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    Clinical Trial Results:
    A phase III multicentre randomised clinical trial comparing rituximab with CHOP given every 14 days and rituximab with CHOP given every 21 days for the treatment of patients with newly diagnosed diffuse large B cell non-Hodgkin’s lymphoma

    Summary
    EudraCT number
    2004-002197-34
    Trial protocol
    GB  
    Global end of trial date
    03 Feb 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Aug 2018
    First version publication date
    12 Aug 2018
    Other versions
    Summary report(s)
    R-CHOP 14vs21 - The Lancet publication 22.04.2013

    Trial information

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    Trial identification
    Sponsor protocol code
    BRD/05/122
    Additional study identifiers
    ISRCTN number
    ISRCTN16017947
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Public contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Scientific contact
    Scientific contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    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
    15 Feb 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the improvement in overall survival of rituximab combined with CHOP given every 14 days (R-CHOP 14) in comparison to rituximab with CHOP given every 21 days (R-CHOP 21).
    Protection of trial subjects
    CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) given every 21 days (CHOP-21) has been considered as standard care for all patients with DLBCL for 40 years. Although one arm of the trial altered this regimen to every 14 days, there was anticipated to be little impact on patient safety. Patients were closely monitored for toxicity and the protocol continuation criterion for therapy and dose modification. Supporting medication, lenograstim 263mg/day sc d4-12 was administered if a patient had a BSA < 1.8m^2 OR 368mg/day sc d4-12 if the BSA was >1.8m^2. The protocol detailed information on pre-medication and supportive medication for Rituximab.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Mar 2005
    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
    United Kingdom: 1080
    Worldwide total number of subjects
    1080
    EEA total number of subjects
    1080
    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)
    679
    From 65 to 84 years
    399
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    First patient recruited: 14-MAR-2005 Last patient recruited: 13-NOV-2008 1080 patients recruited across 119 UK sites.

    Pre-assignment
    Screening details
    Patients were screened for eligibility for inclusion into the study as per the trial protocol and as summarised in the manuscript.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    R-CHOP 14
    Arm description
    Six cycles of R-CHOP (Cyclophosphamide 750mg/m^2, Doxorubicin 50mg/m^2, Vincristine 2mg, Prednisolone 100mg, Rituximab 375mg/m^2) every 14 days (1 cycle). After 6 cycles, two additional infusions of rituximab were given two weeks apart at a dose of 375mg/m^2 each. This was to ensure equal number of rituximab infusions were given in both arms of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 14 (cycle repeats every 14 days for 6 cycles) + Rituximab given for 2 further cycles Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 2mg iv day 1 Prednisolone: 100 mg po days 1 to 5

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 14 (cycle repeats every 14 days for 6 cycles) + Rituximab given for 2 further cycles Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 2mg iv day 1 Prednisolone: 100 mg po days 1 to 5

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 14 (cycle repeats every 14 days for 6 cycles) + Rituximab given for 2 further cycles Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 2mg iv day 1 Prednisolone: 100 mg po days 1 to 5

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    L01XC02
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 14 (cycle repeats every 14 days for 6 cycles) + Rituximab given for 2 further cycles Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 2mg iv day 1 Prednisolone: 100 mg po days 1 to 5

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    A07EA01
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 14 (cycle repeats every 14 days for 6 cycles) + Rituximab given for 2 further cycles Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 2mg iv day 1 Prednisolone: 100 mg po days 1 to 5

    Arm title
    R-CHOP 21
    Arm description
    Six cycles of R-CHOP (Cyclophosphamide 750mg/m^2, Doxorubicin 50mg/m^2, Vincristine 1.4mg/m^2, Prednisolone 40mg/m^2, Rituximab 375mg/m^2) every 21 days (1 cycle). After 6 cycles, two additional infusions of rituximab were given three weeks apart at a dose of 375mg/m^2 each. This was to ensure equal number of rituximab infusions were given in both arms of the study.
    Arm type
    Active comparator

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    L01AA01
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 21 (cycle repeats every 21 days for 6 cycles) + Rituximab given for 2 further cycles. Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 1.4mg/m2 iv day 1 Prednisolone: 40mg/m2 po days 1 to 5

