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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination with Either Bendamustine and Rituximab (BR) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects with Previously Treated Indolent Non-Hodgkin Lymphoma (iNHL)

    Summary
    EudraCT number
    		 2013-003093-27
    Trial protocol
    		 SE   BE   GB   ES   IT   DE   PL   FR  
    Global end of trial date
    21 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2024
    First version publication date
    06 Jul 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PCI-32765FLR3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01974440
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202 South, Raritan, New Jersey, United States, 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to evaluate whether the addition of ibrutinib of either bendamustine and rituximab (BR) to the combination or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combination would result in prolongation of progression-free survival (PFS), as assessed by investigator, compared with either BR or R-CHOP alone in subjects with previously treated indolent Non-Hodgkin lymphoma (iNHL) (follicular lymphoma [FL] or marginal zone lymphoma [MZL]).
    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 Practice and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2014
    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: 10
    Country: Number of subjects enrolled
    Australia: 37
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    China: 57
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Israel: 33
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Korea, Republic of: 26
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Türkiye: 20
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    403
    EEA total number of subjects
    87
    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)
    257
    From 65 to 84 years
    142
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 403 subjects were randomised, of which 400 subjects were treated and 126 subjects completed the study. Placebo+CIT arm subjects discontinued the study treatment post the primary analysis but were assessed for the safety till the end of the study.

    Pre-assignment
    Screening details
    		 Subjects were stratified by background chemotherapy treatment (BR or combination or R-CHOP), refractory versus relapsed disease, Indolent non-Hodgkin lymphoma histology, and number of prior lines of therapy. No further efficacy analyses were done after the primary analysis.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + Chemoimmunotherapy (CIT)
    Arm description
    		 Subjects received 4 capsules of placebo matching to ibrutinib orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m^2 IV on Day 1, cyclophosphamide 750 mg/m^2 IV on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, subjects randomised to arm "Placebo + CIT" 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 placebo (4 capsules) matching to ibrutinib once daily continuously starting on 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
    As a background therapy subjects received BR regimen: rituximab 375 mg/m^2 IV on Day 1 of each cycle of 21 days.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: prednisone 100 mg on Days 1 to 5 of each cycle of 21 days.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: cyclophosphamide 750 mg/m^2 IV on Day 1 of each cycle of 21 days.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: doxorubicin 50 mg/m^2 IV on Day 1 of each cycle of 21 days.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1 of each cycle of 21 days.

    Investigational medicinal product name
    Bendamustine hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received BR regimen: bendamustine hydrochloride 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1 and 2 of each cycle of 21 days.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: rituximab 375 mg/m^2 IV on Day 1 of each cycle of 21 days.

    Arm title
    		 Ibrutinib + CIT
    Arm description
    		 Subjects received ibrutinib 560 mg capsules (4 capsules of 140 mg) orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m^2 IV on Day 1, cyclophosphamide 750 mg/m^2 IV on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, subjects randomised to arm "Ibrutinib + CIT" continued/stopped treatment with ibrutinib at the discretion of the treating physician.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    JNJ-54179060; PCI-32765
    Other name
    Imbruvica
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ibrutinib 560 mg (4 capsules of 140 mg) once daily continuously starting on Cycle 1, Day 1 of each cycle of 21 days.

    Investigational medicinal product name
    Bendamustine hydrochloride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received BR regimen: bendamustine hydrochloride 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1 and 2 of each cycle of 21 days.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received BR regimen: rituximab 375 mg/m^2 IV on Day 1 of each cycle.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: prednisone 100 mg on Days 1 to 5 of each cycle of 21 days.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: cyclophosphamide 750 mg/m^2 IV on Day 1 of each cycle of 21 days.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1 of each cycle of 21 days.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    As a background therapy subjects received R-CHOP regimen: rituximab 375 mg/m^2 IV on Day 1 of each cycle of 21 days.

    Number of subjects in period 1
    		Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Started
    201
    202
    Safety Analysis Set
    199
    201
    Subjects With MZL
    28 [1]
    28 [2]
    Subjects with FL
    173
    174
    Completed
    61
    65
    Not completed
    140
    137
         Consent withdrawn by subject
    24
    20
         Lost to follow-up
    7
    7
         Sponsor decision
    109
    110
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only reported subjects were included in the sub study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only reported subjects were included in the sub study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + Chemoimmunotherapy (CIT)
    Reporting group description
    		 Subjects received 4 capsules of placebo matching to ibrutinib orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m^2 IV on Day 1, cyclophosphamide 750 mg/m^2 IV on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, subjects randomised to arm "Placebo + CIT" discontinued placebo treatment.

