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    Clinical Trial Results:
    A Randomized, Open-label, Multicenter Phase 3 Study of the Combination of Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone (VcR-CAP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Patients With Newly Diagnosed Mantle Cell Lymphoma who are not Eligible for a Bone Marrow Transplant

    Summary
    EudraCT number
    2007-005669-37
    Trial protocol
    BE   PT   CZ   AT   IT   HU   DE   ES   FR  
    Global end of trial date
    30 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jul 2018
    First version publication date
    15 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    26866138LYM3002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00722137
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry group, Janssen-Cilag International N.V, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry group, Janssen-Cilag International N.V, ClinicalTrialsEU@its.jnj.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
    30 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine which regimen of chemotherapy, VELCADE-rituximab-cyclophosphamide-doxorubicin-prednisone (VcR-CAP) or rituximab-cyclophosphamide-doxorubicin-prednisone-vincristine (R-CHOP), provided greater benefit in newly diagnosed mantle cell lymphoma (MCL) subjects with Stage II, III, or IV disease, as assessed by significant prolongation of progression-free survival (PFS).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety was evaluated throughout the study and included adverse events (AEs), Serious Adverse Events (SAEs), routine clinical laboratory tests (hematology, chemistry, and coagulation, Hepatitis B screening and Pregnancy test), vital signs, Electrocardiograms (ECGs).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 May 2008
    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
    Spain: 14
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Thailand: 19
    Country: Number of subjects enrolled
    Tunisia: 6
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Ukraine: 34
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 26
    Country: Number of subjects enrolled
    Brazil: 22
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    China: 95
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    India: 12
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 18
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Russian Federation: 99
    Country: Number of subjects enrolled
    Singapore: 3
    Worldwide total number of subjects
    487
    EEA total number of subjects
    136
    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)
    241
    From 65 to 84 years
    246
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 487 subjects were randomized from 128 centers in 28 countries from 22 May 2008 to 05 December 2011; 244 to the R-CHOP treatment group and 243 to the VcR-CAP treatment group. Of the 487 randomized subjects, 242 in the R-CHOP group and 240 in the VcR-CAP group received at least 1 dose of study drug.

    Period 1
    Period 1 title
    Open-Label
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    R-CHOP
    Arm description
    Rituximab 375 milligram / meter^2 (mg/m^2) intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles; Vincristine 1.4 mg/m^2 intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received vincristine 1.4 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received prednisone 100 mg/m^2 orally on Days 1 through 5 of each 21-day (3-week) cycle

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received doxorubicin 50 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles.

    Arm title
    VcR-CAP
    Arm description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Velcade 1.3 mg/m^2 intravenous on Days 1, 4, 8, and 11 of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rituximab 375 mg/m^2 IV on Day 1 of a 21-day (3-week) cycle of 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Cyclophosphamide 750 mg/m^2 IV on Day 1 of a 21-day (3-week) cycle of 6 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Doxorubicin 50 mg/m^2 IV on Day 1 of a 21-day (3-week) cycle of 6 cycles.

    Investigational medicinal product name
    Velcade
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Velcade 1.3 mg/m^2 IV on Days 1, 4, 8, and 11 of a 21-day (3-week) cycle of 6 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received prednisone 100 mg/m^2 orally (PO) on Day 1 through Day 5 of a 21-day (3-week) cycle of 6 cycles.

    Number of subjects in period 1
    R-CHOP VcR-CAP
    Started
    244
    243
    Treated
    242
    240
    Completed
    199
    195
    Not completed
    45
    48
         Progressive disease
    5
    4
         Death
    12
    7
         Withdrawal by subject
    6
    9
         Unspecified
    3
    4
         Adverse Event
    17
    21
         Randomized, Not treated
    2
    3
    Period 2
    Period 2 title
    Extension Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Extension- R-CHOP
    Arm description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles; Vincristine 1.4 mg/m^2 intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will receive Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received doxorubicin 50 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received vincristine 1.4 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received prednisone 100 mg/m^2 orally on Days 1 through 5 of each 21-day (3-week) cycle

    Arm title
    Extension- VcR-CAP
    Arm description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Velcade 1.3 mg/m^2 intravenous on Days 1,4,8, and 11of a 21 day (3 week) cycle for 6 cycles; Prednisone orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rituximab 375 mg/m^2 IV on Day 1 of a 21-day (3-week) cycle of 6 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Cyclophosphamide 750 mg/m^2 IV on Day 1 of a 21-day (3-week) cycle of 6 cycles.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Doxorubicin 50 mg/m^2 IV on Day 1 of a 21-day (3-week) cycle of 6 cycles.