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    L01DB01
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 21 (cycle repeats every 21 days for 6 cycles) + Rituximab given for 2 further cycles. Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 1.4mg/m2 iv day 1 Prednisolone: 40mg/m2 po days 1 to 5

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    L01CA02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 21 (cycle repeats every 21 days for 6 cycles) + Rituximab given for 2 further cycles. Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 1.4mg/m2 iv day 1 Prednisolone: 40mg/m2 po days 1 to 5

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    L01XC02
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 21 (cycle repeats every 21 days for 6 cycles) + Rituximab given for 2 further cycles. Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 1.4mg/m2 iv day 1 Prednisolone: 40mg/m2 po days 1 to 5

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    A07EA01
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Given as part of the following regimen: R-CHOP 21 (cycle repeats every 21 days for 6 cycles) + Rituximab given for 2 further cycles. Rituximab: 375mg/m2 iv day 1 Cyclophosphamide: 750mg/m2 iv day 1 Doxorubicin: 50mg/m2 iv day 1 Vincristine: 1.4mg/m2 iv day 1 Prednisolone: 40mg/m2 po days 1 to 5

    Number of subjects in period 1
    R-CHOP 14 R-CHOP 21
    Started
    540
    540
    Completed
    536
    535
    Not completed
    4
    5
         incorrect diagnosis (Burkitt‘s lymphoma)
    -
    1
         incorrect diagnosis (CLL)
    1
    -
         LVEF 40–50%
    -
    1
         Adverse event, serious fatal
    2
    2
         coexisting illnesses
    1
    -
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    R-CHOP 14
    Reporting group description
    Six cycles of R-CHOP (Cyclophosphamide 750mg/m^2, Doxorubicin 50mg/m^2, Vincristine 2mg, Prednisolone 100mg, Rituximab 375mg/m^2) every 14 days (1 cycle). After 6 cycles, two additional infusions of rituximab were given two weeks apart at a dose of 375mg/m^2 each. This was to ensure equal number of rituximab infusions were given in both arms of the study.

    Reporting group title
    R-CHOP 21
    Reporting group description
    Six cycles of R-CHOP (Cyclophosphamide 750mg/m^2, Doxorubicin 50mg/m^2, Vincristine 1.4mg/m^2, Prednisolone 40mg/m^2, Rituximab 375mg/m^2) every 21 days (1 cycle). After 6 cycles, two additional infusions of rituximab were given three weeks apart at a dose of 375mg/m^2 each. This was to ensure equal number of rituximab infusions were given in both arms of the study.

    Reporting group values
    R-CHOP 14 R-CHOP 21 Total
    Number of subjects
    540 540 1080
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        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)
    339 340 679
        From 65-84 years
    200 199 399
        85 years and over
    1 1 2
    Age continuous
    Units: years
        median (full range (min-max))
    61 (19 to 85) 61 (19 to 88) -
    Gender categorical
    Units: Subjects
        Female
    251 247 498
        Male
    289 293 582
    WHO performance status
    Units: Subjects
        Nil (0)
    286 258 544
        One (1)
    182 210 392
        Two (2)
    72 72 144
    Disease Stage
    Units: Subjects
        Bulky IA
    26 20 46
        IB
    17 16 33
        II
    157 166 323
        III
    175 142 317
        IV
    162 193 355
        Unknown
    3 3 6
    Bulky Disease
    Units: Subjects
        Bulky Disease
    261 272 533
        Non-Bulky Disease
    279 268 547
    International prognostic index score
    Units: Subjects
        Nil (0)
    40 43 83
        One (1)
    116 117 233
        Two (2)
    163 143 306
        Three (3)
    136 143 279
        Four (4)
    75 79 154
        Five (5)
    10 15 25
    Phenotype
    Units: Subjects
        Germinal centre
    144 145 289
        Non-germinal centre
    141 130 271
        Unknown
    255 265 520
    Proliferation rate
    Units: Subjects
        MIB1 ≥80%
    106 127 233
        MIB1 ≥90%
    49 71 120
        Other
    385 342 727
    Other disease types diagnosed at central review
    Units: Subjects
        Burkitt’s lymphoma
    1 0 1
        B-cell chronic lymphocytic leukaemia
    3 1 4
        Follicular lymphoma
    4 4 8
        Marginal zone lymphoma
    0 2 2
        B-cell non-Hodgkin lymphoma not otherwise classifi
    2 0 2
        Indolent lymphoma not otherwise classifi ed
    0 1 1
        Hodgkin’s lymphoma
    0 2 2
        Lymphocyte predominant Hodgkin’s lymphoma
    0 0 0
        Peripheral T-cell lymphoma
    1 1 2
        No lymphoma
    1 0 1
        Diffuse large B-cell non-Hodgkin lymphoma
    528 529 1057
    B Symptoms
    Units: Subjects
        B Symptoms
    251 238 489
        No B Symptoms
    289 302 591
    Elevated Lactate Dehydrogenase
    Units: Subjects
        Elevated Lactate Dehydrogenase
    351 350 701
        No Elevated Lactate Dehydrogenase
    189 190 379

