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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, PCI-32765 (Ibrutinib), in Combination with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma

    Summary
    EudraCT number
    2013-000959-40
    Trial protocol
    GB   SE   CZ   DE   BE   HU   ES   FI   IT   DK   PL   NL  
    Global end of trial date
    05 Apr 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Apr 2020
    First version publication date
    12 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCI-32765DBL3001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01855750
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    Public contact
    Clinical Registry group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate if the addition of ibrutinib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) prolonged event-free survival (EFS) compared with R-CHOP alone in subjects with newly diagnosed non-germinal center B-cell-like (non GCB) subtype of diffuse large B-cell lymphoma (DLBCL) selected by immunohistochemistry (IHC) or in subjects with newly diagnosed activated B-cell-like (ABC) subtype of DLBCL identified by gene expression profiling (GEP) or both patient populations.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety was evaluated by adverse events, clinical laboratory tests, vital signs, body surface area, physical examinations, echocardiogram or multiple uptake gated acquisition (MUGA) scans and electrocardiograms.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    Turkey: 51
    Country: Number of subjects enrolled
    Ukraine: 19
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    United States: 76
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 20
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Brazil: 12
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    China: 200
    Country: Number of subjects enrolled
    Czech Republic: 30
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    Finland: 14
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Italy: 42
    Country: Number of subjects enrolled
    Japan: 73
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Norway: 7
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Russian Federation: 53
    Worldwide total number of subjects
    838
    EEA total number of subjects
    243
    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)
    490
    From 65 to 84 years
    343
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 838 subjects were enrolled; of those, 419 subjects were randomized to Treatment Group A (placebo+ Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [R CHOP]) and 419 subjects to Treatment Group B (ibrutinib+R-CHOP).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment Arm B: Ibrutinib+R-CHOP
    Arm description
    Subjects received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Subjects received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).
    Arm type
    Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 560 mg orally once daily for 6 or 8 cycles per site preference.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered cyclophosphamide 750 mg/m^2 IV on Day 1 of each cycle for 6 or 8 cycles per site preference.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle (21-day cycles).

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered doxorubicin 50 mg/m^2 IV on Day 1 of each cycle (21-day cycles).

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered vincristine 1.4 mg/m^2 IV on Day 1 of each cycle for 6 or 8 cycles per site preference.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received prednisone 100 mg orally daily on Days 1 to 5 of each cycle for 6 or 8 cycles per site preference.

    Arm title
    Treatment Arm A: Placebo+R-CHOP
    Arm description
    Subjects received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Subjects received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo orally once daily for 6 or 8 cycles per site preference..

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle (21-day cycles).

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered cyclophosphamide 750 mg/m^2 IV on Day 1 of each cycle for 6 or 8 cycles per site preference.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered doxorubicin 50 mg/m^2 IV on Day 1 of each cycle (21-day cycles).

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered vincristine 1.4 mg/m^2 IV on Day 1 of each cycle for 6 or 8 cycles per site preference.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received prednisone 100 mg orally daily on Days 1 to 5 of each cycle for 6 or 8 cycles per site preference.

    Number of subjects in period 1
    Treatment Arm B: Ibrutinib+R-CHOP Treatment Arm A: Placebo+R-CHOP
    Started
    419
    419
    Treated
    416
    418
    Completed
    0
    0
    Not completed
    419
    419
         Death
    78
    78
         Sponsor ends the study
    297
    290
         Consent withdrawn by subject
    35
    28
         Lost to follow-up
    9
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Arm B: Ibrutinib+R-CHOP
    Reporting group description
    Subjects received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Subjects received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).

    Reporting group title
    Treatment Arm A: Placebo+R-CHOP
    Reporting group description
    Subjects received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Subjects received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).