    Investigational medicinal product name
    Velcade
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received VELCADE 1.3 mg/m^2 IV on Days 1, 4, 8, and 11 of a 21-day (3-week) cycle of 6 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received prednisone 100 mg/m^2 orally (PO) on Day 1 through Day 5 of a 21-day (3-week) cycle of 6 cycles.

    Number of subjects in period 2 [1]
    Extension- R-CHOP Extension- VcR-CAP
    Started
    128
    140
    Completed
    0
    0
    Not completed
    128
    140
         Withdrawal by subject
    3
    2
         Adverse event, serious fatal
    51
    32
         Study closed by sponsor
    62
    89
         Unspecified
    2
    4
         Lost to follow-up
    10
    13
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who elected to continue with the follow-up were only continued for extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    R-CHOP
    Reporting group description
    Rituximab 375 milligram / meter^2 (mg/m^2) intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles; Vincristine 1.4 mg/m^2 intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Reporting group title
    VcR-CAP
    Reporting group description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Velcade 1.3 mg/m^2 intravenous on Days 1, 4, 8, and 11 of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Reporting group values
    R-CHOP VcR-CAP Total
    Number of subjects
    244 243 487
    Title for AgeCategorical
    Units: subjects
        infants and toddlers(28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    117 124 241
        From 65 to 84 years
    127 119 246
        85 years and over
    0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    64.4 ± 8.77 64.2 ± 9.69 -
    Title for Gender
    Units: subjects
        Female
    62 65 127
        Male
    182 178 360

    End points

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    End points reporting groups
    Reporting group title
    R-CHOP
    Reporting group description
    Rituximab 375 milligram / meter^2 (mg/m^2) intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles; Vincristine 1.4 mg/m^2 intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Reporting group title
    VcR-CAP
    Reporting group description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Velcade 1.3 mg/m^2 intravenous on Days 1, 4, 8, and 11 of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.
    Reporting group title
    Extension- R-CHOP
    Reporting group description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles; Vincristine 1.4 mg/m^2 intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Reporting group title
    Extension- VcR-CAP
    Reporting group description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Velcade 1.3 mg/m^2 intravenous on Days 1,4,8, and 11of a 21 day (3 week) cycle for 6 cycles; Prednisone orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS was defined as the interval between the date of randomization and the date of progressive disease (PD) or death, whichever occurred first. PD was based on the assessment of an Independent Review Committee. The population consisted of all randomized subjects.
    End point type
    Primary
    End point timeframe
    Median duration of follow-up of 40 months
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    244
    243
    Units: Days
        median (confidence interval 95%)
    437.0 (365.0 to 513.0)
    751.0 (604.0 to 969.0)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Log Rank statistical method was based on the Log rank test stratified with IPI risk and stage of disease and Hazards ratio estimate was based on a Cox´s model stratified by IPI risk and stage of disease. A hazard ratio < 1 indicates an advantage for VcR-CAP.
    Comparison groups
    R-CHOP v VcR-CAP
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.79

    Secondary: Time to Progression (TTP)

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    End point title
    Time to Progression (TTP)
    End point description
    Time to progression was defined as the duration from the date of randomization until the date of first documented evidence of progressive disease (PD) or date of relapse for subjects who experienced complete response (CR) or complete response, unconfirmed (CRu). PD and response were based on the assessment of an Independent Review Committee. The population consisted of all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Median duration of follow-up of 40 months
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    244
    243
    Units: Days
        median (confidence interval 95%)
    490.0 (417.0 to 550.0)
    929.0 (696.0 to 1245.0)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Log Rank statistical method was based on the Log rank test stratified with IPI risk and stage of disease and Hazards ratio estimate was based on a Cox´s model stratified by IPI risk and stage of disease. A hazard ratio < 1 indicates an advantage for VcR-CAP.
    Comparison groups
    R-CHOP v VcR-CAP
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    0.74