    End points

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    End points reporting groups
    Reporting group title
    R-CHOP 14
    Reporting group description
    Six cycles of R-CHOP (Cyclophosphamide 750mg/m^2, Doxorubicin 50mg/m^2, Vincristine 2mg, Prednisolone 100mg, Rituximab 375mg/m^2) every 14 days (1 cycle). After 6 cycles, two additional infusions of rituximab were given two weeks apart at a dose of 375mg/m^2 each. This was to ensure equal number of rituximab infusions were given in both arms of the study.

    Reporting group title
    R-CHOP 21
    Reporting group description
    Six cycles of R-CHOP (Cyclophosphamide 750mg/m^2, Doxorubicin 50mg/m^2, Vincristine 1.4mg/m^2, Prednisolone 40mg/m^2, Rituximab 375mg/m^2) every 21 days (1 cycle). After 6 cycles, two additional infusions of rituximab were given three weeks apart at a dose of 375mg/m^2 each. This was to ensure equal number of rituximab infusions were given in both arms of the study.

    Primary: Overall Survival

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    End point title
    Overall Survival
    End point description
    End point type
    Primary
    End point timeframe
    Two years post-trial treatment.
    End point values
    R-CHOP 14 R-CHOP 21
    Number of subjects analysed
    540
    540
    Units: Percentage
        number (not applicable)
    82.7
    80.8
    Statistical analysis title
    Overall Survival
    Comparison groups
    R-CHOP 14 v R-CHOP 21
    Number of subjects included in analysis
    1080
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.3763
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.15
    Notes
    [1] - hazard ratio 0·90, 95% CI 0·70–1·15; p=0·3763

    Secondary: Progression Free Survival

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    End point title
    Progression Free Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Two years post-trial treatment.
    End point values
    R-CHOP 14 R-CHOP 21
    Number of subjects analysed
    540
    540
    Units: Percentage
        number (not applicable)
    75.4
    74.08
    Statistical analysis title
    Progression Free Survival
    Comparison groups
    R-CHOP 14 v R-CHOP 21
    Number of subjects included in analysis
    1080
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.5907
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.17
    Notes
    [2] - hazard ratio 0·94, 95% CI 0·76–1·17; p=0·5907

    Secondary: Toxicity

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    End point title
    Toxicity
    End point description
    Toxicity assessed according to CTCAE v3.
    End point type
    Secondary
    End point timeframe
    Up to and including 30 days post-trial treatment.
    End point values
    R-CHOP 14 R-CHOP 21
    Number of subjects analysed
    540
    540
    Units: Percentage
    number (not applicable)
        Neutropenia (grade 3 or 4)
    31
    60
        Thrombocytopenia
    9
    5
        Febrile Neutropenia
    11
    5
        Infection
    23
    18
    No statistical analyses for this end point

    Secondary: Complete Response Rate

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    End point title
    Complete Response Rate
    End point description
    End point type
    Secondary
    End point timeframe
    Post-trial treatment.
    End point values
    R-CHOP 14 R-CHOP 21
    Number of subjects analysed
    502
    500
    Units: Percentage
        number (not applicable)
    58
    63
    Statistical analysis title
    Complete Response Rate
    Comparison groups
    R-CHOP 14 v R-CHOP 21
    Number of subjects included in analysis
    1002
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.183
    Method
    Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported up to 30 days after receiving the last dose of study drug, as per the trial protocol.
    Adverse event reporting additional description
    All adverse events were documented on the toxicity page of the Treatment case report form by an appropriately qualified member of staff at each trial site. This documented the severity of the adverse event and causal relationship.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    R-CHOP 14
    Reporting group description
    Six cycles of R-CHOP (Cyclophosphamide 750mg/m^2, Doxorubicin 50mg/m^2, Vincristine 2mg, Prednisolone 100mg, Rituximab 375mg/m^2) every 14 days (1 cycle). After 6 cycles, two additional infusions of rituximab were given two weeks apart at a dose of 375mg/m^2 each. This was to ensure equal number of rituximab infusions were given in both arms of the study.

