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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 Bendamustine and Rituximab (BR) in Subjects With Newly Diagnosed Mantle Cell Lymphoma

    Summary
    EudraCT number
    2012-004056-11
    Trial protocol
    SE   BE   GB   DE   HU   IE   IT   PT   SK   ES   NL   FR   PL   CZ   GR  
    Global end of trial date
    24 Jun 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Jul 2025
    First version publication date
    09 Jul 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCI-32765MCL3002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01776840
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, 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
    03 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the whether the addition of ibrutinib to bendamustine and rituximab resulted in prolongation of progression free survival (PFS) in subjects with newly diagnosed mantle cell lymphoma (MCL) who are 65 years of age or older.
    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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 May 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
    Argentina: 4
    Country: Number of subjects enrolled
    Australia: 31
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Brazil: 21
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    China: 57
    Country: Number of subjects enrolled
    Czechia: 15
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 35
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Sweden: 18
    Country: Number of subjects enrolled
    Türkiye: 14
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Ukraine: 11
    Country: Number of subjects enrolled
    United States: 83
    Worldwide total number of subjects
    523
    EEA total number of subjects
    188
    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)
    0
    From 65 to 84 years
    513
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 523 subjects were randomised in this study.

    Pre-assignment
    Screening details
    A total of 523 subjects were randomised in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo + Bendamustine and Rituximab (BR) (Treatment A)
    Arm description
    Subjects received 4 capsules of ibrutinib-matching placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenous [IV] infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with complete response (CR) or partial response (PR) continued background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 every second cycle starting at Cycle 8 for maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Subjects received treatment A up to 100.1 months. After treatment unblinding at primary analysis, subjects discontinued placebo treatment.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 4 capsules of ibrutinib-matching placebo orally once daily continuously from Cycle 1 Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle) for a maximum of 6 cycles, unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received bendamustine hydrochloride 90 mg/m^2 IV infusion on Days 1 and 2 of each cycle for a maximum of 6 cycles unless disease progression or unacceptable toxicity prior to Cycle 6.

    Arm title
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Arm description
    Subjects received ibrutinib capsules 560 mg (4*140 mg capsule) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 of every second cycle starting at Cycle 8 for maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Subjects received treatment B up to 117.2 months. After treatment unblinding at primary analysis, subjects continued treatment with ibrutinib at discretion of investigator.
    Arm type
    Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    JNJ-54179060
    Other name
    IMBRUVICA, PCI-32765
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ibrutinib capsules 560 milligrams (mg) (4*140 mg capsule) administered orally once daily continuously from Cycle 1 Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle) for a maximum of 6 cycles, unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with a CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 every second cycle starting at Cycle 8 for a maximum of 12 additional doses unless disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received bendamustine hydrochloride 90 mg/m^2 IV infusion on Days 1 and 2 of each cycle for a maximum of 6 cycles, unless disease progression or unacceptable toxicity prior to Cycle 6.

    Number of subjects in period 1
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Started
    262
    261
    Safety analysis set (treated)
    260
    259
    Completed
    129
    119
    Not completed
    133
    142
         Consent withdrawn by subject
    32
    48
         Lost to follow-up
    12
    7
         Sponsor decision
    89
    87

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Bendamustine and Rituximab (BR) (Treatment A)
    Reporting group description
    Subjects received 4 capsules of ibrutinib-matching placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenous [IV] infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with complete response (CR) or partial response (PR) continued background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 every second cycle starting at Cycle 8 for maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Subjects received treatment A up to 100.1 months. After treatment unblinding at primary analysis, subjects discontinued placebo treatment.

    Reporting group title
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Reporting group description
    Subjects received ibrutinib capsules 560 mg (4*140 mg capsule) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 of every second cycle starting at Cycle 8 for maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Subjects received treatment B up to 117.2 months. After treatment unblinding at primary analysis, subjects continued treatment with ibrutinib at discretion of investigator.

    Reporting group values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B) Total
    Number of subjects
    262 261 523
    Age categorical
    Units: Subjects
        In Utero
    0 0 0
        Preterm newborn infants (gestional age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days - 23 months)
    0 0 0
        Children (2 - 11 years)
    0 0 0
        12 - 17 years
    0 0 0
        Adults (18 - 64 years)
    0 0 0
        From 65 - 84 years
    257 256 513
        85 years and over
    5 5 10
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.7 ( 5.2 ) 71.8 ( 5.04 ) -
    Gender categorical
    Units: Subjects
        Male
    186 178 364
        Female
    76 83 159

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Bendamustine and Rituximab (BR) (Treatment A)
    Reporting group description
    Subjects received 4 capsules of ibrutinib-matching placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenous [IV] infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with complete response (CR) or partial response (PR) continued background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 every second cycle starting at Cycle 8 for maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Subjects received treatment A up to 100.1 months. After treatment unblinding at primary analysis, subjects discontinued placebo treatment.