    Reporting group title
    Ibrutinib + CIT
    Reporting group description
    		 Subjects received ibrutinib 560 mg capsules (4 capsules of 140 mg) orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m^2 IV on Day 1, cyclophosphamide 750 mg/m^2 IV on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, subjects randomised to arm "Ibrutinib + CIT" continued/stopped treatment with ibrutinib at the discretion of the treating physician.

    Reporting group values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT Total
    Number of subjects
    		 201 202 403
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 129 128 257
        From 65 to 84 years
    		 69 73 142
        85 years and over
    		 3 1 4
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.7 ( 12.7 ) 58.9 ( 11.86 ) -
    Title for Gender
    Units: subjects
        Female
    		 102 89 191
        Male
    		 99 113 212

    End points

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    End points reporting groups
    Reporting group title
    Placebo + Chemoimmunotherapy (CIT)
    Reporting group description
    		 Subjects received 4 capsules of placebo matching to ibrutinib orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m^2 IV on Day 1, cyclophosphamide 750 mg/m^2 IV on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, subjects randomised to arm "Placebo + CIT" discontinued placebo treatment.

    Reporting group title
    Ibrutinib + CIT
    Reporting group description
    		 Subjects received ibrutinib 560 mg capsules (4 capsules of 140 mg) orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m^2 IV on Day 1, cyclophosphamide 750 mg/m^2 IV on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, subjects randomised to arm "Ibrutinib + CIT" continued/stopped treatment with ibrutinib at the discretion of the treating physician.

    Primary: Primary Analysis: Progression Free Survival (PFS): Stratified Analysis

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    End point title
    		 Primary Analysis: Progression Free Survival (PFS): Stratified Analysis
    End point description
    PFS: duration (in months) from the date of randomisation to the date of disease progression or relapse from complete response (CR) or death, whichever was first reported. Per 2007 Revised Response Criteria for Malignant Lymphoma disease progression: any new lesion or increase by greater than or equal to (>=) 50 percent (%) of previously involved sites from nadir disease progression 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. Subjects who were progression-free and alive or had unknown status were censored at the last tumor assessment. Kaplan-Meier method and stratification factors was used for the analysis. Intent-to-treat (ITT) population: who were enrolled with follicular lymphoma (FL) or marginal zone lymphoma (MZL) and were analysed according to the treatment to which they were randomised.
    End point type
    Primary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    201
    202
    Units: Months
        median (confidence interval 95%)
    23.75 (20.11 to 31.18)
    40.51 (32.62 to 52.80)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Chemoimmunotherapy (CIT) v Ibrutinib + CIT
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0922
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.806
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.626
         upper limit
    		 1.037

    Primary: Supplementary Analysis: Progression Free Survival: Unstratified Analysis - Subjects With Marginal Zone Lymphoma (MZL)

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    End point title
    		 Supplementary Analysis: Progression Free Survival: Unstratified Analysis - Subjects With Marginal Zone Lymphoma (MZL)
    End point description
    PFS in MZL:duration (in months) from date of randomisation to date of disease progression or relapse from CR or death, whichever was first reported. Per 2007 Revised Response Criteria for Malignant Lymphoma: disease progression: any new lesion or increase by >=50% of previously involved sites from nadir disease progression criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in SPD of >1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. Subjects who were progression-free and alive or had unknown status were censored at last tumor assessment. Kaplan-Meier method was used for analysis. Unstratified analysis was performed on subjects with MZL. All randomised subjects who were enrolled with MZL and were analysed according to treatment to which they were randomised. Here, 99999 represents that median and upper limit 95% CI were not calculated due to insufficient number of subjects with events.
    End point type
    Primary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    28
    28
    Units: Months
        median (confidence interval 95%)
    91.63 (9.23 to 99999)
    99999 (49.25 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + Chemoimmunotherapy (CIT) v Ibrutinib + CIT
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4505
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.725
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.312
         upper limit
    		 1.682

    Secondary: Primary Analysis: Overall Survival (OS): Stratified Analysis

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    End point title
    		 Primary Analysis: Overall Survival (OS): Stratified Analysis
    End point description
    OS was defined as the interval (in months) between the date of randomisation and the date of the subject's death due to any cause. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis. ITT population included all randomised subjects who were enrolled with FL or MZL and were analysed according to the treatment to which they were randomised. Here, 99999 represents that median, upper and lower limit of 95% confidence interval (CI) were not calculated due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    201
    202
    Units: Months
        median (confidence interval 95%)
    99999 (94.19 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Supplementary Analysis: Overall Survival: Unstratified Analysis - Subjects With MZL