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    The duration of treatment response was defined as the time from the date of the first response to the date of PD or death due to PD for those subjects with a best response of CR, CRu, or PR as determined by the Independent Review Committee. The duration of response for complete responders was defined as the time from the date of the first response to the date of PD or death due to PD for those subjects with a best response of CR or CRu verified by bone marrow and lactate dehydrogenase (LDH). The response-evaluable population was defined as all subjects who received at least 1 dose of study drug, had >= 1 measurable tumor mass (>1.5 cm in the longest dimension and >1.0 cm in the short axis) at baseline and had at least 1 post-baseline tumor assessment by Independent Review Committee, before any subsequent anti-lymphoma treatment. Here 'n' signifies the number of subjects analyzed at this time point.
    End point type
    Secondary
    End point timeframe
    Median duration of follow-up of 40 months
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    228
    229
    Units: Days
    median (confidence interval 95%)
        Duration of response (n=204, 211)
    459.0 (379.0 to 518.0)
    1110.0 (813.0 to 1320.0)
        Duration for Complete responders (n=95, 122)
    563.0 (486.0 to 738.0)
    1282.0 (933.0 to 1602.0)
    No statistical analyses for this end point

    Secondary: Time to Next Anti-lymphoma Treatment (TTNT)

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    End point title
    Time to Next Anti-lymphoma Treatment (TTNT)
    End point description
    TTNT was measured from the date of initiation of study treatment as per protocol to the start date of new anti-lymphoma treatment. Death due to disease progression prior to subsequent therapy was considered as an event. Otherwise, time to next anti lymphoma treatment was censored at the date of death or the last date known to be alive. The population consisted of all randomized subjects. Here "99999" indicates data was not estimable.
    End point type
    Secondary
    End point timeframe
    Median duration of follow-up of 40 months
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    244
    243
    Units: Days
        median (confidence interval 95%)
    756.0 (674.0 to 837.0)
    1353.0 (1180.0 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Log Rank statistical method was based on the Log rank test stratified with IPI risk and stage of disease and Hazards ratio estimate is based on a Cox´s model stratified by IPI risk and stage of disease. A hazard ratio < 1 indicates an advantage for VcR-CAP.
    Comparison groups
    R-CHOP v VcR-CAP
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    0.65

    Secondary: Treatment-free Interval (TFI)

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    End point title
    Treatment-free Interval (TFI)
    End point description
    TFI was defined as the duration from the date of last dose plus 1 day to the start date of the new treatment. Death due to disease progression prior to subsequent therapy was considered as an event. Otherwise, treatment-free interval was censored at the date of death or the last date known to be alive. Population included all randomized subjects who received at least 1 dose of study medication. Here "99999" indicates data was not estimable.
    End point type
    Secondary
    End point timeframe
    Median duration of follow-up of 40 months
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    242
    240
    Units: Days
        median (confidence interval 95%)
    624.0 (542.0 to 693.0)
    1236.0 (1023.0 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Log Rank statistical method was based on the Log rank test stratified with IPI risk and stage of disease and Hazards ratio estimate was based on a Cox´s model stratified by IPI risk and stage of disease. A hazard ratio < 1 indicates an advantage for VcR-CAP.
    Comparison groups
    R-CHOP v VcR-CAP
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    0.65

    Secondary: Overall Response Rate (ORR)

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    End point title
    Overall Response Rate (ORR)
    End point description
    ORR was defined as complete response (CR) + complete response, unconfirmed (CRu) + partial response (PR) as determined by the Independent Review Committee. Response assessment was carried out every 6 weeks for 18 weeks; thereafter, every 8 weeks until PD/initiation of alternate therapy/withdrawal from study/death. The response-evaluable population was defined as all subjects who received >= 1 dose of study drug, had at least 1 measurable tumor mass (>1.5 cm in the longest dimension and >1.0 cm in the short axis) at baseline and had at least 1 post-baseline tumor assessment by Independent Review Committee, before any subsequent anti-lymphoma treatment.
    End point type
    Secondary
    End point timeframe
    Median duration of follow-up of 40 months
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    228
    229
    Units: Subjects
    209
    219
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mantel-Haenszel estimate of the common odds ratio for stratified tables is used, with IPI risk and Stage of Disease as stratification factors. An odds ratio (OR) > 1 indicates an advantage for VcR-CAP.
    Comparison groups
    R-CHOP v VcR-CAP
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.275
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.428
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.749
         upper limit
    2.722

    Secondary: Overall Complete Response (CR + CRu)