    Reporting group title
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Reporting group description
    Subjects received ibrutinib capsules 560 mg (4*140 mg capsule) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 of every second cycle starting at Cycle 8 for maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Subjects received treatment B up to 117.2 months. After treatment unblinding at primary analysis, subjects continued treatment with ibrutinib at discretion of investigator.

    Primary: Progression-free Survival (PFS)

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    End point title
    Progression-free Survival (PFS)
    End point description
    PFS was defined as the interval between the date of randomization to the date of disease progression (PD) or relapse from complete response (CR) or death, whichever was first reported. Disease assessments were based on the 2007 Revised Response Criteria for Malignant Lymphoma. PD was defined as any new lesion or increase by 50 percent (%) of previously involved sites from nadir (PD criteria: Appearance of new nodal lesion 1.5 centimeters [cm] in any axis, 50% increase in sum of product of diameters [SPD] of greater than [>] 1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis). Intent-to-treat (ITT) analysis set included all randomised subjects and classified according to assigned treatment group, regardless of actual treatment received. '99999' refers that upper limit of 95% confidence interval were not estimable due to low number of subjects with events.
    End point type
    Primary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    262
    261
    Units: months
        median (confidence interval 95%)
    52.9 (43.7 to 71.0)
    80.6 (61.9 to 99999)
    Statistical analysis title
    Statistical Test 1
    Statistical analysis description
    Ibrutinib + BR (Treatment B), Placebo + BR (Treatment A)
    Comparison groups
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) v Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.011
    Method
    Log Rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    0.96

    Secondary: Complete Response Rate

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    End point title
    Complete Response Rate
    End point description
    Complete response (CR) rate was defined as the percentage of subjects who achieve CR (based on investigator assessment) on or prior to the initiation of subsequent anticancer therapy. Criteria for CR: disappearance of all evidence of disease; mass of any size permitted if positron emission tomography (PET) negative; regression to normal size on computed tomography (CT); spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy. ITT analysis set included all randomised subjects and classified according to the assigned treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    262
    261
    Units: percentage of subjects
        number (not applicable)
    57.6
    65.5
    No statistical analyses for this end point

    Secondary: Time-to-Next Treatment

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    End point title
    Time-to-Next Treatment
    End point description
    Time-to-next treatment was measured from the date of randomization to the start date of any anti-mantle cell lymphoma (anti-MCL) treatment subsequent to the study treatment. ITT analysis set included all randomised subjects and classified according to the assigned treatment group, regardless of the actual treatment received. Here, '99999' refers that median, lower and upper 95% confidence interval were not estimable due to low number of subjects with events and '9999' signifies that upper limit of 95% CI could not be estimated due to low number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    262
    261
    Units: months
        median (confidence interval 95%)
    92.0 (71.5 to 9999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall survival was defined as the time from the date of randomization to the date of the subject’s death. Kaplan-Meier estimate was used. Intent-to-treat (ITT) analysis set included all randomised subjects and classified according to assigned treatment group, regardless of actual treatment received. Here, '99999' refers that upper limit of 95% confidence interval were not estimable due to low number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From randomisation (Day -3) up to 121 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    262
    261
    Units: months
        median (confidence interval 95%)
    95.9 (86.1 to 115.3)
    104.3 (81.1 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Overall Response

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    End point title
    Percentage of Subjects With Overall Response
    End point description
    Percentage of subjects with overall response was defined as the portion of subjects who achieved CR or PR. Criteria for CR: disappearance of all evidence of disease; 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. Criteria for PR: greater than or equal to (>=) 50% decrease in sum of the diameter of all target lesions compared with baseline, in absence of new lesions or unequivocal progression of non-target lesions. ITT analysis set included all randomised subjects and classified according to the assigned treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    262
    261
    Units: percentage of subjects
        number (not applicable)
    88.5
    89.7
    No statistical analyses for this end point

    Secondary: Minimal Residual Disease (MRD)-Negative Response Rate

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    End point title
    Minimal Residual Disease (MRD)-Negative Response Rate
    End point description
    Minimal residual disease negative rate was defined as the percentage of subjects with a best overall response of CR with MRD-negative disease status (that is, <5 mantle cell lymphoma [MCL] cell per 10,000 leukocytes for detection using the MRD assay), as assessed by flow cytometry of a bone marrow and/or peripheral blood sample. ITT analysis set included all randomised subjects and classified according to the assigned treatment group, regardless of the actual treatment received. CR subjects with missing MRD data and subjects who did not achieve a CR were considered non-responders.
    End point type
    Secondary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    262
    261
    Units: percentage of subjects
        number (not applicable)
    56.5
    62.1
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    Duration of Response (DoR)
    End point description
    Duration of Response (DoR) was defined as the interval between the date of initial documentation of a response including PR and the date of first documented evidence of PD or death. ITT analysis set included all randomised subjects and classified according to the assigned treatment group, regardless of the actual treatment received. Subjects who achieved a PR or better were included in the analysis of duration of response. Here, "99999" refers that the upper limit of 95% confidence interval was not estimable due to a small number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    232
    234
    Units: months
        median (confidence interval 95%)
    63.5 (47 to 76.9)
    81 (64.2 to 99999)
    No statistical analyses for this end point