    Reporting group values
    Treatment Arm B: Ibrutinib+R-CHOP Treatment Arm A: Placebo+R-CHOP Total
    Number of subjects
    419 419 838
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    231 259 490
        From 65 to 84 years
    186 157 343
        85 years and over
    2 3 5
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    61.1 ± 12.57 58.8 ± 13.57 -
    Title for Gender
    Units: subjects
        Female
    198 193 391
        Male
    221 226 447

    End points

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    End points reporting groups
    Reporting group title
    Treatment Arm B: Ibrutinib+R-CHOP
    Reporting group description
    Subjects received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Subjects received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).

    Reporting group title
    Treatment Arm A: Placebo+R-CHOP
    Reporting group description
    Subjects received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Subjects received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).

    Primary: Event-Free Survival (EFS)-Intent-to-Treat (ITT) Population

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    End point title
    Event-Free Survival (EFS)-Intent-to-Treat (ITT) Population
    End point description
    EFS:duration from randomization to PD, relapse from CR assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either PET-positive/biopsy-proven residual disease on completion of >=6 cycles of R-CHOP therapy/death, whichever occurred first based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or 50% increase of previously involved sites from nadir; PD criteria: new nodal lesion 1.5cm in any axis, 50% increase in SPD of >1 node or 50% increase in longest diameter of previously identified node 1cm in short axis. CR:disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen, liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. ITT population included all randomized subjects, enrolled with GCB of DLBCL subtype by IHC, and analyzed according to treatment they were randomized.
    End point type
    Primary
    End point timeframe
    Up to 5.5 years
    End point values
    Treatment Arm B: Ibrutinib+R-CHOP Treatment Arm A: Placebo+R-CHOP
    Number of subjects analysed
    419 [1]
    419
    Units: Months
        median (confidence interval 95%)
    49.64 (47.47 to 99999)
    54.77 (48.16 to 54.77)
    Notes
    [1] - Here '99999' signifies that upper limit of 95% CI was not estimable due to lesser number of events.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Treatment Arm A: Placebo+R-CHOP v Treatment Arm B: Ibrutinib+R-CHOP
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5167
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.922
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.18

    Primary: Event-Free Survival (EFS) - Activated B-Cell (ABC) Population

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    End point title
    Event-Free Survival (EFS) - Activated B-Cell (ABC) Population
    End point description
    EFS: duration from randomization to disease progression(PD), relapse from complete response(CR) assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either positron emission tomography(PET)-positive/ biopsy-proven residual disease upon completion of >=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in sum of product of diameters(SPD) of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
    End point type
    Primary
    End point timeframe
    Up to 4.5 years
    End point values
    Treatment Arm B: Ibrutinib+R-CHOP Treatment Arm A: Placebo+R-CHOP
    Number of subjects analysed
    285 [2]
    282
    Units: Months
        median (confidence interval 95%)
    48.56 (48.56 to 99999)
    48.16 (48.16 to 99999)
    Notes
    [2] - Here '99999' signifies that upper limit of 95% CI was not estimable due to lesser number of events.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Treatment Arm B: Ibrutinib+R-CHOP v Treatment Arm A: Placebo+R-CHOP
    Number of subjects included in analysis
    567
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7311
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.949
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.704
         upper limit
    1.279

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS: duration from randomization to progression, relapse from CR, or death, whichever occurred first. Responses were as per Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: appearance of new nodal lesion 1.5 centimeter (cm) in any axis, 50% increase in SPD of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. ITT population included all randomized subjects, enrolled with non-GCB of DLBCL subtype by IHC, and were analyzed according to treatment to which they were randomized. 99999 signifies that median and upper limit of CI were not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 years
    End point values
    Treatment Arm B: Ibrutinib+R-CHOP Treatment Arm A: Placebo+R-CHOP
    Number of subjects analysed
    419
    419
    Units: Months
        median (confidence interval 95%)
    48.56 (48.56 to 99999)
    99999 (48.16 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Treatment Arm B: Ibrutinib+R-CHOP v Treatment Arm A: Placebo+R-CHOP
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5027
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.917
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.183

    Secondary: Percentage of Subjects who Achieved Complete Response (CR)