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    End point title
    Overall Complete Response (CR + CRu)
    End point description
    Overall complete response was defined as the number of subjects with complete response (CR) and those with unconfirmed complete response (CRu). Response assessment was carried out every 6 weeks for 18 weeks; thereafter, every 8 weeks until PD/initiation of alternate therapy/withdrawal from study/death. The response-evaluable population was defined as all subjects who received >= 1 dose of study drug, had at least 1 measurable tumor mass (>1.5 cm in the longest dimension and >1.0 cm in the short axis) at baseline and had at least 1 post-baseline tumor assessment by Independent Review Committee, before any subsequent anti-lymphoma treatment.
    End point type
    Secondary
    End point timeframe
    Median duration of follow-up of 40 months
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    228
    229
    Units: Subjects
        Overall complete response
    95
    122
        CR
    79
    106
        CRu
    16
    16
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mantel-Haenszel estimate of the common odds ratio for stratified tables is used, with IPI risk and Stage of Disease as stratification factors. An odds ratio (OR) > 1 indicates an advantage for VcR-CAP.
    Comparison groups
    R-CHOP v VcR-CAP
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.007
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.688
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.148
         upper limit
    2.481

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was measured from the date of randomization to the date of the subject's death. If the subject was alive or the vital status was unknown, OS was censored at the date that the subject was last known to be alive. The population consisted of all randomized subjects. Here "99999" indicates data was not estimable.
    End point type
    Secondary
    End point timeframe
    Median duration of follow-up of approximately 82 months
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    244
    243
    Units: Days
        median (confidence interval 95%)
    1695.0 (1436.0 to 2098.0)
    2760.0 (2172.0 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Log Rank statistical method was based on the Log rank test stratified with IPI risk and stage of disease and Hazards ratio estimate is based on a Cox´s model stratified by IPI risk and stage of disease. A hazard ratio < 1 indicates an advantage for VcR-CAP.
    Comparison groups
    R-CHOP v VcR-CAP
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    0.85

    Secondary: 18-Month Survival

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    End point title
    18-Month Survival
    End point description
    18-month survival was defined as the estimated probability of survival at 18 months (Kaplan-Meier estimate). The population consisted of all radmonized subjects.
    End point type
    Secondary
    End point timeframe
    Up to month 18 from the time of randomization
    End point values
    R-CHOP VcR-CAP
    Number of subjects analysed
    244
    243
    Units: Percentage of Subjects
        arithmetic mean (confidence interval 95%)
    83.8 (78.5 to 88.0)
    85.0 (79.7 to 89.0)
    No statistical analyses for this end point

    Secondary: Number of Subjects Experiencing an Adverse Event (AE)

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    End point title
    Number of Subjects Experiencing an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence associated with the use of a drug, whether or not considered drug related. AEs were collected from the first dose of study drug through 30 days after the last dose of study drug. The safety population was defined as all randomized subjects who received at least 1 dose of study medication. For extension, Follow-up analysis set included subjects with data collected after 02 December 2013.
    End point type
    Secondary
    End point timeframe
    Approximately 9 years
    End point values
    R-CHOP Extension- R-CHOP VcR-CAP Extension- VcR-CAP
    Number of subjects analysed
    244
    128
    240
    140
    Units: Subjects
    238
    1
    238
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 9 years
    Adverse event reporting additional description
    The safety population was defined as all randomized subjects who received at least 1 dose of study medication. For extension, Follow-up analysis set included subjects with data collected after 02 December 2013.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    R-CHOP
    Reporting group description
    Rituximab 375 milligram / meter^2 (mg/m^2) intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles; Vincristine 1.4 mg/m^2 intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Reporting group title
    Extension: R-CHOP
    Reporting group description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles; Vincristine 1.4 mg/m^2 intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Reporting group title
    Extension: VcR-CAP
    Reporting group description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1of a 21 day (3 week) cycle for 6 cycles; Velcade 1.3 mg/m^2 intravenous on Days 1,4,8, and 11of a 21 day (3 week) cycle for 6 cycles; Prednisone orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Reporting group title
    VcR-CAP
    Reporting group description
    Rituximab 375 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Cyclophosphamide 750 mg/m^2 intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Doxorubicin 50 mg/m^2 Intravenous on Day 1 of a 21 day (3 week) cycle for 6 cycles; Velcade 1.3 mg/m^2 intravenous on Days 1, 4, 8, and 11 of a 21 day (3 week) cycle for 6 cycles; Prednisone 100 mg/m^2 orally on Day 1 to Day 5 of a 21 day (3 week) cycle for 6 cycles. Subjects entered to the short-term safety follow-up until PD/initiation of alternate therapy/withdrawal from study/death; and then to long term follow-up (extension) for survival assessment.