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

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    End point title
    Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Questionnaire
    End point description
    Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomisation to the start date of worsening of subject's symptoms. Worsening was defined by a 5-point decrease from baseline, death, or a missing assessment due to being “too ill”, whichever occurred first. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score was the total of reverse scores, ranged 0 to 60. Higher scores indicated a better quality of life. ITT analysis set included all randomised subjects and classified according to the assigned treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    262
    261
    Units: months
        median (confidence interval 95%)
    22.2 (9.3 to 34.0)
    17.4 (8.3 to 27.6)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    Time to Response
    End point description
    Time to response was defined as the interval between the date of randomization and the date of initial documentation of a response. ITT analysis set included all randomised subjects and classified according to the assigned treatment group, regardless of the actual treatment received. Subjects who achieved a PR or better were included in the analysis of time to response.
    End point type
    Secondary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    232
    234
    Units: months
        median (full range (min-max))
    2.79 (1.9 to 11.2)
    2.79 (2.1 to 10.1)
    No statistical analyses for this end point

    Secondary: Duration of Complete Response (DoCR)

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    End point title
    Duration of Complete Response (DoCR)
    End point description
    Duration of complete response (DoCR) was defined as the interval between the date of initial documentation of a CR and the date of first documented evidence of PD or death whichever occurs first. ITT analysis set included all randomised subjects and classified according to the assigned treatment group, regardless of the actual treatment received. Subjects who achieved a CR or better were included in the analysis of duration of complete response. Here, "99999" refers that that the median and upper limit of 95% confidence interval were not estimable due to a small number of subjects and 9999 signifies that upper limit of 95% CI could not be estimated due to low number of subjects with events. .
    End point type
    Secondary
    End point timeframe
    Up to 97 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    151
    171
    Units: months
        median (confidence interval 95%)
    78.1 (65.6 to 9999)
    99999 (81.7 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
    End point description
    Number of subjects with TEAEs were reported. An AE was any untoward medical occurrence in a clinical study subject administered a medicinal (investigational or non investigational) product. An AE does not necessarily have a causal relationship with the intervention. Treatment-emergent adverse events are defined as adverse events with onset or worsening on or after date of first dose of study treatment up to and including 30 days after date of last dose of study medication, or the initiation of subsequent anticancer therapy, whichever is earlier. Safety analysis set included all randomised subjects who received at least 1 dose of study drug (ibrutinib or placebo).
    End point type
    Secondary
    End point timeframe
    Placebo + BR (Treatment A): From first dose of study treatment (Day 1) up to 100.1 months; Ibrutinib + BR (Treatment B): From first dose of study treatment (Day 1) up to 117.2 months
    End point values
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    260
    259
    Units: subjects
    257
    259
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State

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    End point title
    Area Under the Concentration Curve of Ibrutinib During 24 Hours After Dosing at Steady State [1]
    End point description
    Area under the concentration curve of ibrutinib during 24 hours after dosing at steady state was determined using PopPK modeling. Pharmacokinetic-evaluable population included subjects who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be reported for specified arms only.
    End point values
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    259
    Units: nanogram*hour per millilitre (ng*h/ mL)
        arithmetic mean (standard deviation)
    425 ( 267 )
    No statistical analyses for this end point

    Secondary: Oral Volume of Distribution at Steady State of Ibrutinib

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    End point title
    Oral Volume of Distribution at Steady State of Ibrutinib [2]
    End point description
    Oral volume of distribution at steady state of ibrutinib was determined using PopPK modeling Pharmacokinetic-evaluable population included subjects who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be reported for specified arms only.
    End point values
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    259
    Units: litre
        arithmetic mean (standard deviation)
    7286 ( 7.87 )
    No statistical analyses for this end point

    Secondary: Oral Plasma Clearance (CL/F) of Ibrutinib

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    End point title
    Oral Plasma Clearance (CL/F) of Ibrutinib [3]
    End point description
    CL/F was defined as apparent total systemic clearance of ibrutinib after extravascular administration. Cl/F of Ibrutinib was determined using population pharmacokinetics (PopPK modeling). Pharmacokinetic-evaluable population included subjects who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be reported for specified arms only.
    End point values
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    259
    Units: litre per hour (L/h)
        arithmetic mean (standard error)
    1123 ( 4.83 )
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration of Ibrutinib

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    End point title
    Minimum Observed Plasma Concentration of Ibrutinib [4]
    End point description
    Minimum observed plasma concentration of ibrutinib was determined using PopPK modeling. Pharmacokinetic-evaluable population included subjects who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be reported for specified arms only.
    End point values
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    259
    Units: ng/mL
        arithmetic mean (standard deviation)
    3.90 ( 2.64 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration of Ibrutinib