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    End point title
    		 Supplementary Analysis: Overall Survival: Unstratified Analysis - Subjects With MZL
    End point description
    OS in MZL subjects was defined as the interval (in months) between the date of randomisation and the date of the subject's death due to any cause. Kaplan-Meier method was used for the analysis. For this end point, unstratified analysis was performed on subjects with MZL. All randomised subjects who were enrolled with MZL and were analysed according to the treatment to which they were randomised. Here, 99999 represents that median, upper and lower limit of 95% CI were not calculated due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    28
    28
    Units: Months
        median (confidence interval 95%)
    99999 (75.86 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Primary Analysis: Complete Response Rate (CRR): Stratified Analysis

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    End point title
    		 Primary Analysis: Complete Response Rate (CRR): Stratified Analysis
    End point description
    CRR was defined as the percentage of subjects who achieved a complete response (CR); (based on investigator assessment) on or prior to the initiation of subsequent antilymphoma 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 CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy and no new sites of disease detected during assessment. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis. ITT population included all randomised subjects who were enrolled with FL or MZL and were analysed according to the treatment to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    201
    202
    Units: Percentage of subjects
        number (not applicable)
    50.2
    55
    No statistical analyses for this end point

    Secondary: Supplementary Analysis: Complete Response Rate: Unstratified Analysis - Subjects With MZL

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    End point title
    		 Supplementary Analysis: Complete Response Rate: Unstratified Analysis - Subjects With MZL
    End point description
    CRR in MZL subjects was defined as the percentage of subjects who achieved a CR (based on investigator assessment) on or prior to the initiation of subsequent antilymphoma therapy. 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 and no new sites of disease detected during assessment. Kaplan-Meier method was used for the analysis. For this end point, unstratified analysis was performed on subjects with MZL. All randomised subjects who were enrolled with MZL and were analysed according to the treatment to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    28
    28
    Units: Percentage of subjects
        number (not applicable)
    60.7
    64.3
    No statistical analyses for this end point

    Secondary: Primary Analysis: Overall Response Rate (ORR): Stratified Analysis

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    End point title
    		 Primary Analysis: Overall Response Rate (ORR): Stratified Analysis
    End point description
    ORR was defined as the percentage of subjects who achieved a CR or partial response (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 and no new sites of disease detected during assessment. Criteria for PR: >=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. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis. ITT population included all randomised subjects who were enrolled with FL or MZL and were analysed according to the treatment to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    201
    202
    Units: Percentage of subjects
        number (not applicable)
    90.5
    91.6
    No statistical analyses for this end point

    Secondary: Supplementary Analysis: Overall Response Rate: Unstratified Analysis - Subjects With MZL

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    End point title
    		 Supplementary Analysis: Overall Response Rate: Unstratified Analysis - Subjects With MZL
    End point description
    ORR in MZL subjects was defined as the percentage of subjects who achieved a 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 and no new sites of disease detected during assessment. Criteria for PR: >=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. Kaplan-Meier method was used for the analysis. For this end point, unstratified analysis was performed on subjects with MZL. All randomised subjects who were enrolled with MZL and were analysed according to the treatment to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    28
    28
    Units: Percentage of subjects
        number (not applicable)
    82.1
    89.3
    No statistical analyses for this end point

    Secondary: Primary Analysis: Duration of Response (DOR): Stratified Analysis

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    End point title
    		 Primary Analysis: Duration of Response (DOR): Stratified Analysis
    End point description
    DOR:the interval (in months) between the date of initial documentation of response (CR or PR) and the date of first documented evidence of progressive disease (or relapse for subjects who experienced CR during the study) or death, whichever occurred first. 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 and no new sites of disease detected during assessment. Criteria for PR: >=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. Kaplan-Meier method and stratification factors were used for the analysis. ITT population: randomised subjects enrolled with FL or MZL and were analysed according to the treatment to which they were randomised. Subjects achieved a PR or better included in this analysis.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    182
    185
    Units: Months
        median (confidence interval 95%)
    21.68 (17.61 to 32.36)
    44.32 (32.89 to 60.02)
    No statistical analyses for this end point

    Secondary: Supplementary Analysis: Duration of Response: Unstratified Analysis - Subjects With MZL

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    End point title
    		 Supplementary Analysis: Duration of Response: Unstratified Analysis - Subjects With MZL
    End point description
    DOR in MZL:interval (in months) between the date of initial documentation of response (CR or PR) and first evidence of progressive disease (or relapse for subjects with CR during the study) or death, whichever occurred first. CR criteria: disappearance of all evidence of disease; mass of any size permitted (PET negative); regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy and no new disease sites detected at assessment. PR criteria:>=50% decrease in diameter of target lesions compared to baseline, in absence of new lesions or unequivocal progression of non-target lesions. Kaplan-Meier method and unstratified analysis was performed. All randomised subjects enrolled with MZL and analysed according to the treatment to which they were randomised. Subjects who achieved a PR or better were included in this analysis. 99999:median and upper limit 95% CI not calculated due to insufficient subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    23
    25
    Units: Months
        median (confidence interval 95%)
    89.17 (42.48 to 99999)
    99999 (73.23 to 99999)
    No statistical analyses for this end point