    Reporting group title
    R-CHOP 21
    Reporting group description
    Six cycles of R-CHOP (Cyclophosphamide 750mg/m^2, Doxorubicin 50mg/m^2, Vincristine 1.4mg/m^2, Prednisolone 40mg/m^2, Rituximab 375mg/m^2) every 21 days (1 cycle). After 6 cycles, two additional infusions of rituximab were given three weeks apart at a dose of 375mg/m^2 each. This was to ensure equal number of rituximab infusions were given in both arms of the study.

    Serious adverse events
    R-CHOP 14 R-CHOP 21
    Total subjects affected by serious adverse events
         subjects affected / exposed
    242 / 540 (44.81%)
    333 / 540 (61.67%)
         number of deaths (all causes)
    177
    48
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial ischaemia
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SVC
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    CNS Relapse
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    3 / 540 (0.56%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema Knee
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema limb
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 540 (0.37%)
    3 / 540 (0.56%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    6 / 540 (1.11%)
    10 / 540 (1.85%)
         occurrences causally related to treatment / all
    5 / 6
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flu like symptoms
         subjects affected / exposed
    0 / 540 (0.00%)
    3 / 540 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Symptoms -Initially, Constipation- Post Admission
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other - Pain
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other - Generally unwell
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Fever
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rigor
         subjects affected / exposed
    4 / 540 (0.74%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood altered
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    2 / 540 (0.37%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    0 / 540 (0.00%)
    7 / 540 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Creatinine
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytes
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine urine increased
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight Loss
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    7 / 540 (1.30%)
    6 / 540 (1.11%)
         occurrences causally related to treatment / all
    5 / 7
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    0 / 540 (0.00%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infarction
         subjects affected / exposed
    2 / 540 (0.37%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 540 (0.56%)
    5 / 540 (0.93%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular diastolic dysfunction
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Systolic Dysfunction
         subjects affected / exposed
    1 / 540 (0.19%)
    3 / 540 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other - Cardiac disorders
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular arrhythmia
         subjects affected / exposed
    0 / 540 (0.00%)
    3 / 540 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular systolic dysfunction
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 540 (0.19%)
    3 / 540 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophils/granulocytes (ANC/AGC)
         subjects affected / exposed
    2 / 540 (0.37%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Illness
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    30 / 540 (5.56%)
    65 / 540 (12.04%)
         occurrences causally related to treatment / all
    30 / 30
    65 / 65
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Haemoglobin anaemia
         subjects affected / exposed
    2 / 540 (0.37%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    17 / 540 (3.15%)
    27 / 540 (5.00%)
         occurrences causally related to treatment / all
    17 / 17
    27 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 540 (0.37%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    3 / 540 (0.56%)
    5 / 540 (0.93%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Adult Respiratory Distress Syndrome
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 540 (0.00%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Bronchial
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chylothorax
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 540 (0.37%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 540 (0.19%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 540 (0.37%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 540 (0.56%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Ischaemia cerobrovascular
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CNS iscenemia
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CNS Ischaemia - Stroke
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dizziness
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness and pain
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 540 (0.37%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal nerve dysfunction
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    2 / 540 (0.37%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy motor
         subjects affected / exposed
    3 / 540 (0.56%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy Sensory
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other - Nervous system disorders
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Seizure