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    End point title
    Maximum Observed Plasma Concentration of Ibrutinib [5]
    End point description
    Maximum observed plasma concentration of ibrutinib was determined using PopPK modeling. Pharmacokinetic-evaluable population included subjects who have received at least 1 dose of ibrutinib/placebo and had at least 1 pharmacokinetic sample obtained posttreatment.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 2 of Cycles 1, 2 and 3; and 1, 2 and 4 hours post-dose on Day 2 of Cycles 1 and 2
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be reported for specified arms only.
    End point values
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Number of subjects analysed
    259
    Units: ng/mL
        arithmetic mean (standard deviation)
    74.5 ( 48.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Placebo + BR (Treatment A): From first dose of study treatment (Day 1) up to 100.1 months; Ibrutinib + BR (Treatment B): From first dose of study treatment (Day 1) up to 117.2 months
    Adverse event reporting additional description
    Safety analysis set included all randomised subjects who received at least 1 dose of study drug (ibrutinib or placebo).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo + Bendamustine and Rituximab (BR) (Treatment A)
    Reporting group description
    Subjects received 4 capsules of ibrutinib-matching placebo administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 milligrams per meter square [mg/m^2] intravenous [IV] infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with complete response (CR) or partial response (PR) continued background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 every second cycle starting at Cycle 8 for maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Subjects received treatment A up to 100.1 months. After treatment unblinding at primary analysis, subjects discontinued placebo treatment.

    Reporting group title
    Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Reporting group description
    Subjects received ibrutinib capsules 560 mg (4*140 mg capsule) administered orally once daily continuously starting on Day 1, Cycle 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a maximum of 6 cycles of BR background therapy (bendamustine hydrochloride 90 mg/m^2 IV infusion on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV infusion on Day 1 of each cycle), unless disease progression or unacceptable toxicity prior to Cycle 6. Subjects with CR or PR continued to receive background therapy with rituximab maintenance (375 mg/m^2 IV infusion) on Day 1 of every second cycle starting at Cycle 8 for maximum of 12 additional doses unless disease progression or unacceptable toxicity. Each cycle was of 28 days. Subjects received treatment B up to 117.2 months. After treatment unblinding at primary analysis, subjects continued treatment with ibrutinib at discretion of investigator.

