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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, phase 3 study of brentuximab vedotin and CHP (A+CHP) versus CHOP in the frontline treatment of patients with CD30-positive mature T-cell lymphomas

    Summary
    EudraCT number
    		 2012-002751-42
    Trial protocol
    		 GB   CZ   DE   ES   DK   IT   HU  
    Global end of trial date
    02 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2021
    First version publication date
    07 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SGN35-014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01777152
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Seagen Inc.
    Sponsor organisation address
    21823 30th Drive S.E., Bothell, United States, 98021
    Public contact
    Chief Medical Officer, Seagen Inc., 1 8554732436, medinfo@seagen.com
    Scientific contact
    Chief Medical Officer, Seagen Inc., 1 8554732436, medinfo@seagen.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
    11 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the progression-free survival (PFS) as determined by an independent review facility (IRF) between the 2 treatment arms
    Protection of trial subjects
    This study was conducted in accordance with applicable Food and Drug Administration (FDA) regulations/guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312 and with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Essential documents are retained in accordance with ICH GCP.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 127
    Country: Number of subjects enrolled
    Japan: 43
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    Italy: 37
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Czechia: 22
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Romania: 2
    Worldwide total number of subjects
    452
    EEA total number of subjects
    180
    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)
    313
    From 65 to 84 years
    138
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Jan2013-Nov2016

    Pre-assignment
    Screening details
    		 Participants were screened for eligibility prior to enrollment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 A+CHP
    Arm description
    		 brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone brentuximab vedotin: 1.8 mg/kg every 3 weeks by IV infusion for 6-8 cycles doxorubicin: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles prednisone: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles cyclophosphamide: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brentuximab vedotin
    Investigational medicinal product code
    Other name
    ADCETRIS
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Brentuximab vedotin (SGN-35, ADCETRIS) 1.8 mg/kg administered IV on Day 1 of each cycle for up to 6 to 8 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 750 mg/m2 administered IV on Day 1 of each cycle for up to 6 to 8 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 50 mg/m2 administered IV on Day 1 of each cycle for up to 6 to 8 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 100 mg daily administered orally on Days 1-5 of each cycle for up to 6 to 8 cycles.

    Arm title
    		 CHOP
    Arm description
    		 cyclophosphamide, doxorubicin, vincristine, and prednisone doxorubicin: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles prednisone: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles vincristine: 1.4 mg/m2 (maximum 2 mg) every 3 weeks by IV infusion for 6-8 cycles cyclophosphamide: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 100 mg daily administered orally on Days 1-5 of each cycle for up to 6 to 8 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 750 mg/m2 administered IV on Day 1 of each cycle for up to 6 to 8 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 50 mg/m2 administered IV on Day 1 of each cycle for up to 6 to 8 cycles.

    Number of subjects in period 1
    		A+CHP CHOP
    Started
    226
    226
    Completed
    131
    116
    Not completed
    95
    110
         Adverse event, serious fatal
    68
    89
         Consent withdrawn by subject
    22
    16
         Change of diagnosis
    1
    -
         Lost to follow-up
    3
    5
         Not eligible, no study drug received
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    A+CHP
    Reporting group description
    		 brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone brentuximab vedotin: 1.8 mg/kg every 3 weeks by IV infusion for 6-8 cycles doxorubicin: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles prednisone: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles cyclophosphamide: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles

    Reporting group title
    CHOP
    Reporting group description
    		 cyclophosphamide, doxorubicin, vincristine, and prednisone doxorubicin: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles prednisone: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles vincristine: 1.4 mg/m2 (maximum 2 mg) every 3 weeks by IV infusion for 6-8 cycles cyclophosphamide: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles

    Reporting group values
    		 A+CHP CHOP Total
    Number of subjects
    		 226 226 452
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 157 156 313
        >=65 years
    		 69 70 139
    Age Continuous
    Units: years
        median (full range (min-max))
    		 58 (18 to 85) 58 (18 to 83) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 93 75 168
        Male
    		 133 151 284
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 4 14
        Not Hispanic or Latino
    		 186 193 379
        Unknown or Not Reported
    		 30 29 59
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 45 54 99
        Black or African American
    		 12 6 18
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        White
    		 139 142 281
        Other
    		 3 2 5
        Unknown
    		 26 22 48
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    0=Normal activity; 1=Symptoms but ambulatory; 2=In bed <50% of the time; 3= In bed >50% of the time; 4=100% bedridden; 5=Dead. One participant (ECOG=0) was assessed after start of treatment.
    Units: Subjects
        Grade 0
    		 85 93 178
        Grade 1
    		 90 86 176
        Grade 2
    		 51 47 98

    End points

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    End points reporting groups
    Reporting group title
    A+CHP
    Reporting group description
    		 brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone brentuximab vedotin: 1.8 mg/kg every 3 weeks by IV infusion for 6-8 cycles doxorubicin: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles prednisone: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles cyclophosphamide: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles

    Reporting group title
    CHOP
    Reporting group description
    		 cyclophosphamide, doxorubicin, vincristine, and prednisone doxorubicin: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles prednisone: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles vincristine: 1.4 mg/m2 (maximum 2 mg) every 3 weeks by IV infusion for 6-8 cycles cyclophosphamide: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles

    Primary: Progression-free survival per independent review facility (IRF)

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    End point title
    		 Progression-free survival per independent review facility (IRF)
    End point description
    The time from the date of randomization to the date of first documentation of progressive disease (PD), death due to any cause, or receipt of subsequent anticancer chemotherapy to treat residual or progressive disease whichever occurred first.
    End point type
    Primary
    End point timeframe
    Up to 60 months
    End point values
    		 A+CHP CHOP
    Number of subjects analysed
    226 [1]
    226 [2]
    Units: months
        median (inter-quartile range (Q1-Q3))
    48.20 (8.87 to 999)
    20.80 (4.70 to 999)
    Notes
    [1] - 999 = Not Available (follow up is not long enough to assess an upper bound)
    [2] - 999 = Not Available (follow up is not long enough to assess an upper bound)
    Statistical analysis title
    		 Progression-free survival per IRF
    Statistical analysis description
    The primary analysis of PFS used a stratified log-rank test at a two-sided alpha level of 0.025. A stratified Cox regression of PFS was used to estimate the hazard ratio of the A+CHP arm to the CHOP arm. A hazard ratio <1 indicates that the duration of PFS is prolonged for patients on the A+CHP arm compared with patients on the CHOP arm. Confidence intervals (CIs) were calculated at a two-sided 95% level.
    Comparison groups
    A+CHP v CHOP
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.93

    Secondary: Progression-free survival per IRF in patients with systemic anaplastic large cell lymphoma (sALCL)

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    End point title
    		 Progression-free survival per IRF in patients with systemic anaplastic large cell lymphoma (sALCL)
    End point description
    The time from the date of randomization to the date of first documentation of progressive disease (PD), death due to any cause, or receipt of subsequent anticancer chemotherapy to treat residual or progressive disease whichever occurred first.
    End point type
    Secondary
    End point timeframe
    Up to 60 months
    End point values
    		 A+CHP CHOP
    Number of subjects analysed
    162 [3]
    154 [4]
    Units: months
        median (inter-quartile range (Q1-Q3))
    55.66 (15.61 to 999)
    32.03 (4.57 to 999)
    Notes
    [3] - 999 = Not Available (follow up is not long enough to assess an upper bound)
    [4] - 999 = Not Available (follow up is not long enough to assess an upper bound)
    No statistical analyses for this end point

    Secondary: Incidence of adverse events (AEs)

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    End point title
    		 Incidence of adverse events (AEs)
    End point description
    Any untoward medical occurrence in a clinical investigational participant administered a medicinal product which does not necessarily have a causal relationship with this treatment.
    End point type
    Secondary
    End point timeframe
    Up to 8.28 months
    End point values
    		 A+CHP CHOP
    Number of subjects analysed
    223
    226
    Units: Number of Participants
        Any treatment-emergent AE
    221
    221
        Blinded study treatment-related AE
    201
    193
        CHP treatment-related AE
    198
    205
        Any serious adverse event (SAE)
    87
    87
        Blinded study treatment-related SAE
    58
    45
        CHP treatment-related SAE
    62
    53
        Treatment discontinuations (TDs) due to AE
    14
    15
        TDs due to blinded study treatment-related AE
    10
    10
        TDs due to CHP treatment-related AE
    8
    7
    No statistical analyses for this end point