    Serious adverse events
    R-CHOP Extension: R-CHOP Extension: VcR-CAP VcR-CAP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    72 / 242 (29.75%)
    0 / 128 (0.00%)
    1 / 140 (0.71%)
    90 / 240 (37.50%)
         number of deaths (all causes)
    86
    1
    2
    69
         number of deaths resulting from adverse events
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    3 / 242 (1.24%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    3 / 240 (1.25%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poor Venous Access
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous Thrombosis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    1 / 140 (0.71%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Acute Phase Reaction
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Death
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 242 (1.24%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 242 (1.65%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    10 / 240 (4.17%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
    8 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Compression Fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Lung Injury
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Left Ventricular Failure
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic Shock
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    3 / 240 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left Ventricular Failure
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular Extrasystoles
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 242 (2.07%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    4 / 240 (1.67%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Marrow Failure
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    20 / 242 (8.26%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    26 / 240 (10.83%)
         occurrences causally related to treatment / all
    27 / 28
    0 / 0
    0 / 0
    33 / 33
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    3 / 242 (1.24%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    6 / 240 (2.50%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    26 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    13 / 242 (5.37%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    12 / 240 (5.00%)
         occurrences causally related to treatment / all
    15 / 16
    0 / 0
    0 / 0
    17 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    8 / 240 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 242 (2.07%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Infiltration
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    3 / 240 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    4 / 240 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillar Haemorrhage
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Autonomic Neuropathy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed Level of Consciousness
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Sensorimotor Neuropathy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Adhesions
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Fissure
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 242 (1.24%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    4 / 240 (1.67%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus Paralytic
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth Ulceration
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periproctitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Function Abnormal
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Soft Tissue Necrosis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid Retention
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Neck
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Abscess
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Candidiasis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis Bacterial
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella Sepsis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nosocomial Infection
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral Fungal Infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral Herpes
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal Candidiasis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar Abscess
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 242 (2.89%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    19 / 240 (7.92%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
    0 / 0
    14 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Cytomegaloviral
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Abscess
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Mycosis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Abscess
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    4 / 240 (1.67%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    0 / 240 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 242 (0.41%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 242 (0.00%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    R-CHOP Extension: R-CHOP Extension: VcR-CAP VcR-CAP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    228 / 242 (94.21%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    235 / 240 (97.92%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 242 (3.72%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    21 / 240 (8.75%)
         occurrences all number
    15
    0
    0
    39
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    26 / 242 (10.74%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    38 / 240 (15.83%)
         occurrences all number
    45
    0
    0
    85
    Chills
         subjects affected / exposed
    4 / 242 (1.65%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    12 / 240 (5.00%)
         occurrences all number
    4
    0
    0
    14
    Fatigue
         subjects affected / exposed
    45 / 242 (18.60%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    56 / 240 (23.33%)
         occurrences all number
    90
    0
    0
    114
    Oedema Peripheral
         subjects affected / exposed
    24 / 242 (9.92%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    37 / 240 (15.42%)
         occurrences all number
    38
    0
    0
    64
    Pyrexia
         subjects affected / exposed
    34 / 242 (14.05%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    66 / 240 (27.50%)
         occurrences all number
    53
    0
    0
    127
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    18 / 242 (7.44%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    27 / 240 (11.25%)
         occurrences all number
    22
    0
    0
    31
    Investigations
    Weight Decreased
         subjects affected / exposed
    10 / 242 (4.13%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    14 / 240 (5.83%)
         occurrences all number
    16
    0
    0
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    88 / 242 (36.36%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    122 / 240 (50.83%)
         occurrences all number
    276
    0
    0
    596
    Febrile Neutropenia
         subjects affected / exposed
    16 / 242 (6.61%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    16 / 240 (6.67%)