    Serious adverse events
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    157 / 260 (60.38%)
    201 / 259 (77.61%)
         number of deaths (all causes)
    129
    120
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma Gastric
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myeloid Leukaemia
         subjects affected / exposed
    3 / 260 (1.15%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Bladder Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's Disease
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain Neoplasm Malignant
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign Anorectal Neoplasm
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Cancer
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of Colon
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendix Cancer
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    4 / 260 (1.54%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Myelomonocytic Leukaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Adenocarcinoma
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Langerhans' Cell Histiocytosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Adenocarcinoma
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic Malignant Melanoma
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic Syndrome
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Non-Small Cell Lung Cancer
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ocular Neoplasm
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Cell Carcinoma
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Squamous Cell Carcinoma Metastatic
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Cell Lung Cancer Metastatic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of Skin
         subjects affected / exposed
    4 / 260 (1.54%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid Cancer
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional Cell Carcinoma
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of Lung
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic Stenosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial Thrombosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Giant Cell Arteritis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Urgency
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Artery Aneurysm
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Raynaud's Phenomenon
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary Artery Bypass
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy Closure
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Fatigue
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 260 (0.00%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Chills
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised Oedema
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         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 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal Inflammation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    14 / 260 (5.38%)
    19 / 259 (7.34%)
         occurrences causally related to treatment / all
    5 / 18
    15 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug Hypersensitivity
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serum Sickness
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic Obstruction
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balanoposthitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    5 / 260 (1.92%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    2 / 260 (0.77%)
    7 / 259 (2.70%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infiltration
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising Pneumonia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity Pneumonitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive Cough
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 260 (0.38%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tonsillar Disorder
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device End of Service
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchoscopy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Stoma Output Increased
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    3 / 260 (1.15%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scan Abnormal
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus Test Positive
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial Bones Fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Related Reaction
         subjects affected / exposed
    4 / 260 (1.54%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head Injury
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb Injury
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Laceration
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma Complication
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    4 / 260 (1.54%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic Intracranial Haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal Fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Odontogenic Cyst
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    4 / 260 (1.54%)
    14 / 259 (5.41%)
         occurrences causally related to treatment / all
    1 / 5
    8 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         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
    4 / 260 (1.54%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 260 (0.38%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 260 (0.38%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    Coronary Artery Stenosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 260 (0.38%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Cardiomyopathy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Failure
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral Valve Stenosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    6 / 260 (2.31%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal Rhythm
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Silent Myocardial Infarction
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Bradycardia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular Extrasystoles
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic Lateral Sclerosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain Oedema
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Carotid Artery Stenosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central Nervous System Lesion
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dizziness
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial Paralysis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic Stroke
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar Stroke
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of Consciousness
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Motor Neuropathy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Herpetic Neuralgia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic Infarction
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 260 (1.92%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriplegia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Global Amnesia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Encephalopathy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         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
    3 / 260 (1.15%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    3 / 6
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    9 / 260 (3.46%)
    16 / 259 (6.18%)
         occurrences causally related to treatment / all
    8 / 12
    11 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic Infarction
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Methaemoglobinaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 260 (1.15%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 260 (0.38%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 260 (1.15%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Exophthalmos
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative Keratitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Abdomen
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 260 (0.77%)
    8 / 259 (3.09%)
         occurrences causally related to treatment / all
    2 / 2
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Perforation
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental Caries
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis Haemorrhagic
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth Haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth Ulceration
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 260 (0.38%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 260 (0.00%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Function Abnormal
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis Allergic
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Actinic Keratosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis Bullous
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Foot
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug Eruption
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug Reaction with Eosinophilia and Systemic Symptoms
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 260 (0.00%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 260 (0.38%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus Urinary
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Kidney Injury
         subjects affected / exposed