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    End point title
    Percentage of Subjects who Achieved Complete Response (CR)
    End point description
    Percentage of subjects with measurable disease who achieved CR were reported. CR: disappearance of all evidence of disease. CR Criteria: Complete disappearance of all disease-related symptoms; all lymph nodes and nodal masses regressed to normal size (less than or equal to [<=]1.5 cm in greatest transverse diameter [GTD] for nodes greater than [>]1.5 cm before therapy). Previous nodes of 1.1 to 1.5 cm in long axis and greater than (>)1.0 cm in short axis before treatment decreased to <=1.0 cm in short axis after treatment. Disappearance of all splenic and hepatic nodules and other extranodal disease; a negative PET scan. A posttreatment residual mass of any size but PET-negative; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. ITT population included all randomized subjects, enrolled with non-GCB of DLBCL subtype by IHC, and were analyzed according to treatment to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 years
    End point values
    Treatment Arm B: Ibrutinib+R-CHOP Treatment Arm A: Placebo+R-CHOP
    Number of subjects analysed
    419
    419
    Units: Percentage of subjects
        number (not applicable)
    67.3
    68.0
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Treatment Arm B: Ibrutinib+R-CHOP v Treatment Arm A: Placebo+R-CHOP
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8229
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.967
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.722
         upper limit
    1.296

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival was defined as the duration from the date of randomization to the date of the subject’s death. Median Overall Survival was estimated by using the Kaplan-Meier method. ITT population included all randomized subjects, who were enrolled with the non-GCB of DLBCL subtype by IHC and were analyzed according to the treatment to which they were randomized. Here, 99999 signifies that median and upper limit of CI was not estimable due to lesser number of events and -99999 signifies that lower limit of CI was not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 5.5 years
    End point values
    Treatment Arm B: Ibrutinib+R-CHOP Treatment Arm A: Placebo+R-CHOP
    Number of subjects analysed
    419
    419
    Units: Months
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Treatment Arm B: Ibrutinib+R-CHOP v Treatment Arm A: Placebo+R-CHOP
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8549
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.754
         upper limit
    1.407

    Secondary: Time to Worsening in the Lymphoma Subscale of Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)

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    End point title
    Time to Worsening in the Lymphoma Subscale of Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)
    End point description
    Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as interval from the date of randomization to the start date of worsening of subject symptoms. Worsening was defined by a 5-point decrease from baseline. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life. ITT population included all randomized subjects, enrolled with non-GCB of DLBCL subtype by IHC, and were analyzed according to treatment to which they were randomized.Here, 99999 signifies that median and upper limit of CI was not estimable due to lesser number of events.
    End point type
    Secondary
    End point timeframe
    Up to 4.5 years
    End point values
    Treatment Arm B: Ibrutinib+R-CHOP Treatment Arm A: Placebo+R-CHOP
    Number of subjects analysed
    419
    419
    Units: Months
        median (confidence interval 95%)
    11.7 (4.9 to 23.5)
    35.0 (19.8 to 99999)
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Treatment Arm B: Ibrutinib+R-CHOP v Treatment Arm A: Placebo+R-CHOP
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.358
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.115
         upper limit
    1.654

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 5.5 years
    Adverse event reporting additional description
    Safety population included all randomized subjects who received at least 1 dose of study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Treatment Arm A: Placebo+R-CHOP
    Reporting group description
    Subjects received matching placebo (4 capsules) orally once daily (21-day cycles) along with R-CHOP background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Subjects received background chemotherapy plus matching placebo for 6 or 8 cycles per site preference (21 days per cycle).

