malignant disease. For patients aged ≥10 years ECOG PS ≤2 was requested.

    Pre-assignment
    Screening details
    		 Out of total 502 randomized patients, 8 patients (2 palonosetron 10 mcg/kg, 4 palonosetron 20 mcg/kg and 2 ondansetron) did not receive the study drug and 1 patient (palonosetron 10 mcg/kg) received study drug but did not receive highly or moderate emetogenic chemotherapy (HEC or MEC), was excluded from the FAS, but included in Safety Population.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Palonosetron 10 mcg/kg
    Arm description
    		 Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palonosetron
    Investigational medicinal product code
    NA
    Other name
    Aloxi
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg.

    Investigational medicinal product name
    Placebo to Ondansetron
    Investigational medicinal product code
    NA
    Other name
    NA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose matching placebo IV.

    Arm title
    		 Palonosetron 20 mcg/kg
    Arm description
    		 Palonosetron and Placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron
    Arm type
    		 Experimental

    Investigational medicinal product name
    Palonosetron
    Investigational medicinal product code
    NA
    Other name
    Aloxi
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg.

    Investigational medicinal product name
    Placebo to Ondansetron
    Investigational medicinal product code
    NA
    Other name
    NA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose matching placebo IV.

    Arm title
    		 Ondansetron
    Arm description
    		 Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ondansetron
    Investigational medicinal product code
    NA
    Other name
    Zofran
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg.

    Investigational medicinal product name
    Placebo to Palonosetron
    Investigational medicinal product code
    NA
    Other name
    NA
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single dose matching placebo IV.

    Number of subjects in period 1
    		Palonosetron 10 mcg/kg Palonosetron 20 mcg/kg Ondansetron
    Started
    166
    165
    162
    Completed
    166
    160
    159
    Not completed
    0
    5
    3
         Consent withdrawn by subject
    -
    -
    1
         Adverse event, non-fatal
    -
    2
    1
         Not eligible for subsequent cycles
    -
    2
    -
         Death
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Palonosetron 10 mcg/kg
    Reporting group description
    		 Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron

    Reporting group title
    Palonosetron 20 mcg/kg
    Reporting group description
    		 Palonosetron and Placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron

    Reporting group title
    Ondansetron
    Reporting group description
    		 Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron

    Reporting group values
    		 Palonosetron 10 mcg/kg Palonosetron 20 mcg/kg Ondansetron Total
    Number of subjects
    		 166 165 162 493
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.07 ± 4.81 8.39 ± 4.91 8.18 ± 5.17 -
    Gender categorical
    Units: Subjects
        Female
    		 78 89 64 231
        Male
    		 88 76 98 262
    Age, customised
    Units: Subjects
        <2 years
    		 15 15 15 45
        2 to <6 years
    		 54 54 54 162
        6 to <12 years
    		 46 46 44 136
        12 to <17 years
    		 51 50 49 150
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 26 26 12 64
        Not Hispanic or Latino
    		 140 139 150 429
    Race
    Units: Subjects
        Asian
    		 2 0 0 2
        Black or African American
    		 2 0 0 2
        White
    		 156 154 159 469
        More than one race
    		 5 11 3 19
        Unknown or Not Reported
    		 1 0 0 1
    Emetogenicity of chemotherapy in Cycle 1
    Units: Subjects
        MEC
    		 112 116 111 339
        HEC
    		 54 49 51 154

    End points

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    End points reporting groups
    Reporting group title
    Palonosetron 10 mcg/kg
    Reporting group description
    		 Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron

    Reporting group title
    Palonosetron 20 mcg/kg
    Reporting group description
    		 Palonosetron and Placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron

    Reporting group title
    Ondansetron
    Reporting group description
    		 Ondansetron and placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron

    Primary: Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1

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    End point title
    		 Proportion of Patients With Complete Response 0 to 24 Hours (Acute Phase) in Cycle 1
    End point description
    Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from 0 to 24 hours (acute phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle. Time 0 (T0) is defined as the time when the patient starts the first cycle of chemotherapy. Full Analysis Set (FAS) population which included all randomized patients receiving the active study drug and HEC or MEC. Following the intent-to-treat principle, patients were assigned to the study treatment group according to the randomized treatment.
    End point type
    Primary
    End point timeframe
    0 to 24 hours after T0
    End point values
    		 Palonosetron 10 mcg/kg Palonosetron 20 mcg/kg Ondansetron
    Number of subjects analysed
    166
    165
    162
    Units: percentage of patients
        number (confidence interval 95%)
    54.2 (46.3 to 61.9)
    59.4 (51.5 to 66.9)
    58.6 (50.6 to 66.2)
    Statistical analysis title
    		 Palonosetron 20 mcg/kg vs. Ondansetron
    Statistical analysis description
    The stratum adjusted Mantel-Haenszel method was used to compute the confidence interval (CI) of the difference in proportion. If the lower bound of the 97.5% CI of either the difference (CR0-24h palonosetron 20 mcg/kg - CR0-24h ondansetron) or the difference (CR0-24h palonosetron 10 mcg/kg - CR0-24h ondansetron) was strictly superior to the non-inferiority margin (δ=-0.15) then the null hypothesis (H0) was rejected. A power of 80% was used for sample size computation.
    Comparison groups
    Palonosetron 20 mcg/kg v Ondansetron
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.36
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -11.7
         upper limit
    		 12.4
    Notes
    [1] - Non-inferiority margin of 15% at an alpha level of 2.5% in a 1-sided test (equivalent to 5.0% 2-sided test) to reject the null hypothesis that the study drug was inferior to the active control drug by more than the non-inferiority margin.
    Statistical analysis title
    		 Palonosetron 10 mcg/kg vs. Ondansetron
    Statistical analysis description
    The stratum adjusted Mantel-Haenszel method was used to compute the confidence interval (CI) of the difference in proportion. If the lower bound of the 97.5% CI of either the difference (CR0-24h palonosetron 20 mcg/kg - CR0-24h ondansetron) or the difference (CR0-24h palonosetron 10 mcg/kg - CR0-24h ondansetron) was strictly superior to the non-inferiority margin (δ=-0.15) then the null hypothesis (H0) was rejected. A power of 80% was used for sample size computation.
    Comparison groups
    Ondansetron v Palonosetron 10 mcg/kg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.4
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -16.4
         upper limit
    		 7.6
    Notes
    [2] - Non-inferiority margin of 15% at an alpha level of 2.5% in a 1-sided test (equivalent to 5.0% 2-sided test) to reject the null hypothesis that the study drug was inferior to the active control drug by more than the non-inferiority margin.

    Secondary: Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1

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    End point title
    		 Proportion of Patients With Complete Response >24 to 120 Hours (Delayed Phase) in Cycle 1
    End point description
    Complete Response (CR) was defined as no vomiting, no retching, and no use of antiemetic rescue medication from >24 to 120 hours (delayed phase) after T0 (start of administration of the most emetogenic chemotherapy) during first cycle. Full Analysis Set (FAS) population.
    End point type
    Secondary
    End point timeframe
    >24 to 120 hours (delayed phase) after T0
    End point values
    		 Palonosetron 10 mcg/kg Palonosetron 20 mcg/kg Ondansetron
    Number of subjects analysed
    166
    165
    162
    Units: percentage of patients
        number (confidence interval 95%)
    28.9 (22.3 to 36.5)
    38.8 (31.4 to 46.7)
    28.4 (21.7 to 36.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days post treatment
    Adverse event reporting additional description
    Safety population (SAF), which allocated patients to treatment groups based on the treatment actually received. Patients received study treatment on Study Day 1 of each cycle for up to 4 cycles. The number of patients included in the SAF at each cycle was the following: 494 (cycle 1), 260 (cycle 2), 146 (cycle 3) and 69 (cycle 4).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Palonosetron 10 mcg/kg
    Reporting group description
    		 Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 10 mcg/kg up to a maximum total dose of 0.75 mg Placebo to Ondansetron

    Reporting group title
    Palonosetron 20 mcg/kg
    Reporting group description
    		 Palonosetron and placebo to Ondansetron Intervention: Drug: Palonosetron Palonosetron: Single dose Palonosetron IV 20 mcg/kg up to a maximum total dose of 1.5 mg Placebo to Ondansetron

    Reporting group title
    Ondansetron
    Reporting group description
    		 Ondansetron and Placebo to Palonosetron Drug: Comparator: Ondansetron Ondansetron: Single three (every 4 hours) Ondansetron IV doses 0.15 mg/kg up to a maximum total dose of 32 mg Placebo to Palonosetron