    2 / 260 (0.77%)
    8 / 259 (3.09%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Cyst Haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Obstruction
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperaldosteronism
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         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 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Finger Deformity
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw Cyst
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic Fracture
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Disorder
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Osteoarthritis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis Bacterial
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess Intestinal
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess Limb
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 260 (1.54%)
    7 / 259 (2.70%)
         occurrences causally related to treatment / all
    0 / 4
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    0 / 260 (0.00%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Campylobacter Gastroenteritis
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida Sepsis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 260 (1.15%)
    9 / 259 (3.47%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Colitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Covid-19 Pneumonia
         subjects affected / exposed
    2 / 260 (0.77%)
    8 / 259 (3.09%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 12
         deaths causally related to treatment / all
    0 / 0
    1 / 4
    Cystitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus Colitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         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 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Bacteraemia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal Oesophagitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 260 (0.38%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster Disseminated
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatitis B Reactivation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    3 / 260 (1.15%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Salmonella
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nosocomial Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Moraxella Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral Candidiasis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal Candidiasis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster Oticus
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histoplasmosis Disseminated
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infective Exacerbation of Chronic Obstructive Airways Disease
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Abscess
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningococcal Bacteraemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Candidiasis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis Chronic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parasitic Gastroenteritis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    35 / 260 (13.46%)
    58 / 259 (22.39%)
         occurrences causally related to treatment / all
    25 / 61
    52 / 85
         deaths causally related to treatment / all
    0 / 1
    2 / 3
    Periorbital Cellulitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal Bacteraemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Paronychia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Cytomegaloviral
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Fungal
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pseudomembranous Colitis
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia Pseudomonal
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Postoperative Wound Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive Multifocal Leukoencephalopathy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Sepsis
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Chronic
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 260 (0.77%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    2 / 260 (0.77%)
    5 / 259 (1.93%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 260 (2.31%)
    10 / 259 (3.86%)
         occurrences causally related to treatment / all
    2 / 7
    8 / 12
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Septic Shock
         subjects affected / exposed
    2 / 260 (0.77%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis Bacterial
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis Fungal
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Sepsis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal Bacteraemia
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suspected Covid-19
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Toxoplasmosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 260 (1.15%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 260 (0.77%)
    7 / 259 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 260 (1.15%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 260 (1.92%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    3 / 260 (1.15%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Hypoglycaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (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
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic Acidosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Placebo + Bendamustine and Rituximab (BR) (Treatment A) Ibrutinib + Bendamustine and Rituximab (BR) (Treatment B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    255 / 260 (98.08%)
    256 / 259 (98.84%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous Cell Carcinoma of Skin
         subjects affected / exposed
    13 / 260 (5.00%)
    12 / 259 (4.63%)
         occurrences all number
    24
    16
    Vascular disorders
    Haematoma
         subjects affected / exposed
    3 / 260 (1.15%)
    20 / 259 (7.72%)
         occurrences all number
    4
    34
    Hypertension
         subjects affected / exposed
    29 / 260 (11.15%)
    37 / 259 (14.29%)
         occurrences all number
    42
    57
    Hypotension
         subjects affected / exposed
    16 / 260 (6.15%)
    22 / 259 (8.49%)
         occurrences all number
    17
    24
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    25 / 260 (9.62%)
    30 / 259 (11.58%)
         occurrences all number
    38
    47
    Chest Pain
         subjects affected / exposed
    12 / 260 (4.62%)
    14 / 259 (5.41%)
         occurrences all number
    17
    15
    Pyrexia
         subjects affected / exposed
    76 / 260 (29.23%)
    88 / 259 (33.98%)
         occurrences all number
    115
    172
    Oedema Peripheral
         subjects affected / exposed
    42 / 260 (16.15%)
    50 / 259 (19.31%)
         occurrences all number
    60
    75
    Mucosal Inflammation
         subjects affected / exposed
    15 / 260 (5.77%)
    14 / 259 (5.41%)
         occurrences all number
    20
    20
    Malaise
         subjects affected / exposed
    14 / 260 (5.38%)
    12 / 259 (4.63%)
         occurrences all number
    19
    13
    Influenza Like Illness
         subjects affected / exposed
    13 / 260 (5.00%)
    14 / 259 (5.41%)
         occurrences all number
    15
    21
    Fatigue
         subjects affected / exposed
    77 / 260 (29.62%)
    79 / 259 (30.50%)
         occurrences all number
    134
    135
    Chills
         subjects affected / exposed
    39 / 260 (15.00%)
    17 / 259 (6.56%)
         occurrences all number
    46
    21
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    14 / 260 (5.38%)
    9 / 259 (3.47%)
         occurrences all number
    14
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    85 / 260 (32.69%)
    78 / 259 (30.12%)
         occurrences all number
    139
    127
    Dyspnoea
         subjects affected / exposed
    45 / 260 (17.31%)
    27 / 259 (10.42%)
         occurrences all number
    73
    39
    Epistaxis
         subjects affected / exposed
    13 / 260 (5.00%)
    31 / 259 (11.97%)
         occurrences all number
    19
    59
    Nasal Congestion
         subjects affected / exposed
    14 / 260 (5.38%)
    7 / 259 (2.70%)
         occurrences all number
    16
    11
    Oropharyngeal Pain
         subjects affected / exposed
    24 / 260 (9.23%)
    23 / 259 (8.88%)
         occurrences all number
    26
    28
    Productive Cough
         subjects affected / exposed
    18 / 260 (6.92%)
    16 / 259 (6.18%)
         occurrences all number
    29
    22
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    28 / 260 (10.77%)
    29 / 259 (11.20%)
         occurrences all number
    34
    35
    Anxiety
         subjects affected / exposed
    17 / 260 (6.54%)
    14 / 259 (5.41%)
         occurrences all number
    21
    22
    Depression
         subjects affected / exposed
    12 / 260 (4.62%)
    16 / 259 (6.18%)
         occurrences all number
    13
    19
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    12 / 260 (4.62%)
    23 / 259 (8.88%)
         occurrences all number
    17
    42
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    14 / 260 (5.38%)
    24 / 259 (9.27%)
         occurrences all number
    21
    45
    Blood Creatinine Increased
         subjects affected / exposed
    22 / 260 (8.46%)
    23 / 259 (8.88%)
         occurrences all number
    57
    32
    Lymphocyte Count Decreased
