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    Clinical Trial Results:
    Phase III multicentre open-label randomised study of ICE plus Rituximab (R-ICE) versus DHAP plus Rituximab (R-DHAP) in previously treated patients with CD 20 positive diffuse large B-cell lymphoma, eligible for transplantation followed by randomised maintenance treatment with Rituximab

    Summary
    EudraCT number
    2004-002103-32
    Trial protocol
    IE  
    Global end of trial date
    16 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    12 May 2018
    First version publication date
    12 May 2018
    Other versions
    Summary report(s)
    CORAL_SUMMARY OF RESULTS

    Trial information

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    Trial identification
    Sponsor protocol code
    50-03B
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    LYSARC
    Sponsor organisation address
    Centre Hospitalier Lyon-Sud - Secteur Sainte Eugénie - Pavillon 6D, PIERRE-BENITE, France, 69495
    Public contact
    Julie Assémat, LYSARC, 33 0472669333, julie.assemat@lysarc.org
    Scientific contact
    Pr Christian Gisselbrecht, LYSA, christian.gisselbrecht@gmail.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Nov 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Oct 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the induction therapy is to evaluate the efficacy and safety of ICE plus Rituximab (R-ICE) in comparison with DHAP plus Rituximab (R-DHAP) in previously treated patients with CD20 positive diffuse large B cell lymphoma eligibale for autologous transplantation The objective of the maintenance therapy is to evaluate the efficacy and safety of Rituximab maintenance therapy after transplantation
    Protection of trial subjects
    If a patient does not respond, relapses or has progressive disease, every center was free to initiate further treatment according to local guidelines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Jul 2003
    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
    Ireland: 4
    Country: Number of subjects enrolled
    Australia: 42
    Country: Number of subjects enrolled
    Belgium: 31
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    France: 128
    Country: Number of subjects enrolled
    Germany: 111
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    New Zealand: 16
    Country: Number of subjects enrolled
    Switzerland: 24
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    United Kingdom: 50
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    477
    EEA total number of subjects
    373
    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)
    460
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment period from January 2003 until mid/end 2008

    Pre-assignment
    Screening details
    - Patient with histologically proven, CD 20+ diffuse large B cell lymphoma in 1st relapse afterCR, less than PR or partial response to first line treatment - Aged from 18 to 65 years, inclusive - Eligible for transplant - Previously treated with chemotherapy regimen containing anthracyclines with or without rituximab - ECOG performance status

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    R-ICE
    Arm description
    -
    Arm type
    standard

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/m2

    Arm title
    R-DHAP
    Arm description
    -
    Arm type
    standard

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/m2

    Number of subjects in period 1
    R-ICE R-DHAP
    Started
    243
    234
    Completed
    205
    196
    Not completed
    38
    38
         Protocol deviation
             3
             1
         Lack of efficacy
             20
             24
         death
             4
             6
         unknown
             2
             1
         Adverse event, non-fatal
             7
             4
         Consent withdrawn by subject
             2
             2
    Period 2
    Period 2 title
    Consolidation
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BEAM + ASCT (R-ICE)
    Arm description
    Consolidation treatment after R-ICE
    Arm type
    consolidation

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    BEAM + ASCT (R-DHAP)
    Arm description
    Consolidation treatment after R-DHAP
    Arm type
    consolidation

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    BEAM + ASCT (R-ICE) BEAM + ASCT (R-DHAP)
    Started
    205
    196
    Completed
    116
    126
    Not completed
    89
    70
         Protocol deviation
             1
             -
         Lack of efficacy
             74
             49
         death
             3
             2
         unknown
             10
             11
         Adverse event, non-fatal
             -
             6
         Consent withdrawn by subject
             1
             2
    Period 3
    Period 3 title
    Maintenance
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Observation
    Arm description
    -
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Rituximab
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375mg/m2

    Number of subjects in period 3
    Observation Rituximab
    Started
    120
    122
    Completed
    41
    30
    Not completed
    81
    92
         Transferred to other arm/group
             -
             2
         Lack of efficacy
             38
             35
         death
             39
             42
         Adverse event, serious fatal
             1
             3
         Adverse event, non-fatal
             -
             3
         Consent withdrawn by subject
             3
             6
         Lost to follow-up
             -
             1
    Joined
    2
    0
         Transferred in from other group/arm
             2
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    R-ICE
    Reporting group description
    -

    Reporting group title
    R-DHAP
    Reporting group description
    -

    Reporting group values
    R-ICE R-DHAP Total
    Number of subjects
    243 234 477
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    R-ICE (N=242): mean = 50.7 median = 54.0 min = 19; max = 65 R-DHAP (N=234) mean = 52.3 median = 55.0 min = 19; max = 65
    Units: years
        median (full range (min-max))
    54 (19 to 65) 55 (19 to 65) -
    Gender categorical
    Units: Subjects
        Female
    87 87 174
        Male
    156 147 303
    Subject analysis sets

    Subject analysis set title
    Induction Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    (following the intent-to-treat principle) refers to all randomized patients regardless they have received study treatment or not: 477 patients analyzed according the therapy they were randomized to receive (243 in R-ICE arm and 234 in RDHAP arm).