    Serious adverse events
    		 Palonosetron 10 mcg/kg Palonosetron 20 mcg/kg Ondansetron
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 167 (40.72%)
    62 / 163 (38.04%)
    70 / 164 (42.68%)
         number of deaths (all causes)
    0
    3
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 167 (3.59%)
    3 / 163 (1.84%)
    7 / 164 (4.27%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    3 / 167 (1.80%)
    1 / 163 (0.61%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Apathy
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    6 / 167 (3.59%)
    6 / 163 (3.68%)
    4 / 164 (2.44%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 167 (1.20%)
    3 / 163 (1.84%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 163 (0.61%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute disseminated encephalomyelitis
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    27 / 167 (16.17%)
    30 / 163 (18.40%)
    23 / 164 (14.02%)
         occurrences causally related to treatment / all
    0 / 31
    0 / 38
    0 / 35
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    17 / 167 (10.18%)
    14 / 163 (8.59%)
    15 / 164 (9.15%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 17
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    12 / 167 (7.19%)
    10 / 163 (6.13%)
    11 / 164 (6.71%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 13
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    14 / 167 (8.38%)
    8 / 163 (4.91%)
    9 / 164 (5.49%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 11
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    10 / 167 (5.99%)
    4 / 163 (2.45%)
    9 / 164 (5.49%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 7
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    6 / 167 (3.59%)
    2 / 163 (1.23%)
    6 / 164 (3.66%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 167 (2.40%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 167 (0.00%)
    2 / 163 (1.23%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Caecitis
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal mucosal disorder
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis bullous
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin erosion
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tubular disorder
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    4 / 167 (2.40%)
    1 / 163 (0.61%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 163 (0.61%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candidiasis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 167 (0.00%)
    2 / 163 (1.23%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 167 (0.60%)
    3 / 163 (1.84%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 163 (0.00%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 163 (0.61%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 167 (0.00%)
    0 / 163 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Palonosetron 10 mcg/kg Palonosetron 20 mcg/kg Ondansetron
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    126 / 167 (75.45%)
    112 / 163 (68.71%)
    125 / 164 (76.22%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    10 / 167 (5.99%)
    9 / 163 (5.52%)
    10 / 164 (6.10%)
         occurrences all number
    13
    12
    19
    White blood cell count decreased
         subjects affected / exposed
    12 / 167 (7.19%)
    15 / 163 (9.20%)
    15 / 164 (9.15%)
         occurrences all number
    14
    18
    24
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 167 (10.18%)
    9 / 163 (5.52%)
    16 / 164 (9.76%)
         occurrences all number
    24
    10
    28
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    65 / 167 (38.92%)
    60 / 163 (36.81%)
    61 / 164 (37.20%)
         occurrences all number
    107
    89
    105
    Febrile neutropenia
         subjects affected / exposed
    11 / 167 (6.59%)
    4 / 163 (2.45%)
    4 / 164 (2.44%)
         occurrences all number
    13
    4
    7
    Leukopenia
         subjects affected / exposed
    37 / 167 (22.16%)
    27 / 163 (16.56%)
    43 / 164 (26.22%)
         occurrences all number
    74
    59
    104
    Neutropenia
         subjects affected / exposed
    35 / 167 (20.96%)
    31 / 163 (19.02%)
    22 / 164 (13.41%)
         occurrences all number
    60
    51
    40
    Thrombocytopenia
         subjects affected / exposed
    35 / 167 (20.96%)
    33 / 163 (20.25%)
    37 / 164 (22.56%)
         occurrences all number
    69
    61
    90
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    32 / 167 (19.16%)
    19 / 163 (11.66%)
    21 / 164 (12.80%)
         occurrences all number
    40
    35
    38
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    15 / 167 (8.98%)
    13 / 163 (7.98%)
    18 / 164 (10.98%)
         occurrences all number
    20
    16
    24
    Constipation
         subjects affected / exposed
    8 / 167 (4.79%)
    10 / 163 (6.13%)
    8 / 164 (4.88%)
         occurrences all number
    9
    12
    9
    Diarrhoea
         subjects affected / exposed
    13 / 167 (7.78%)
    6 / 163 (3.68%)
    14 / 164 (8.54%)
         occurrences all number
    14
    7
    15
    Nausea
         subjects affected / exposed
    8 / 167 (4.79%)
    6 / 163 (3.68%)
    13 / 164 (7.93%)
         occurrences all number
    10
    8
    19
    Stomatitis
         subjects affected / exposed
    11 / 167 (6.59%)
    12 / 163 (7.36%)
    12 / 164 (7.32%)
         occurrences all number
    15
    14
    16
    Vomiting
         subjects affected / exposed
    13 / 167 (7.78%)
    17 / 163 (10.43%)
    22 / 164 (13.41%)
         occurrences all number
    21
    39
    31
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 167 (4.79%)
    4 / 163 (2.45%)
    9 / 164 (5.49%)
         occurrences all number
    8
    4
    10
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    6 / 167 (3.59%)
    3 / 163 (1.84%)
    9 / 164 (5.49%)
         occurrences all number
    8
    3
    9

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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? No

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