         occurrences all number
    19
    0
    0
    19
    Leukopenia
         subjects affected / exposed
    91 / 242 (37.60%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    120 / 240 (50.00%)
         occurrences all number
    455
    0
    0
    1135
    Lymphopenia
         subjects affected / exposed
    32 / 242 (13.22%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    73 / 240 (30.42%)
         occurrences all number
    175
    0
    0
    736
    Neutropenia
         subjects affected / exposed
    174 / 242 (71.90%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    211 / 240 (87.92%)
         occurrences all number
    725
    0
    0
    1297
    Thrombocytopenia
         subjects affected / exposed
    46 / 242 (19.01%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    172 / 240 (71.67%)
         occurrences all number
    141
    0
    0
    1223
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 242 (8.26%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    49 / 240 (20.42%)
         occurrences all number
    24
    0
    0
    78
    Dyspnoea
         subjects affected / exposed
    11 / 242 (4.55%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    18 / 240 (7.50%)
         occurrences all number
    14
    0
    0
    25
    Oropharyngeal Pain
         subjects affected / exposed
    10 / 242 (4.13%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    14 / 240 (5.83%)
         occurrences all number
    15
    0
    0
    20
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 242 (3.72%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    15 / 240 (6.25%)
         occurrences all number
    11
    0
    0
    27
    Headache
         subjects affected / exposed
    11 / 242 (4.55%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    13 / 240 (5.42%)
         occurrences all number
    12
    0
    0
    23
    Hypoaesthesia
         subjects affected / exposed
    15 / 242 (6.20%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    15 / 240 (6.25%)
         occurrences all number
    20
    0
    0
    22
    Neuralgia
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    24 / 240 (10.00%)
         occurrences all number
    3
    0
    0
    42
    Neuropathy Peripheral
         subjects affected / exposed
    19 / 242 (7.85%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    19 / 240 (7.92%)
         occurrences all number
    26
    0
    0
    30
    Paraesthesia
         subjects affected / exposed
    12 / 242 (4.96%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    16 / 240 (6.67%)
         occurrences all number
    18
    0
    0
    32
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    48 / 242 (19.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    54 / 240 (22.50%)
         occurrences all number
    73
    0
    0
    99
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    5 / 242 (2.07%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    22 / 240 (9.17%)
         occurrences all number
    6
    0
    0
    29
    Abdominal Pain
         subjects affected / exposed
    9 / 242 (3.72%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    18 / 240 (7.50%)
         occurrences all number
    12
    0
    0
    20
    Abdominal Pain Upper
         subjects affected / exposed
    11 / 242 (4.55%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    16 / 240 (6.67%)
         occurrences all number
    11
    0
    0
    26
    Constipation
         subjects affected / exposed
    38 / 242 (15.70%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    60 / 240 (25.00%)
         occurrences all number
    50
    0
    0
    95
    Diarrhoea
         subjects affected / exposed
    22 / 242 (9.09%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    72 / 240 (30.00%)
         occurrences all number
    38
    0
    0
    170
    Dyspepsia
         subjects affected / exposed
    14 / 242 (5.79%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    13 / 240 (5.42%)
         occurrences all number
    15
    0
    0
    14
    Nausea
         subjects affected / exposed
    33 / 242 (13.64%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    59 / 240 (24.58%)
         occurrences all number
    46
    0
    0
    110
    Stomatitis
         subjects affected / exposed
    20 / 242 (8.26%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    26 / 240 (10.83%)
         occurrences all number
    33
    0
    0
    36
    Vomiting
         subjects affected / exposed
    12 / 242 (4.96%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    28 / 240 (11.67%)
         occurrences all number
    23
    0
    0
    46
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    12 / 242 (4.96%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    14 / 240 (5.83%)
         occurrences all number
    25
    0
    0
    52
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    33 / 242 (13.64%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    33 / 240 (13.75%)
         occurrences all number
    42
    0
    0
    39
    Rash
         subjects affected / exposed
    8 / 242 (3.31%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    13 / 240 (5.42%)
         occurrences all number
    10
    0
    0
    18
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    15 / 242 (6.20%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    15 / 240 (6.25%)
         occurrences all number
    17
    0
    0
    20
    Pain in Extremity
         subjects affected / exposed
    5 / 242 (2.07%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    20 / 240 (8.33%)
         occurrences all number
    5
    0
    0
    39
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    23 / 242 (9.50%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    45 / 240 (18.75%)
         occurrences all number
    32
    0
    0
    83
    Hypoalbuminaemia
         subjects affected / exposed
    11 / 242 (4.55%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    14 / 240 (5.83%)
         occurrences all number
    15
    0
    0
    25
    Hyperglycaemia
         subjects affected / exposed
    20 / 242 (8.26%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    18 / 240 (7.50%)
         occurrences all number
    74
    0
    0
    31
    Hypokalaemia
         subjects affected / exposed
    15 / 242 (6.20%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    20 / 240 (8.33%)
         occurrences all number
    16
    0
    0
    42
    Infections and infestations
    Herpes Zoster
         subjects affected / exposed
    2 / 242 (0.83%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    16 / 240 (6.67%)
         occurrences all number
    2
    0
    0
    22
    Bronchitis
         subjects affected / exposed
    9 / 242 (3.72%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    17 / 240 (7.08%)
         occurrences all number
    9
    0
    0
    20
    Pneumonia
         subjects affected / exposed
    9 / 242 (3.72%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    12 / 240 (5.00%)
         occurrences all number
    10
    0
    0
    17
    Upper Respiratory Tract Infection
         subjects affected / exposed
    8 / 242 (3.31%)
    0 / 128 (0.00%)
    0 / 140 (0.00%)
    19 / 240 (7.92%)
         occurrences all number
    15
    0
    0
    25