    Secondary: Incidence of laboratory abnormalities

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    End point title
    		 Incidence of laboratory abnormalities
    End point description
    Number of participants who experienced a Grade 3 or higher laboratory toxicity.
    End point type
    Secondary
    End point timeframe
    Up to 8.28 months
    End point values
    		 A+CHP CHOP
    Number of subjects analysed
    223
    226
    Units: Number of Participants
        Any Chemistry Test
    25
    23
        Alanine Aminotransferase High
    3
    1
        Albumin Low
    2
    3
        Alkaline Phosphatase High
    1
    0
        Calcium Low
    1
    1
        Glucose High
    8
    6
        Phosphate Low
    4
    3
        Potassium High
    0
    2
        Potassium Low
    3
    2
        Sodium High
    1
    0
        Sodium Low
    4
    6
        Urate High
    5
    2
        Any Hematology Test
    68
    78
        Absolute Neutrophil Count Low
    17
    19
        Hemoglobin High
    1
    0
        Hemoglobin Low
    9
    13
        Leukocytes Low
    12
    21
        Lymphocytes High
    0
    1
        Lymphocytes Low
    52
    61
        Neutrophils Low
    17
    19
        Platelets Low
    1
    1
    No statistical analyses for this end point

    Secondary: Complete Remission (CR) Rate Per IRF at End of Treatment (EOT)

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    End point title
    		 Complete Remission (CR) Rate Per IRF at End of Treatment (EOT)
    End point description
    The proportion of participants with CR per IRF following the completion of study treatment (at end of treatment or at the first assessment after the last dose of study treatment and prior to long-term follow-up) according to the Revised Response Criteria for Malignant Lymphoma.
    End point type
    Secondary
    End point timeframe
    Up to 8.34 months
    End point values
    		 A+CHP CHOP
    Number of subjects analysed
    226
    226
    Units: Number of Participants
    153
    126
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    The time from randomization to death due to any cause.
    End point type
    Secondary
    End point timeframe
    Until death or study closure, up to 7 years post-treatment. Median OS follow-up time of 66.76 months
    End point values
    		 A+CHP CHOP
    Number of subjects analysed
    226 [5]
    226 [6]
    Units: Months
        median (full range (min-max))
    .9999999999 (0.0 to 86.5)
    .9999999999 (0.1 to 90.0)
    Notes
    [5] - .9999999999 = The median OS was not reached in either treatment arm.
    [6] - .9999999999 = The median OS was not reached in either treatment arm.
    No statistical analyses for this end point

    Secondary: Objective response rate (ORR) per IRF at end of treatment

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    End point title
    		 Objective response rate (ORR) per IRF at end of treatment
    End point description
    The proportion of participants with CR or partial response (PR) per IRF following the completion of study treatment (at end of treatment or the first assessment after the last dose of study treatment and prior to long-term follow-up) according to the Revised Response Criteria for Malignant Lymphoma.
    End point type
    Secondary
    End point timeframe
    Up to 8.34 months
    End point values
    		 A+CHP CHOP
    Number of subjects analysed
    226
    226
    Units: Number of Participants
    188
    163
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious AEs followed up to 8 months. Serious AEs followed up to 90 months
    Adverse event reporting additional description
    Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment. Investigator and study personnel report all adverse events (AEs) and serious adverse events (SAEs) whether elicited during patient questioning, discovered during physical examination, laboratory testing and/or other means.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    CHOP
    Reporting group description
    		 cyclophosphamide, doxorubicin, vincristine, and prednisone doxorubicin: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles prednisone: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles vincristine: 1.4 mg/m2 (maximum 2 mg) every 3 weeks by IV infusion for 6-8 cycles cyclophosphamide: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles

    Reporting group title
    A+CHP
    Reporting group description
    		 brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone brentuximab vedotin: 1.8 mg/kg every 3 weeks by IV infusion for 6-8 cycles doxorubicin: 50 mg/m2 every 3 weeks by IV infusion for 6-8 cycles prednisone: 100 mg on Days 1 to 5 of each 3-week cycle, orally for 6-8 cycles cyclophosphamide: 750 mg/m2 every 3 weeks by IV infusion for 6-8 cycles

    Serious adverse events
    		 CHOP A+CHP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 226 (39.82%)
    89 / 223 (39.91%)
         number of deaths (all causes)
    89
    67
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Peripheral T-cell lymphoma unspecified
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaplastic large cell lymphoma T- and null-cell types
         subjects affected / exposed
    11 / 226 (4.87%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 0
         deaths causally related to treatment / all
    0 / 8
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    2 / 226 (0.88%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cutaneous T-cell lymphoma
         subjects affected / exposed
    1 / 226 (0.44%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    T-cell type acute leukaemia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 226 (0.88%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (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
    Pyrexia
         subjects affected / exposed
    8 / 226 (3.54%)
    9 / 223 (4.04%)
         occurrences causally related to treatment / all
    3 / 9
    3 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    3 / 226 (1.33%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 226 (0.00%)
    5 / 223 (2.24%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 226 (0.88%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 226 (2.65%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary cavitation
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device issue
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CSF volume decreased
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Splenic rupture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Sinus tachycardia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 226 (0.88%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Arrhythmia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autonomic neuropathy
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (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
    26 / 226 (11.50%)
    32 / 223 (14.35%)
         occurrences causally related to treatment / all
    33 / 38
    34 / 42
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neutropenia
         subjects affected / exposed
    6 / 226 (2.65%)
    8 / 223 (3.59%)
         occurrences causally related to treatment / all
    4 / 8
    13 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 226 (1.33%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 226 (1.33%)
    4 / 223 (1.79%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis haemorrhagic
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 226 (1.77%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 226 (1.33%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (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
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 226 (0.88%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative gastritis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blister
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 226 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (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
    Bone pain
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral column mass
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 226 (1.33%)
    11 / 223 (4.93%)
         occurrences causally related to treatment / all
    4 / 4
    10 / 14
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sepsis
         subjects affected / exposed
    4 / 226 (1.77%)
    5 / 223 (2.24%)
         occurrences causally related to treatment / all
    5 / 6
    4 / 5
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    Cellulitis
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 226 (0.44%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 226 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 226 (0.88%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    2 / 226 (0.88%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 226 (0.88%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 226 (1.33%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    2 / 226 (0.88%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 226 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 226 (1.33%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CHOP A+CHP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    218 / 226 (96.46%)