         subjects affected / exposed
    0 / 540 (0.00%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diclofenac Ptosis
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occular - other
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdomen Pain
         subjects affected / exposed
    7 / 540 (1.30%)
    4 / 540 (0.74%)
         occurrences causally related to treatment / all
    6 / 7
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bleeding GI
         subjects affected / exposed
    3 / 540 (0.56%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 540 (0.37%)
    7 / 540 (1.30%)
         occurrences causally related to treatment / all
    2 / 2
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased oral intake
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    12 / 540 (2.22%)
    11 / 540 (2.04%)
         occurrences causally related to treatment / all
    12 / 12
    7 / 11
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Esophagitis
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophagus pain
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula Oesophagus
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 540 (0.37%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    8 / 540 (1.48%)
    5 / 540 (0.93%)
         occurrences causally related to treatment / all
    5 / 8
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other - Gastrointestinal disorders
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other - Mouth/throat
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other - Perforated Caecum
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Epigastrium and lower abdomen
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perforation
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    10 / 540 (1.85%)
    10 / 540 (1.85%)
         occurrences causally related to treatment / all
    7 / 10
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic Cystitis
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incontinence, urinary
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    2 / 540 (0.37%)
    4 / 540 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shingles
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 540 (0.37%)
    3 / 540 (0.56%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 540 (0.37%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    2 / 540 (0.37%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar pain
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    ADH Hyponatremic
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    1 / 540 (0.19%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 540 (0.56%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 540 (0.00%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 540 (0.37%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucose intolerance
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchus
         subjects affected / exposed
    0 / 540 (0.00%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Infection
         subjects affected / exposed
    5 / 540 (0.93%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    17 / 540 (3.15%)
    32 / 540 (5.93%)
         occurrences causally related to treatment / all
    14 / 17
    32 / 32
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenic sepsis
         subjects affected / exposed
    9 / 540 (1.67%)
    7 / 540 (1.30%)
         occurrences causally related to treatment / all
    9 / 9
    7 / 7
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    Non-neutropenic sepsis
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other - Infections and infestations
         subjects affected / exposed
    1 / 540 (0.19%)
    1 / 540 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 540 (0.19%)
    0 / 540 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 540 (0.37%)
    2 / 540 (0.37%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    R-CHOP 14 R-CHOP 21
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    290 / 540 (53.70%)
    380 / 540 (70.37%)
    Cardiac disorders
    Cardiac Toxicity
         subjects affected / exposed
    11 / 540 (2.04%)
    2 / 540 (0.37%)
         occurrences all number
    11
    2
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    50 / 540 (9.26%)
    28 / 540 (5.19%)
         occurrences all number
    50
    28
    Nervous system disorders
    Neurological Toxicity
         subjects affected / exposed
    53 / 540 (9.81%)
    38 / 540 (7.04%)
         occurrences all number
    53
    38
    General disorders and administration site conditions
    All Toxicity
         subjects affected / exposed
    290 / 540 (53.70%)
    380 / 540 (70.37%)
         occurrences all number
    290
    380
    Gastrointestinal disorders
    Mucositis
         subjects affected / exposed
    14 / 540 (2.59%)
    10 / 540 (1.85%)
         occurrences all number
    14
    10
    Nausea
         subjects affected / exposed
    22 / 540 (4.07%)
    20 / 540 (3.70%)
         occurrences all number
    22
    20
    Vomiting
         subjects affected / exposed
    19 / 540 (3.52%)
    17 / 540 (3.15%)
         occurrences all number
    19
    17
    Infections and infestations
    Neutropenia
         subjects affected / exposed
    167 / 540 (30.93%)
    318 / 540 (58.89%)
         occurrences all number
    167
    318
    Febrile neutropenia
         subjects affected / exposed
    28 / 540 (5.19%)
    58 / 540 (10.74%)
         occurrences all number
    28
    58
    Infection
         subjects affected / exposed
    96 / 540 (17.78%)
    125 / 540 (23.15%)
         occurrences all number
    96
    125