    Reporting group title
    Treatment Arm B: Ibrutinib+R-CHOP
    Reporting group description
    Subjects received ibrutinib 560 milligram (mg) (4*140 mg) capsules orally once daily (Cycle 1 Day 1 to Day 21 of last cycle; 21-day cycles) along with R-CHOP (Rituximab - Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) as a background chemotherapy. R-CHOP regimen included rituximab 375 milligram per square meter (mg/m^2) intravenously (IV), cyclophosphamide 750 mg/m^2 IV, doxorubicin 50 mg/m^2 IV, and vincristine 1.4 mg/m^2 IV, administered on Day 1 and prednisone 100 mg capsules orally on Days 1 to 5 of each cycle. Subjects received background chemotherapy plus ibrutinib for 6 or 8 cycles per site preference (21 days per cycle).

    Serious adverse events
    Treatment Arm A: Placebo+R-CHOP Treatment Arm B: Ibrutinib+R-CHOP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    143 / 418 (34.21%)
    221 / 416 (53.13%)
         number of deaths (all causes)
    77
    78
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic Aneurysm
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    2 / 418 (0.48%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 418 (0.24%)
    6 / 416 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock Haemorrhagic
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena Cava Thrombosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angioimmunoblastic T-Cell Lymphoma
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal Adenocarcinoma
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Cancer Metastatic
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of Skin
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         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
    Asthenia
         subjects affected / exposed
    1 / 418 (0.24%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Thrombosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 418 (0.24%)
    5 / 416 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    1 / 418 (0.24%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection Site Extravasation
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal Inflammation
         subjects affected / exposed
    0 / 418 (0.00%)
    3 / 416 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 418 (2.63%)
    12 / 416 (2.88%)
         occurrences causally related to treatment / all
    6 / 12
    8 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    2 / 418 (0.48%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    Psychiatric disorders
    Bipolar I Disorder
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional State
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal Fistula
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Compression Fracture
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    2 / 418 (0.48%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Related Reaction
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative Thrombosis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis Fracture
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull Fractured Base
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    3 / 418 (0.72%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-Reactive Protein Increased
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    2 / 418 (0.48%)
    5 / 416 (1.20%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 418 (0.00%)
    3 / 416 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Increased
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina Pectoris
         subjects affected / exposed
    1 / 418 (0.24%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    2 / 418 (0.48%)
    13 / 416 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
    10 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    5 / 418 (1.20%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 418 (0.24%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital Neuropathy
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyloric Stenosis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alveolitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Atelectasis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse Alveolar Damage
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    4 / 418 (0.96%)
    7 / 416 (1.68%)
         occurrences causally related to treatment / all
    4 / 4
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obliterative Bronchiolitis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal Haemorrhage
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 418 (0.72%)
    6 / 416 (1.44%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    3 / 418 (0.72%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Mass
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 418 (0.24%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinus Polyp
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 418 (1.20%)
    15 / 416 (3.61%)
         occurrences causally related to treatment / all
    4 / 6
    13 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    44 / 418 (10.53%)
    78 / 416 (18.75%)
         occurrences causally related to treatment / all
    42 / 55
    71 / 100
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 418 (0.48%)
    4 / 416 (0.96%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    13 / 418 (3.11%)
    17 / 416 (4.09%)
         occurrences causally related to treatment / all
    11 / 16
    14 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 418 (0.24%)
    9 / 416 (2.16%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered State of Consciousness
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central Nervous System Inflammation
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal Fluid Leakage
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Disorder
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness Postural
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Convulsion
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hemiparesis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial Hypotension
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve Compression
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sciatica
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 418 (0.24%)
    5 / 416 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye Haemorrhage
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 418 (0.48%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 418 (0.00%)
    3 / 416 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 418 (0.96%)
    15 / 416 (3.61%)
         occurrences causally related to treatment / all
    5 / 5
    13 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular Perforation