    220 / 223 (98.65%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    14 / 226 (6.19%)
    15 / 223 (6.73%)
         occurrences all number
    16
    17
    Hypertension
         subjects affected / exposed
    68 / 226 (30.09%)
    71 / 223 (31.84%)
         occurrences all number
    75
    76
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    80 / 226 (35.40%)
    83 / 223 (37.22%)
         occurrences all number
    142
    135
    Pyrexia
         subjects affected / exposed
    74 / 226 (32.74%)
    86 / 223 (38.57%)
         occurrences all number
    109
    134
    Asthenia
         subjects affected / exposed
    20 / 226 (8.85%)
    35 / 223 (15.70%)
         occurrences all number
    27
    45
    Oedema peripheral
         subjects affected / exposed
    36 / 226 (15.93%)
    40 / 223 (17.94%)
         occurrences all number
    48
    53
    Mucosal inflammation
         subjects affected / exposed
    14 / 226 (6.19%)
    15 / 223 (6.73%)
         occurrences all number
    17
    17
    Chest pain
         subjects affected / exposed
    8 / 226 (3.54%)
    14 / 223 (6.28%)
         occurrences all number
    8
    15
    Malaise
         subjects affected / exposed
    12 / 226 (5.31%)
    8 / 223 (3.59%)
         occurrences all number
    26
    8
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    14 / 226 (6.19%)
    9 / 223 (4.04%)
         occurrences all number
    16
    9
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    33 / 226 (14.60%)
    39 / 223 (17.49%)
         occurrences all number
    60
    54
    Oropharyngeal pain
         subjects affected / exposed
    19 / 226 (8.41%)
    21 / 223 (9.42%)
         occurrences all number
    23
    23
    Cough
         subjects affected / exposed
    44 / 226 (19.47%)
    37 / 223 (16.59%)
         occurrences all number
    45
    53
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    49 / 226 (21.68%)
    52 / 223 (23.32%)
         occurrences all number
    54
    62
    Anxiety
         subjects affected / exposed
    13 / 226 (5.75%)
    30 / 223 (13.45%)
         occurrences all number
    14
    34
    Depression
         subjects affected / exposed
    15 / 226 (6.64%)
    16 / 223 (7.17%)
         occurrences all number
    15
    16
    Investigations
    Weight decreased
         subjects affected / exposed
    43 / 226 (19.03%)
    54 / 223 (24.22%)
         occurrences all number
    48
    62
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 226 (0.00%)
    11 / 223 (4.93%)
         occurrences all number
    0
    13
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    108 / 226 (47.79%)
    112 / 223 (50.22%)
         occurrences all number
    152
    179
    Headache
         subjects affected / exposed
    36 / 226 (15.93%)
    37 / 223 (16.59%)
         occurrences all number
    52
    48
    Dizziness
         subjects affected / exposed
    24 / 226 (10.62%)
    32 / 223 (14.35%)
         occurrences all number
    38
    52
    Dysgeusia
         subjects affected / exposed
    15 / 226 (6.64%)
    13 / 223 (5.83%)
         occurrences all number
    19
    14
    Paraesthesia
         subjects affected / exposed
    19 / 226 (8.41%)
    13 / 223 (5.83%)
         occurrences all number
    25
    14
    Peripheral motor neuropathy
         subjects affected / exposed
    18 / 226 (7.96%)
    8 / 223 (3.59%)
         occurrences all number
    23
    15
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    81 / 226 (35.84%)
    87 / 223 (39.01%)
         occurrences all number
    203
    285
    Anaemia
         subjects affected / exposed
    49 / 226 (21.68%)
    64 / 223 (28.70%)
         occurrences all number
    163
    218
    Leukopenia
         subjects affected / exposed
    13 / 226 (5.75%)
    18 / 223 (8.07%)
         occurrences all number
    76
    63
    Febrile neutropenia
         subjects affected / exposed
    9 / 226 (3.98%)
    16 / 223 (7.17%)
         occurrences all number
    12
    36
    Thrombocytopenia
         subjects affected / exposed
    14 / 226 (6.19%)
    21 / 223 (9.42%)
         occurrences all number
    42
    77
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    91 / 226 (40.27%)
    114 / 223 (51.12%)
         occurrences all number
    172
    228
    Diarrhoea
         subjects affected / exposed
    55 / 226 (24.34%)
    93 / 223 (41.70%)
         occurrences all number
    71
    174
    Constipation
         subjects affected / exposed
    94 / 226 (41.59%)
    98 / 223 (43.95%)
         occurrences all number
    124
    145
    Vomiting
         subjects affected / exposed
    37 / 226 (16.37%)
    60 / 223 (26.91%)
         occurrences all number
    58
    92
    Stomatitis
         subjects affected / exposed
    27 / 226 (11.95%)
    28 / 223 (12.56%)
         occurrences all number
    42
    41
    Abdominal pain upper