         subjects affected / exposed
    26 / 260 (10.00%)
    32 / 259 (12.36%)
         occurrences all number
    189
    213
    Neutrophil Count Decreased
         subjects affected / exposed
    43 / 260 (16.54%)
    39 / 259 (15.06%)
         occurrences all number
    188
    166
    Platelet Count Decreased
         subjects affected / exposed
    28 / 260 (10.77%)
    41 / 259 (15.83%)
         occurrences all number
    118
    144
    Weight Decreased
         subjects affected / exposed
    20 / 260 (7.69%)
    26 / 259 (10.04%)
         occurrences all number
    24
    45
    White Blood Cell Count Decreased
         subjects affected / exposed
    34 / 260 (13.08%)
    30 / 259 (11.58%)
         occurrences all number
    242
    229
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    12 / 260 (4.62%)
    23 / 259 (8.88%)
         occurrences all number
    15
    30
    Fall
         subjects affected / exposed
    13 / 260 (5.00%)
    16 / 259 (6.18%)
         occurrences all number
    16
    20
    Infusion Related Reaction
         subjects affected / exposed
    26 / 260 (10.00%)
    19 / 259 (7.34%)
         occurrences all number
    44
    24
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    13 / 260 (5.00%)
    9 / 259 (3.47%)
         occurrences all number
    16
    17
    Atrial Fibrillation
         subjects affected / exposed
    14 / 260 (5.38%)
    32 / 259 (12.36%)
         occurrences all number
    14
    33
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 260 (7.31%)
    22 / 259 (8.49%)
         occurrences all number
    26
    26
    Headache
         subjects affected / exposed
    40 / 260 (15.38%)
    33 / 259 (12.74%)
         occurrences all number
    65
    43
    Paraesthesia
         subjects affected / exposed
    13 / 260 (5.00%)
    13 / 259 (5.02%)
         occurrences all number
    15
    15
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    104 / 260 (40.00%)
    109 / 259 (42.08%)
         occurrences all number
    579
    412
    Lymphopenia
         subjects affected / exposed
    14 / 260 (5.38%)
    18 / 259 (6.95%)
         occurrences all number
    139
    93
    Leukopenia
         subjects affected / exposed
    14 / 260 (5.38%)
    27 / 259 (10.42%)
         occurrences all number
    121
    85
    Anaemia
         subjects affected / exposed
    60 / 260 (23.08%)
    83 / 259 (32.05%)
         occurrences all number
    187
    249
    Thrombocytopenia
         subjects affected / exposed
    43 / 260 (16.54%)
    62 / 259 (23.94%)
         occurrences all number
    146
    196
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    13 / 260 (5.00%)
    11 / 259 (4.25%)
         occurrences all number
    21
    16
    Eye disorders
    Dry Eye
         subjects affected / exposed
    5 / 260 (1.92%)
    16 / 259 (6.18%)
         occurrences all number
    5
    25
    Cataract
         subjects affected / exposed
    17 / 260 (6.54%)
    21 / 259 (8.11%)
         occurrences all number
    19
    30
    Vision Blurred
         subjects affected / exposed
    10 / 260 (3.85%)
    14 / 259 (5.41%)
         occurrences all number
    15
    24
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    29 / 260 (11.15%)
    25 / 259 (9.65%)
         occurrences all number
    36
    45
    Vomiting
         subjects affected / exposed
    48 / 260 (18.46%)
    56 / 259 (21.62%)
         occurrences all number
    86
    98
    Stomatitis
         subjects affected / exposed
    6 / 260 (2.31%)
    23 / 259 (8.88%)
         occurrences all number
    10
    33
    Nausea
         subjects affected / exposed
    107 / 260 (41.15%)
    109 / 259 (42.08%)
         occurrences all number
    217
    241
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    16 / 260 (6.15%)
    18 / 259 (6.95%)
         occurrences all number
    18
    21
    Dyspepsia
         subjects affected / exposed
    21 / 260 (8.08%)
    21 / 259 (8.11%)
         occurrences all number
    28
    28
    Dry Mouth
         subjects affected / exposed
    6 / 260 (2.31%)
    18 / 259 (6.95%)
         occurrences all number
    6
    22
    Diarrhoea
         subjects affected / exposed
    96 / 260 (36.92%)
    119 / 259 (45.95%)
         occurrences all number
    176
    268
    Constipation
         subjects affected / exposed
    66 / 260 (25.38%)
    52 / 259 (20.08%)
         occurrences all number
    87
    85
    Abdominal Pain Upper
         subjects affected / exposed
    10 / 260 (3.85%)
    19 / 259 (7.34%)
         occurrences all number
    18
    27
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    11 / 260 (4.23%)
    21 / 259 (8.11%)
         occurrences all number
    11
    23
    Erythema
         subjects affected / exposed
    12 / 260 (4.62%)
    13 / 259 (5.02%)
         occurrences all number
    18
    15
    Pruritus
         subjects affected / exposed
    56 / 260 (21.54%)
    47 / 259 (18.15%)
         occurrences all number
    73
    77
    Rash
         subjects affected / exposed
    57 / 260 (21.92%)
    95 / 259 (36.68%)
         occurrences all number
    87
    193
    Rash Maculo-Papular
         subjects affected / exposed
    10 / 260 (3.85%)
    22 / 259 (8.49%)
         occurrences all number
    15
    29
    Skin Lesion
         subjects affected / exposed
    11 / 260 (4.23%)
    16 / 259 (6.18%)
         occurrences all number
    16
    23
    Urticaria
         subjects affected / exposed
    7 / 260 (2.69%)
    16 / 259 (6.18%)
         occurrences all number
    9
    18
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    7 / 260 (2.69%)
    16 / 259 (6.18%)
         occurrences all number
    7
    23
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    44 / 260 (16.92%)
    46 / 259 (17.76%)
         occurrences all number
    62
    70
    Back Pain
         subjects affected / exposed
    38 / 260 (14.62%)
    36 / 259 (13.90%)
         occurrences all number
    50
    46
    Muscle Spasms
         subjects affected / exposed
    13 / 260 (5.00%)
    21 / 259 (8.11%)
         occurrences all number
    14
    29
    Muscular Weakness
         subjects affected / exposed
    5 / 260 (1.92%)
    15 / 259 (5.79%)
         occurrences all number
    7
    23
    Myalgia
         subjects affected / exposed
    30 / 260 (11.54%)
    33 / 259 (12.74%)
         occurrences all number
    44
    43
    Pain in Extremity
         subjects affected / exposed
    24 / 260 (9.23%)
    18 / 259 (6.95%)
         occurrences all number
    35
    22
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    36 / 260 (13.85%)
    33 / 259 (12.74%)
         occurrences all number
    55
    51
    Urinary Tract Infection
         subjects affected / exposed
    32 / 260 (12.31%)
    36 / 259 (13.90%)
         occurrences all number
    55
    76
    Conjunctivitis
         subjects affected / exposed
    6 / 260 (2.31%)
    26 / 259 (10.04%)
         occurrences all number
    6
    36
    Covid-19
         subjects affected / exposed
    3 / 260 (1.15%)
    17 / 259 (6.56%)
         occurrences all number
    3
    20
    Herpes Zoster
         subjects affected / exposed
    27 / 260 (10.38%)
    15 / 259 (5.79%)
         occurrences all number
    32
    16
    Influenza
         subjects affected / exposed
    16 / 260 (6.15%)
    9 / 259 (3.47%)
         occurrences all number
    23
    13
    Upper Respiratory Tract Infection
         subjects affected / exposed
    69 / 260 (26.54%)
    70 / 259 (27.03%)
         occurrences all number
    124
    115
    Skin Infection
         subjects affected / exposed
    5 / 260 (1.92%)
    18 / 259 (6.95%)
         occurrences all number
    5
    20
    Sinusitis
         subjects affected / exposed
    34 / 260 (13.08%)
    25 / 259 (9.65%)
         occurrences all number
    62
    44
    Rhinitis
         subjects affected / exposed
    13 / 260 (5.00%)
    10 / 259 (3.86%)
         occurrences all number
    15
    14
    Pneumonia
         subjects affected / exposed
    39 / 260 (15.00%)
    53 / 259 (20.46%)
         occurrences all number
    59
    73
    Oral Candidiasis
         subjects affected / exposed
    7 / 260 (2.69%)
    19 / 259 (7.34%)
         occurrences all number
    7
    31
    Nasopharyngitis
         subjects affected / exposed
    28 / 260 (10.77%)
    25 / 259 (9.65%)
         occurrences all number
    68
    53
    Lower Respiratory Tract Infection
         subjects affected / exposed
    9 / 260 (3.46%)
    13 / 259 (5.02%)
         occurrences all number
    15
    22
    Cellulitis
         subjects affected / exposed
    4 / 260 (1.54%)
    15 / 259 (5.79%)
         occurrences all number
    4
    20
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    36 / 260 (13.85%)
    54 / 259 (20.85%)
         occurrences all number
    57
    84
    Hyperglycaemia
         subjects affected / exposed
    10 / 260 (3.85%)
    15 / 259 (5.79%)
         occurrences all number
    22
    21
    Hyperuricaemia
         subjects affected / exposed
    20 / 260 (7.69%)
    24 / 259 (9.27%)
         occurrences all number
    25
    44
    Hypocalcaemia
         subjects affected / exposed
    7 / 260 (2.69%)
    17 / 259 (6.56%)
         occurrences all number
    7
    26
    Hypokalaemia
         subjects affected / exposed
    30 / 260 (11.54%)
    39 / 259 (15.06%)
         occurrences all number
    61
    80
    Hypomagnesaemia
         subjects affected / exposed
    18 / 260 (6.92%)
    24 / 259 (9.27%)
         occurrences all number
    44
    50