    Subject analysis set title
    Induction Intent To Treat Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    refers to patients receiving at least one injection of study treatment, regardless the quantity injected: 469 patients analyzed according the therapy they were randomized to receive (239 in R-ICE arm and 230 in RDHAP arm).

    Subject analysis set title
    Induction Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    refers to patients receiving at least one injection of study treatment: 469 patients analyzed according the therapy they actually received (239 in R-ICE arm and 230 in R-DHAP arm).

    Subject analysis set title
    Maintenance Intent To Treat Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    refers to all patients formally randomized in the 2nd part of the study: 242 patients analyzed according the therapy they were randomized to receive (122 in rituximab arm and 120 in observation arm).

    Subject analysis set title
    Maintenance Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    refers to all patients formally randomized in the 2nd part of the study and have received at least one dose of rituximab or have only been observed, and have at least one maintenance follow-up assessment: 235 patients analyzed according the therapy they actually received, i.e. patient will be included in rituximab arm if he/she had received at least one dose of rituximab during any maintenance visit otherwise, he/she will be included in observation arm (thus, 116 in rituximab arm and 119 in observation arm).

    Subject analysis sets values
    Induction Full Analysis Set Induction Intent To Treat Population Induction Safety population Maintenance Intent To Treat Population Maintenance Safety Population
    Number of subjects
    477
    469
    469
    242
    235
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    R-ICE (N=242): mean = 50.7 median = 54.0 min = 19; max = 65 R-DHAP (N=234) mean = 52.3 median = 55.0 min = 19; max = 65
    Units: years
        median (full range (min-max))
    54 (19 to 65)
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    R-ICE
    Reporting group description
    -

    Reporting group title
    R-DHAP
    Reporting group description
    -
    Reporting group title
    BEAM + ASCT (R-ICE)
    Reporting group description
    Consolidation treatment after R-ICE

    Reporting group title
    BEAM + ASCT (R-DHAP)
    Reporting group description
    Consolidation treatment after R-DHAP
    Reporting group title
    Observation
    Reporting group description
    -

    Reporting group title
    Rituximab
    Reporting group description
    -

    Subject analysis set title
    Induction Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    (following the intent-to-treat principle) refers to all randomized patients regardless they have received study treatment or not: 477 patients analyzed according the therapy they were randomized to receive (243 in R-ICE arm and 234 in RDHAP arm).

    Subject analysis set title
    Induction Intent To Treat Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    refers to patients receiving at least one injection of study treatment, regardless the quantity injected: 469 patients analyzed according the therapy they were randomized to receive (239 in R-ICE arm and 230 in RDHAP arm).

    Subject analysis set title
    Induction Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    refers to patients receiving at least one injection of study treatment: 469 patients analyzed according the therapy they actually received (239 in R-ICE arm and 230 in R-DHAP arm).

    Subject analysis set title
    Maintenance Intent To Treat Population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    refers to all patients formally randomized in the 2nd part of the study: 242 patients analyzed according the therapy they were randomized to receive (122 in rituximab arm and 120 in observation arm).

    Subject analysis set title
    Maintenance Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    refers to all patients formally randomized in the 2nd part of the study and have received at least one dose of rituximab or have only been observed, and have at least one maintenance follow-up assessment: 235 patients analyzed according the therapy they actually received, i.e. patient will be included in rituximab arm if he/she had received at least one dose of rituximab during any maintenance visit otherwise, he/she will be included in observation arm (thus, 116 in rituximab arm and 119 in observation arm).

    Primary: Mobilization Adjusted Response Rate after induction chemotherapy

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    End point title
    Mobilization Adjusted Response Rate after induction chemotherapy
    End point description
    MARR = overall response rate (ORR) (CR/CRu/PR) adjusted with successful mobilization at the end of 2 and/or 3 cycles of induction chemotherapy treatment before high-dose chemotherapy and autologous transplantation Responses are defined, according to Cheson et al (6), response after 3 cycles of treatment will be evaluated by an external expert committee after recommendation from the steering committee (CR, CRu, PR, SD, PD and relpased disease for patients in CR or CRu).
    End point type
    Primary
    End point timeframe
    It will be a composite endpoint including response rate and success of mobilization of stem cells. Response rate after 3 cycles of chemotherapy and at the end of treatment.
    End point values
    R-ICE R-DHAP
    Number of subjects analysed
    239 [1]
    230 [2]
    Units: percent
        number (confidence interval 95%)
    51.5 (44.9 to 58.0)
    56.5 (49.8 to 63.0)
    Notes
    [1] - Induction ITT set R-ICE arm
    [2] - Induction ITT arm R-CHOP arm
    Statistical analysis title
    Primary criterion - Induction
    Comparison groups
    R-DHAP v R-ICE
    Number of subjects included in analysis
    469
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.272
    Method
    Chi-squared
    Parameter type
    OR rates difference
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.1
         upper limit
    4