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    1 / 418 (0.24%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Perforation
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 418 (0.48%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical Ileus
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 418 (0.72%)
    6 / 416 (1.44%)
         occurrences causally related to treatment / all
    1 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Colitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction Gastric
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Perforation
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 418 (0.48%)
    8 / 416 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 418 (0.24%)
    4 / 416 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis Haemorrhagic
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    2 / 418 (0.48%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hepatic Function Abnormal
         subjects affected / exposed
    2 / 418 (0.48%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis Allergic
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         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
    Arthralgia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis Pyrophosphate
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    2 / 418 (0.48%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 418 (0.48%)
    8 / 416 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    6 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid Overload
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 418 (0.00%)
    4 / 416 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 418 (0.24%)
    3 / 416 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arteritis Infective
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus Infection
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Atypical Pneumonia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain Abscess
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    1 / 418 (0.24%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Aspergillosis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial Infection
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cryptococcal Fungaemia
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus Gastrointestinal Infection
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    1 / 418 (0.24%)
    4 / 416 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal Sepsis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Bacterial
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus Infection
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B Reactivation
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    3 / 418 (0.72%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision Site Infection
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 418 (0.48%)
    3 / 416 (0.72%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella Sepsis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection Fungal
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Abscess
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    7 / 418 (1.67%)
    14 / 416 (3.37%)
         occurrences causally related to treatment / all
    5 / 8
    9 / 15
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Lymph Gland Infection
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal Infection
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Infection
         subjects affected / exposed
    1 / 418 (0.24%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    2 / 418 (0.48%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    0 / 418 (0.00%)
    3 / 416 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    14 / 418 (3.35%)
    28 / 416 (6.73%)
         occurrences causally related to treatment / all
    9 / 18
    20 / 34
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pneumonia Cryptococcal
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Cytomegaloviral
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Klebsiella
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Respiratory Syncytial Viral
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous Colitis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Mycosis
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection Bacterial
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection Fungal
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 418 (0.72%)
    7 / 416 (1.68%)
         occurrences causally related to treatment / all
    1 / 4
    5 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Septic Shock
         subjects affected / exposed
    1 / 418 (0.24%)
    5 / 416 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sialoadenitis
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 418 (0.48%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 418 (0.24%)
    3 / 416 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    3 / 418 (0.72%)
    5 / 416 (1.20%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 418 (0.24%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 418 (0.00%)
    2 / 416 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 418 (0.00%)
    1 / 416 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    1 / 418 (0.24%)
    0 / 416 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment Arm A: Placebo+R-CHOP Treatment Arm B: Ibrutinib+R-CHOP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    411 / 418 (98.33%)
    411 / 416 (98.80%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 418 (4.31%)
    23 / 416 (5.53%)
         occurrences all number
    21
    34
    Hypotension
         subjects affected / exposed
    10 / 418 (2.39%)
    23 / 416 (5.53%)
         occurrences all number
    11
    28
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 418 (3.83%)
    28 / 416 (6.73%)
         occurrences all number
    29
    48
    Fatigue
         subjects affected / exposed
    102 / 418 (24.40%)
    138 / 416 (33.17%)
         occurrences all number
    182
    241
    Malaise
         subjects affected / exposed
    21 / 418 (5.02%)
    25 / 416 (6.01%)
         occurrences all number
    43
    33
    Mucosal Inflammation
         subjects affected / exposed
    23 / 418 (5.50%)
    34 / 416 (8.17%)
         occurrences all number
    29
    52
    Oedema Peripheral
         subjects affected / exposed
    29 / 418 (6.94%)
    46 / 416 (11.06%)
         occurrences all number
    33
    66
    Pyrexia
         subjects affected / exposed
    68 / 418 (16.27%)
    83 / 416 (19.95%)
         occurrences all number
    109
    145
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    43 / 418 (10.29%)
    39 / 416 (9.38%)
         occurrences all number
    54
    43
    Injury, poisoning and procedural complications