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Dec 2013
    The purpose of the protocol amendment 1 was to update the protocol with new safety-related information and safety instructions; further clarify study treatment dosing instructions and dose modifications; revise operational aspects of the study; provide updates based on new information, and perform minor modifications and formatting changes.
    15 Dec 2014
    The purpose of the protocol amendment 2 was to update the protocol with safety-related information for monitoring ocular events and atrial fibrillation, update to potential risks with ibrutinib, and update to administration of ibrutinib with certain concomitant medications.
    20 Aug 2015
    The purpose of the protocol amendment 3 was to update the safety language for diarrhea and other safety topics in the Introduction, the background safety information for ibrutinib had been aligned with the recently updated ibrutinib Investigator’s Brochure (IB) and other protocols within the clinical development program.
    29 Apr 2016
    The purpose of the protocol amendment 4 was knowledge gained on the efficacy of ibrutinib from completed randomised clinical studies, which was not available at time of MCL3002 study design, and the lower than expected event rate, were the key drivers for this amendment. The sponsor has added a second interim analysis to occur at approximately 180 PFS events to mitigate for the potential long interval between the planned first interim analysis (134 PFS events) and the final analysis (265 PFS events).
    12 Jul 2017
    The purpose of the protocol amendment 5 was to clarify that independent Data Monitoring Committee (DMC) recommendations, including treatment unblinding and stopping placebo treatment, may be implemented following an interim analysis. This amendment also updated the protocol to align with the most recent Investigator’s Brochure for ibrutinib: specifically, changes associated with dose modification for subjects with chronic hepatic impairment, and antimicrobial prophylaxis as a permitted medication in subjects who were at increased risk for opportunistic infections.
    16 Aug 2019
    The purpose of the protocol amendment 6 was to halt the collection of the complete response (CR) minimal residual disease (MRD) samples, except in subjects whose first assessment of CR was after the issue date of this amendment. Stopping the collection of MRD samples from current CR subjects will have no impact on the MRD-negative rate secondary endpoint, as all current CR subjects who were still on study and providing samples already have an MRD-negative sample.
    19 Dec 2019
    The purpose of the protocol amendment 7 was to update safety information to align with the ibrutinib Investigator’s Brochure (IB) to include information regarding cerebrovascular accidents as a new safety observation identified from the post-marketing setting, and clarified that assessment of pulse/heart rate and blood pressure was expected at every protocol-specified visit until end of treatment.
    27 Jun 2022
    The purpose of the protocol amendment 8 was to update the dose modification guidance and the data that was being collected after the final analysis of PFS.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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