    Primary: Event free survival after transplant

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    End point title
    Event free survival after transplant
    End point description
    Events are defined as follows:  - Progression of the lymphoma during or after treatment for patients who achieved a response qualified as stable disease or PR,  - Relapse for CR and CRu patients,  - Institution of a new treatment for the lymphoma  - Death from any cause, without progression. Event-Free Survival (EFS) is measured from date of 2nd randomization to date of first event on the Maintenance ITT population.
    End point type
    Primary
    End point timeframe
    EFS at 2-years in months
    End point values
    Observation Rituximab
    Number of subjects analysed
    120
    122
    Units: percent
        number (confidence interval 95%)
    59.3 (49.8 to 67.5)
    59.2 (49.7 to 67.5)
    Statistical analysis title
    Primary criterion - Maintenance
    Comparison groups
    Observation v Rituximab
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.7435
    Method
    Logrank
    Confidence interval
    Notes
    [3] - The event free survival post transplant will be analyzed using the stratified log rank test.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) occurring during the treatment period and until 30 days after the end of the last cycle of treatment or last dose of Rituximab will be recorded on the toxicity forms
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    R-ICE
    Reporting group description
    -

    Reporting group title
    R-DHAP
    Reporting group description
    -

    Serious adverse events
    R-ICE R-DHAP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    66 / 239 (27.62%)
    84 / 234 (35.90%)
         number of deaths (all causes)
    126
    15
         number of deaths resulting from adverse events
    9
    15
    Vascular disorders
    Thrombosis
    Additional description: All vascular disorders are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hepatectomy
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 234 (0.43%)
         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)
    Oesophageal carcinoma
    Additional description: All these neoplasms are reported in the table below
         subjects affected / exposed
    4 / 239 (1.67%)
    3 / 234 (1.28%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    social stay hospitalisation
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    pyrexia
    Additional description: All general disorders are reported in the table below
         subjects affected / exposed
    5 / 239 (2.09%)
    6 / 234 (2.56%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Psychiatric disorders
    Depression
    Additional description: All psychiatric disorders are reported in the table below
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
    Additional description: All these complications are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    cardiac failure
    Additional description: All cardiac disorders are reported in the able below
         subjects affected / exposed
    6 / 239 (2.51%)
    5 / 234 (2.14%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 5
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    Blood and lymphatic system disorders
    Neutropenia
    Additional description: All blood and lymphatic system disorders are reported in the table below
         subjects affected / exposed
    11 / 239 (4.60%)
    16 / 234 (6.84%)
         occurrences causally related to treatment / all
    0 / 11
    2 / 16
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Respiratory, thoracic and mediastinal disorders
    respiratory failure
    Additional description: All respiratory, thoracic and mediastinal disorders are reported in the table below
         subjects affected / exposed
    6 / 239 (2.51%)
    5 / 234 (2.14%)
         occurrences causally related to treatment / all
    2 / 6
    5 / 5
         deaths causally related to treatment / all
    2 / 2
    5 / 5
    Nervous system disorders
    Cerebrovascular accident
    Additional description: All nervous system disorders are reported in the table below
         subjects affected / exposed
    4 / 239 (1.67%)
    13 / 234 (5.56%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    deafness
    Additional description: All ear and labyrinth disorders are reported in the table below
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
    Additional description: All gastrointestinal disorders are reported in the table below
         subjects affected / exposed
    10 / 239 (4.18%)
    19 / 234 (8.12%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
    Additional description: All renal and urinary disorders are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    12 / 234 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    hepatitis
    Additional description: All hepatobiliary disorders are reported in the table below
         subjects affected / exposed
    3 / 239 (1.26%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin reaction
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 234 (0.43%)
         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
    Additional description: All these disorders are reported in the table below
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: All metabolism and nutrition disorders are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    6 / 234 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Neutropenic sepsis
    Additional description: All SAE related to infections and infestations are reported in the table below
         subjects affected / exposed
    46 / 239 (19.25%)
    55 / 234 (23.50%)
         occurrences causally related to treatment / all
    3 / 46
    4 / 55
         deaths causally related to treatment / all
    3 / 3
    4 / 4
    Frequency threshold for reporting non-serious adverse events: 0.7%