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Oct 2008
    The main reason of this amendment was to provide the clarification was added that the IDMC would review data for interim analyses of safety, efficacy and the concordance rate of histological review; TFI added as a secondary objective; MRU added as an exploratory objective; subjects who withdrew could agree to provide information (ie, outcome of adverse events and survival status); subjects with initial response documented in Cycle 6 could receive 2 further cycles of therapy; central radiology review and assessments based on modified IWRC criteria; clarifications to definition of PFS, TTP. OS, TTNT, TFI; clarifications to definitions of measureable and assessable disease, criteria for response categories; ECG/ECHO/MUGA scans added to document baseline abnormalities; clarification that carriers of hepatitis B were allowed, but those with active hepatitis B or human immunodeficiency virus (HIV) were excluded; guidance on management of study drug toxicities added; defined minimum laboratory requirements at the beginning of each cycle (other than Cycle 1) before study drug administration; clarification was added that patients for whom bone marrow transplantation was not available and patients who refused a transplant as frontline treatment were eligible for the study; additional clarifications were made to other subject inclusion/exclusion criteria, dose adjustments, and statistical analyses.
    26 Feb 2009
    The main reason of this amendment was to do the modification of inclusion criterion restricting enrollment to patients who are truly not eligible for transplantation and the criterion for platelet counts was modified to include patients with lower baseline platelet counts secondary to mantle cell lymphoma. Exclusion criterion regarding serious medical conditions was clarified. Criteria for efficacy response were modified to make measurements operationally feasible and to comply with modified IWRC recommendations. Some laboratory tests considered not to be mandatory were eliminated. Adverse event collection wording was clarified to ensure the capture of adverse events relevant to the study.
    16 Sep 2009
    The IDMC recommendation for an additional interim analysis on safety. To ensure the potential for feedback to the investigator regarding the quality of the samples sent for central review and whether they will be adequate for analysis. Provide clarity on what constitutes central MCL diagnosis. Changes to inclusion and exclusion criteria to include that a check of the quality of the lymph node sample be performed before the patient can be randomized and added in the potential to use steroids if they are waiting for the quality check of sample, and the patient has high burden disease.
    23 Sep 2010
    The main reason for this amendment in the protocol was to provide clarification that randomization could occur only after central confirmation of the diagnosis of MCL, except for potential patients in China where central confirmation of sample adequacy on lymph node tissue was required; mandatory hepatitis B screening added as per IDMC, with additional safety monitoring for subjects at risk for hepatitis B reactivation and recommendation to prophylactically treat hepatitis B surface antigen positive subjects with lamivudine or equivalent agent; subjects with moderate/severe hepatic impairment (total bilirubin =<1.5x the upper limit of normal [ULN]) excluded; reconstitution of VELCADE added as per SmPC.
    09 Aug 2011
    The main reason for this amendment in protocol was to add a futility stopping guideline for the prospectively planned interim analysis.

    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.
    A limitation of this study is that current recommendations for rituximab maintenance therapy were not established when this study was initiated.
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