    Infusion Related Reaction
         subjects affected / exposed
    26 / 418 (6.22%)
    23 / 416 (5.53%)
         occurrences all number
    29
    30
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    24 / 418 (5.74%)
    25 / 416 (6.01%)
         occurrences all number
    46
    36
    Lymphocyte Count Decreased
         subjects affected / exposed
    42 / 418 (10.05%)
    44 / 416 (10.58%)
         occurrences all number
    326
    358
    Neutrophil Count Decreased
         subjects affected / exposed
    81 / 418 (19.38%)
    99 / 416 (23.80%)
         occurrences all number
    412
    395
    Platelet Count Decreased
         subjects affected / exposed
    38 / 418 (9.09%)
    83 / 416 (19.95%)
         occurrences all number
    171
    454
    Weight Decreased
         subjects affected / exposed
    18 / 418 (4.31%)
    36 / 416 (8.65%)
         occurrences all number
    29
    57
    White Blood Cell Count Decreased
         subjects affected / exposed
    104 / 418 (24.88%)
    107 / 416 (25.72%)
         occurrences all number
    764
    626
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    116 / 418 (27.75%)
    173 / 416 (41.59%)
         occurrences all number
    476
    714
    Febrile Neutropenia
         subjects affected / exposed
    22 / 418 (5.26%)
    41 / 416 (9.86%)
         occurrences all number
    28
    56
    Leukopenia
         subjects affected / exposed
    74 / 418 (17.70%)
    70 / 416 (16.83%)
         occurrences all number
    412
    402
    Lymphopenia
         subjects affected / exposed
    36 / 418 (8.61%)
    23 / 416 (5.53%)
         occurrences all number
    245
    191
    Neutropenia
         subjects affected / exposed
    248 / 418 (59.33%)
    213 / 416 (51.20%)
         occurrences all number
    1079
    865
    Thrombocytopenia
         subjects affected / exposed
    53 / 418 (12.68%)
    102 / 416 (24.52%)
         occurrences all number
    141
    352
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    47 / 418 (11.24%)
    55 / 416 (13.22%)
         occurrences all number
    53
    71
    Dyspnoea
         subjects affected / exposed
    25 / 418 (5.98%)
    30 / 416 (7.21%)
         occurrences all number
    30
    38
    Oropharyngeal Pain
         subjects affected / exposed
    25 / 418 (5.98%)
    32 / 416 (7.69%)
         occurrences all number
    32
    42
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    19 / 418 (4.55%)
    26 / 416 (6.25%)
         occurrences all number
    23
    27
    Headache
         subjects affected / exposed
    43 / 418 (10.29%)
    29 / 416 (6.97%)
         occurrences all number
    70
    54
    Hypoaesthesia
         subjects affected / exposed
    22 / 418 (5.26%)
    28 / 416 (6.73%)
         occurrences all number
    28
    35
    Neuropathy Peripheral
         subjects affected / exposed
    35 / 418 (8.37%)
    65 / 416 (15.63%)
         occurrences all number
    49
    96
    Paraesthesia
         subjects affected / exposed
    16 / 418 (3.83%)
    28 / 416 (6.73%)
         occurrences all number
    22
    42
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    63 / 418 (15.07%)
    77 / 416 (18.51%)
         occurrences all number
    81
    134
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    34 / 418 (8.13%)
    37 / 416 (8.89%)
         occurrences all number
    47
    44
    Abdominal Pain Upper
         subjects affected / exposed
    34 / 418 (8.13%)
    28 / 416 (6.73%)
         occurrences all number
    57
    34
    Constipation
         subjects affected / exposed
    110 / 418 (26.32%)
    111 / 416 (26.68%)
         occurrences all number
    149
    147
    Diarrhoea
         subjects affected / exposed
    81 / 418 (19.38%)
    149 / 416 (35.82%)
         occurrences all number
    122
    291
    Dry Mouth
         subjects affected / exposed
    17 / 418 (4.07%)
    22 / 416 (5.29%)
         occurrences all number
    22
    27
    Dyspepsia
         subjects affected / exposed
    22 / 418 (5.26%)
    26 / 416 (6.25%)
         occurrences all number
    27
    30
    Mouth Ulceration
         subjects affected / exposed
    20 / 418 (4.78%)
    32 / 416 (7.69%)
         occurrences all number
    27
    52
    Nausea
         subjects affected / exposed
    135 / 418 (32.30%)
    170 / 416 (40.87%)
         occurrences all number
    304
    356
    Stomatitis
         subjects affected / exposed
    47 / 418 (11.24%)
    64 / 416 (15.38%)
         occurrences all number
    65
    110
    Vomiting
         subjects affected / exposed
    59 / 418 (14.11%)
    91 / 416 (21.88%)
         occurrences all number
    89
    157
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    106 / 418 (25.36%)
    69 / 416 (16.59%)
         occurrences all number
    117
    78
    Pruritus
         subjects affected / exposed
    21 / 418 (5.02%)
    11 / 416 (2.64%)
         occurrences all number
    24
    14
    Rash
         subjects affected / exposed
    21 / 418 (5.02%)
    22 / 416 (5.29%)
         occurrences all number
    23
    32
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    40 / 418 (9.57%)
    34 / 416 (8.17%)
         occurrences all number
    59
    42
    Bone Pain
         subjects affected / exposed
    21 / 418 (5.02%)
    17 / 416 (4.09%)
         occurrences all number
    29
    32
    Muscle Spasms
         subjects affected / exposed
    14 / 418 (3.35%)
    30 / 416 (7.21%)
         occurrences all number
    21
    35
    Myalgia
         subjects affected / exposed
    24 / 418 (5.74%)
    18 / 416 (4.33%)
         occurrences all number
    27
    26
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    51 / 418 (12.20%)
    64 / 416 (15.38%)
         occurrences all number
    71
    100
    Hypoalbuminaemia
         subjects affected / exposed
    9 / 418 (2.15%)
    24 / 416 (5.77%)
         occurrences all number
    11
    46
    Hypokalaemia
         subjects affected / exposed
    23 / 418 (5.50%)
    75 / 416 (18.03%)
         occurrences all number
    40
    157
    Hypomagnesaemia
         subjects affected / exposed
    7 / 418 (1.67%)
    22 / 416 (5.29%)
         occurrences all number
    9
    32
    Hyponatraemia
         subjects affected / exposed
    11 / 418 (2.63%)
    28 / 416 (6.73%)
         occurrences all number
    15
    42
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    9 / 418 (2.15%)
    22 / 416 (5.29%)
         occurrences all number
    11
    27
    Upper Respiratory Tract Infection
         subjects affected / exposed
    29 / 418 (6.94%)
    35 / 416 (8.41%)
         occurrences all number
    37
    39
    Urinary Tract Infection
         subjects affected / exposed
    15 / 418 (3.59%)
    24 / 416 (5.77%)
         occurrences all number
    19
    29