    Non-serious adverse events
    R-ICE R-DHAP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    154 / 239 (64.44%)
    172 / 234 (73.50%)
    Vascular disorders
    Thrombosis
    Additional description: All vascular disorders are reported in the table below
         subjects affected / exposed
    6 / 239 (2.51%)
    7 / 234 (2.99%)
         occurrences all number
    6
    7
    Surgical and medical procedures
    Hepatectomy
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 234 (0.43%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour lysis syndrome
    Additional description: All these neoplasms are reported in the table below
         subjects affected / exposed
    4 / 239 (1.67%)
    7 / 234 (2.99%)
         occurrences all number
    4
    7
    Immune system disorders
    Drug hypersensitivity
    Additional description: All immune system disorders are reported in the table below
         subjects affected / exposed
    4 / 239 (1.67%)
    5 / 234 (2.14%)
         occurrences all number
    4
    5
    Social circumstances
    Social stay hospitalisation
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 234 (0.43%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
    Additional description: All general disorders are reported in the table below
         subjects affected / exposed
    40 / 239 (16.74%)
    51 / 234 (21.79%)
         occurrences all number
    40
    51
    Psychiatric disorders
    depression
    Additional description: All psychiatric disorders are reported in the table below
         subjects affected / exposed
    1 / 239 (0.42%)
    3 / 234 (1.28%)
         occurrences all number
    1
    3
    Injury, poisoning and procedural complications
    drug toxicity
    Additional description: All these complications are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    2 / 234 (0.85%)
         occurrences all number
    2
    2
    Investigations
    Blood creatinine increased
    Additional description: All investigations are reported in the table below
         subjects affected / exposed
    12 / 239 (5.02%)
    17 / 234 (7.26%)
         occurrences all number
    12
    17
    Cardiac disorders
    cadiac failure
    Additional description: All cardiac disorders are reported in the table below
         subjects affected / exposed
    7 / 239 (2.93%)
    6 / 234 (2.56%)
         occurrences all number
    7
    6
    Blood and lymphatic system disorders
    neutropenia
    Additional description: All blood and lymphatic disorders are reported in the table below
         subjects affected / exposed
    64 / 239 (26.78%)
    116 / 234 (49.57%)
         occurrences all number
    64
    116
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    Additional description: All respiratory, thoracic and mediastinal disorders are reported in the table below
         subjects affected / exposed
    10 / 239 (4.18%)
    11 / 234 (4.70%)
         occurrences all number
    10
    11
    Nervous system disorders
    Cerebrovascular accident
    Additional description: All nervous system disorders are reported in the table below
         subjects affected / exposed
    7 / 239 (2.93%)
    19 / 234 (8.12%)
         occurrences all number
    7
    19
    Ear and labyrinth disorders
    deafness
    Additional description: All ear and labyrinth disorders are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    4 / 234 (1.71%)
         occurrences all number
    2
    4
    Gastrointestinal disorders
    Vomiting
    Additional description: All GI disorders are reported in the table below
         subjects affected / exposed
    33 / 239 (13.81%)
    65 / 234 (27.78%)
         occurrences all number
    33
    65
    Hepatobiliary disorders
    hepatitis
    Additional description: All hepatobiliary disorders are reported in the table below
         subjects affected / exposed
    3 / 239 (1.26%)
    5 / 234 (2.14%)
         occurrences all number
    3
    5
    Renal and urinary disorders
    renal failure acute
    Additional description: All renal and urinary disorders are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    21 / 234 (8.97%)
         occurrences all number
    2
    21
    Skin and subcutaneous tissue disorders
    Skin reaction
    Additional description: All skin and subcutaneous tissue disorders are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 234 (0.43%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Bone pain
    Additional description: All musculoskeletal and connective tissue disorders are reported in the table below
         subjects affected / exposed
    2 / 239 (0.84%)
    4 / 234 (1.71%)
         occurrences all number
    2
    4
    Metabolism and nutrition disorders
    hypokaliemia
    Additional description: All metabolism and nutrition disorders are reported in the table below
         subjects affected / exposed
    11 / 239 (4.60%)
    40 / 234 (17.09%)
         occurrences all number
    11
    40
    Infections and infestations
    Infection
    Additional description: All infections and infestations are reported in the table below
         subjects affected / exposed
    135 / 239 (56.49%)
    166 / 234 (70.94%)
         occurrences all number
    135
    166

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jul 2007
    La première analyse de sécurité et l’analyse intermédiaire réalisées dans le cadre de l’étude citée en référence ont montré que le nombre de randomisations prévues dans la deuxième partie de l’étude ne serait pas atteint. Le taux de sorti d’essai avant la deuxième randomisation atteignant 50 %. L’augmentation du recrutement à 480 patients est nécessaire pour atteindre l’objectif de la deuxième partie de l’étude. En second lieu, l’amendement prend en compte le changement du Résumé des Caractéristiques du Produit du Mabthera mis à jour au 12 janvier 2007.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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