         subjects affected / exposed
    10 / 226 (4.42%)
    23 / 223 (10.31%)
         occurrences all number
    11
    26
    Dyspepsia
         subjects affected / exposed
    12 / 226 (5.31%)
    17 / 223 (7.62%)
         occurrences all number
    12
    21
    Abdominal pain
         subjects affected / exposed
    22 / 226 (9.73%)
    26 / 223 (11.66%)
         occurrences all number
    26
    39
    Gastrooesophageal reflux disease
         subjects affected / exposed
    16 / 226 (7.08%)
    22 / 223 (9.87%)
         occurrences all number
    16
    23
    Haemorrhoids
         subjects affected / exposed
    12 / 226 (5.31%)
    8 / 223 (3.59%)
         occurrences all number
    12
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    56 / 226 (24.78%)
    58 / 223 (26.01%)
         occurrences all number
    61
    66
    Rash
         subjects affected / exposed
    21 / 226 (9.29%)
    27 / 223 (12.11%)
         occurrences all number
    25
    37
    Night sweats
         subjects affected / exposed
    63 / 226 (27.88%)
    46 / 223 (20.63%)
         occurrences all number
    68
    56
    Pruritus
         subjects affected / exposed
    15 / 226 (6.64%)
    22 / 223 (9.87%)
         occurrences all number
    16
    28
    Dry skin
         subjects affected / exposed
    17 / 226 (7.52%)
    10 / 223 (4.48%)
         occurrences all number
    18
    10
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    11 / 226 (4.87%)
    12 / 223 (5.38%)
         occurrences all number
    11
    12
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    21 / 226 (9.29%)
    27 / 223 (12.11%)
         occurrences all number
    38
    45
    Arthralgia
         subjects affected / exposed
    20 / 226 (8.85%)
    31 / 223 (13.90%)
         occurrences all number
    28
    49
    Back pain
         subjects affected / exposed
    43 / 226 (19.03%)
    44 / 223 (19.73%)
         occurrences all number
    49
    47
    Pain in extremity
         subjects affected / exposed
    21 / 226 (9.29%)
    23 / 223 (10.31%)
         occurrences all number
    24
    25
    Bone pain
         subjects affected / exposed
    12 / 226 (5.31%)
    15 / 223 (6.73%)
         occurrences all number
    15
    18
    Neck pain
         subjects affected / exposed
    8 / 226 (3.54%)
    11 / 223 (4.93%)
         occurrences all number
    9
    12
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 226 (5.31%)
    18 / 223 (8.07%)
         occurrences all number
    13
    19
    Nasopharyngitis
         subjects affected / exposed
    12 / 226 (5.31%)
    10 / 223 (4.48%)
         occurrences all number
    13
    12
    Urinary tract infection
         subjects affected / exposed
    9 / 226 (3.98%)
    12 / 223 (5.38%)
         occurrences all number
    9
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    47 / 226 (20.80%)
    53 / 223 (23.77%)
         occurrences all number
    54
    74
    Hypokalaemia
         subjects affected / exposed
    24 / 226 (10.62%)
    29 / 223 (13.00%)
         occurrences all number
    52
    55
    Diabetes mellitus
         subjects affected / exposed
    13 / 226 (5.75%)
    14 / 223 (6.28%)
         occurrences all number
    13
    14
    Hypercholesterolaemia
         subjects affected / exposed
    12 / 226 (5.31%)
    10 / 223 (4.48%)
         occurrences all number
    12
    10
    Hyperlipidaemia
         subjects affected / exposed
    13 / 226 (5.75%)
    9 / 223 (4.04%)
         occurrences all number
    13
    9
    Hyperglycaemia
         subjects affected / exposed
    9 / 226 (3.98%)
    11 / 223 (4.93%)
         occurrences all number
    14
    21
    Hyperuricaemia
         subjects affected / exposed
    9 / 226 (3.98%)
    11 / 223 (4.93%)
         occurrences all number
    9
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2012
    Excludes subjects with known HIV or hepatitis B or suspected hepatitis C infection. Included ECG or MUGA scan to screening procedures. Removes a planned interim analysis.
    31 Jan 2013
    Excludes subjects with the demyelinating form of Charcot-Marie-Tooth syndrome, subjects previously treated with complete cumulative doses of doxorubicin or other anthracyclines, and subjects with known urinary outflow obstruction. Update to baseline laboratory inclusion criteria. Increases the period of time following the end of treatment that contraception must be used. Adds Objective Response Rate as a secondary endpoint.
    05 Mar 2015
    Increases the planned enrollment from 300 to 450 subjects.
    15 Mar 2018
    Clarification to timing of final primary analysis.
    18 Dec 2018
    Administrative clarifications and organizational changes.

    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
    For support, Contact us.
    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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