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2013
    Amendment INT-1: The overall reason for the amendment was to remove the biopsy/tissue requirement for confirmation of DLBCL diagnosis; update the protocol with new safety-related information and instructions; further clarify study treatment dosing instructions; revise operational aspects of the study; and perform minor modifications and formatting changes.
    05 Aug 2015
    Amendment INT-2: The overall reason for amendment was to clarify protocol recommendations for monitoring of subject subgroups who are considered, based on emerging literature, at increased risk of hepatitis B virus reactivation due to R-CHOP + ibrutinib/placebo therapy. Additionally, the protocol was updated with new safety-related information for consistency with the ibrutinib Investigator’s Brochure.
    16 Oct 2017
    Amendment INT-3: The overall reason for the amendment was to omit the interim analysis due to a lower than expected event-free survival event rate observed. To change retrospective analysis of the activated B cell like (ABC) diffuse large B cell lymphoma (DLBCL) population by gene expression profiling (GEP) from a secondary objective to a co-primary objective (ie, in addition to the already pre specified non germinal center B cell-like [non GCB] DLBCL population by immunohistochemistry [IHC]). The hypothesis and primary endpoint analysis were updated to include the ABC by GEP population and the statistical method was clarified.

    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.
    Sponsor decided to stop the study as all participants had concluded study treatment and outcomes were not expected to change and study was considered as completed.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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