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Aug 2005
    The protocol was amended to include the following: Page 3. Dr Ian Chau no longer Clinical Coordinator. Any clinical queries should now be directed to Prof. David Cunningham as stated in protocol. Section 6.3 Administration of Rituximab in both treatment arms Page 13. Data on the safe, fast infusion of Rituximab became available. Some hospital trusts are now using this method of administration of Rituximab. This has therefore been incorporated into the protocol.Section 6.6 Central Nervous System (CNS) Prophylaxis Page 14. In keeping with the DOH intrathecal guidance which states “It is not acceptable to inconvenience patients by asking them to attend on two occasions”, the protocol has been altered so that intrathecal methotrexate will be given on the same day as CHOP, once the intravenous cytotoxic drugs have been given. Section 14.2 Safety Reporting Page 28. Amendments to the safety reporting have been made to make it clear that expected toxicities with CHOP chemotherapy and Rituximab do not need to be reported as adverse events.Section 14.4 Indemnity and Compensation Page 29. As a legal requirement the role of the sponsor of the trial and definitions of negligent and non-negligent harm are now included in the protocol.Appendix 3 Patient Information Sheet Page 34. CT scans are performed at diagnosis, after 4 cycles and at end of treatment. They are also performed at 3 months and 1 year after treatment. It has been brought to our attention that this final CT scan at 1 year post treatment, although performed routinely in some centres, is not universal practice. Therefore for some patients this is an additional scan and information regarding the implications of this is now incorporated into the patient information sheet. Definitions of negligent and non-negligent harm are now also included in the patient information sheet. Appendix 6 Expected Toxicities. Typographical error - doxorubicin to replace doxycycline. Appendix 7 Trial Management Group -Cathy Burton added
    31 Jul 2006
    The protocol was amended to include the addition of a sub-protocol to allow the collection of constitutional DNA from buccal smears. The costs associated with this sub-study (i.e. kits for collecting smears, postage and storage) will be met from a Translational Research in Clinical Trials grant provided by Cancer Research UK. This amendment also included the addition of a second sub-protocol which will prospectively evaluate the prognostic value of PET scanning after 2 cycles of RCHOP chemotherapy. This sub-study will be funded by a subvention from the Department of Health.
    19 Sep 2006
    The Lymphoma Trials Office moved premises, so contact details were amended in the protocol.
    27 Nov 2006
    The Patient Information Sheet and consent form for the Buccal Smear Substudy were rewritten to make it clearer to patients that this was an add-on to the main trial that they were already taking part in and that any DNA extracted from the samples given would be stored and used anonymously for future research projects. This was not clear in the previous versions, v2.0 of both forms were approved for use in this amendment.
    26 Jul 2007
    The protocol and substudy protocol were amended to update a number of contact telephone numbers, fax numbers and email addresses. In addition, the protocol had the following amended: - Change length of study from 3 to 4 years (page 5) - Now states that CT scans should be done within 28 days pre-randomisation (page 9) - Stage IB addition into inclusion criteria (page 10) - Update stratification variables (page 11) - Remove request for consent form (page 11) - Reworded when CT scan should be done on 14 arm (page 23) - Complete rewriting of Safety Reporting (page 28) - PIS Replace CERES with CancerBACUP (page 38) - PIS Change of side effects (page 41) - Consent form - Change date and version number of PIS (page 46) - Change in expected toxicities (to fit in with PIS) (page 49) In addition, the substudy protocol had the following amended: - PIS Replace CERES with CancerBACUP (page 13) - Addition of Appendix 4. Stating PET centres involved (page 18)
    26 Aug 2008
    This substantial amendment allowed for an extension to the R-CHOP 14 vs 21 study. This was in the form of a single arm registration phase, post the initial 1080 patients randomised into the study. This was designed to enable the PET sub study to recruit its full 200 patients. Only patients that can be recruited onto the PET substudy were consented onto the registration phase of R-CHOP 14 vs 21. On the 4th August 2008, 60 patients had been entered onto the PET substudy, so it was estimated 75 patients would be enrolled at the close of the randomisation section of the protocol. Therefore, it was expected that the registration phase was to be for a further 125 patients. The registration phase was single arm. This was initially R-CHOP 21 as this is the standard arm. When analysis of the 1080 patients was complete and the results are known treatment could change, this is laid out on pages 11 and 12 of the main protocol. This enabled the study to react to any change in standard treatment in the UK. Patients will be treated as per protocol. Both the R-CHOP and the PET protocol had a new Patient Information Sheet and consent form when the registration phase began, replacing the previous PISs and CFs post 1080 patients. The Trial Management Group felt that the PET sub-study is a decisive trial in answering how patients should be treated in the future, and we needed to be able to recruit the full number of patients set out in the protocol.
    30 Mar 2010
    This substantial amendment allowed for the number of CHOP cycles in the control arm (R-CHOP 21) to be reduced from 8 to 6 cycles. The following documents were amended to reflect this change: 1. Protocol (version 6.0) 2. Patient Information Sheet for registration (version 5.0) 3. Consent Form for registration (version 5.0) 4. GP letter for registration (version 4.0) 5. PET sub-study Protocol (version 5.0) 6. PET sub-study Patient Information Sheet for registration (version 4.0) 7. PET sub-study Consent Form for registration (version 4.0) In addition, contact details were updated in both the protocol and sub-study protocol. There was also a new site added to the trial and changes in PI at two sites: NEW SITE: Dr Naheed Mir - The Lewisham Hospital NHS Trust CHANGE IN PIs: Dr Toby Nicholson (was Dr Gnanam Satchi) - Whiston Hospital Dr Humayun Ahmad (Dr Adrian Smith) – Queens Hospital, Burton-on-Trent
    11 Jan 2011
    This amendment was primarily to amend an error in the GP letter. Version 4.0 of the GP letter referred to Version 4.0 (dated 30/03/2010) of the protocol. This is an error, and should read version 6.0 (dated 30/03/2010) of the protocol. This was corrected and version 4.1 was approved in this amendment. Also approved in this amendment, North Cheshire NHS Trust (Warrington Hospital & Halton Hospital, PI Dr Peter Clark) had not recruited any patients into the trial and requested that they were closed in order to archive. Hannah Farrant left the UCL CTC and was replaced by Jo Gambell, the REC was asked to update their contact details to reflect this.
    17 Mar 2011
    This substantial amendment allowed for an additional assessment of the response by PET scan using new criteria. The response using this new criteria was compared with the original criteria. This substantial amendment also allowed for analysis of the effect of cell proliferation, as measured by MIB1. The protocol and substudy protocol were amended to reflect this.
    15 Jul 2011
    This amendment was to correct an error in the GP letter. Version 4.0 of the GP letter referred to Version 4.0 (dated 30/03/2010) of the protocol. This was an error, and should have read version 6.0 (dated 30/03/2010) of the protocol. North Cheshire NHS Trust (Warrington Hospital & Halton Hospital) had not recruited any patients into the trial and requested that they could close in order to archive. Lastly, Hannah Farrant had left the Haematology Trials Group and was was replaced by Jo Gambell, so the REC were informed of a change in contact information for the trial.
    29 Oct 2012
    This substantial amendment was made to provide clarification of the methods of pathology review. An additional paragraph was added to section 9.0 of the trial protocol to clarify the methods of pathology review already approved within this clinical trial. The contact details of the UCL Cancer Trials Centre were also updated on page 3.
    29 Feb 2016
    This amendment was made to the trial protocol to allow trial data to be shared with the German High Grade Lymphoma Group and with the SEAL project, there was no scope to do this in the previously approved version. The entirety of ‘Section 18 – Data Sharing’ was new and reads as follows: “In accordance with Cancer Research UK data sharing policy which states that “Cancer Research UK is committed to ensuring that the data generated through its funding should be put to maximum use by the cancer research community and, whenever possible, is translated to deliver patient benefit. It is therefore our policy that all data generated as a result of our funding be considered for sharing and made as widely and freely accessible as possible whilst safeguarding intellectual property, the privacy of patients and confidential data.” All requests for data sharing will be considered by the Trial Management Group. If they approve the request data will provided in a confidential and secure manner i.e. no patient identifiable material will be sent and data will be sent in an encrypted format. As of February 2016 two requests to share data have been received. The first project is in collaboration with the German High Grade Lymphoma group and they have requested data from this trial to try to confirm that the outcome of treatment with rituximab differs between the sexes because the drug is metabolised differently in men and women. The second project (SEAL) is in collaboration with an international consortium and will explore whether progression-free survival can be used as a surrogate endpoint for overall survival in this patient population. The analysis for this project will be done in America and the results of the analysis will be made available to the pharmaceutical company, Celgene. Release of data for these projects was approved by London – Hampstead NRES committee. Any further requests for data will require separate ethical approval.”

    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.
    Non-serious AEs: 'Occurrences all number' cannot be provided, highest grade experienced collected on CRF; 'subjects affected number' listed instead.Serious AEs and non-serious AEs are listed under non-serious adverse events (only grade 3-4 reported).
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