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

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    End point title
    		 Primary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire
    End point description
    Time-to-worsening in the Lymphoma subscale of the FACT-Lym was defined as the time (in months) from the date of randomisation to the start date of the worsening of subject symptoms. Worsening was defined by a 5-point decrease from baseline in subject symptoms. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (0 = not at all, 1 = a little bit, 2 = some what, 3 = quite a bit and 4 = very much, where the higher score indicated worse condition). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life. ITT population included all randomised subjects who were enrolled with FL or MZL and were analysed according to the treatment to which they were randomised.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    201
    202
    Units: Months
        median (confidence interval 95%)
    37.03 (24.21 to 48.33)
    24.84 (14.95 to 31.28)
    No statistical analyses for this end point

    Secondary: Supplementary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire: Subjects with MZL

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    End point title
    		 Supplementary Analysis: Time to Worsening (TTW) in the Lymphoma (Lym) Subscale of the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) Questionnaire: Subjects with MZL
    End point description
    TTW in MZL subjects in the Lymphoma subscale of the FACT-Lym was defined as the time (in months) from the date of randomisation to the start date of the worsening of subject symptoms. Worsening was defined by a 5-point decrease from baseline in subject symptoms. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (0 = not at all, 1 = a little bit, 2 = some what, 3 = quite a bit and 4 = very much, where the higher score indicated worse condition). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Higher scores indicate a better quality of life. All randomised subjects who were enrolled with MZL and were analysed according to the treatment to which they were randomised. Here, 99999 represents that upper limit of 95% CI was not calculated due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Up to 8 years
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    28
    28
    Units: Months
        median (confidence interval 95%)
    36.83 (4.86 to 99999)
    58.91 (5.82 to 85.88)
    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. Adverse event (AE) was defined as any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non investigational) product. An AE did not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs were 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. Safety analysis population included all randomised subjects who received at least 1 dose of study drug, and were analysed according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Placebo + Chemoimmunotherapy (CIT) arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years); Ibrutinib + CIT arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years 8 months)
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    199
    201
    Units: Subjects
    197
    199
    No statistical analyses for this end point

    Secondary: Number of Subjects with TEAEs: Subjects with MZL

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    End point title
    		 Number of Subjects with TEAEs: Subjects with MZL
    End point description
    Number of MZL subjects with TEAEs were reported. AE was defined as any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non investigational) product. An AE did not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAEs were 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. Safety analysis population included all randomised subjects with MZL who received at least 1 dose of study drug, and were analysed according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Placebo + Chemoimmunotherapy (CIT) arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years); Ibrutinib + CIT arm: From Day 1 up to 30 days after date of last dose of study medication (up to 8 years 8 months)
    End point values
    		 Placebo + Chemoimmunotherapy (CIT) Ibrutinib + CIT
    Number of subjects analysed
    28
    28
    Units: Subjects
    28
    28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious & non-serious AEs:up to 30 days after last dose of study medication (up to 8 years for Placebo+CIT arm and 8 years 8 months for Ibrutinib+CIT arm); all cause deaths:Placebo+CIT: up to 8 years 4 months; Ibrutinib+CIT: up to 9 years 1 month
    Adverse event reporting additional description
    All AEs were based on safety analysis: who received at least 1 dose of study drug, analysed as per actual treatment received. Subjects not received study drug not included in the safety analysis. Placebo+CIT arm subjects discontinued the study treatment post the primary analysis but were assessed for the safety till the end of the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0.
    Reporting groups
    Reporting group title
    Ibrutinib + CIT
    Reporting group description
    		 Subjects received ibrutinib 560 mg capsules (4 capsules of 140 mg) orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 mg/m^2 IV on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m^2 IV on Day 1, cyclophosphamide 750 mg/m^2 IV on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, subjects randomised to arm "Placebo + CIT" discontinued placebo treatment.

    Reporting group title
    Placebo + Chemoimmunotherapy (CIT)
    Reporting group description
    		 Subjects received 4 capsules of placebo matching to ibrutinib orally once daily continuously starting on Cycle 1, Day 1 until disease progression, or unacceptable toxicity, or study end, whichever occurred first. All subjects also received a background therapy for maximum of 6 cycles (each cycle = 21 days) either with BR: bendamustine hydrochloride 90 milligrams per meter square (mg/m^2) intravenously (IV) on Days 1 and 2 of each cycle and rituximab 375 mg/m^2 IV on Day 1 of each cycle; or background therapy with R-CHOP: rituximab 375 mg/m^2 IV on Day 1, cyclophosphamide 750 mg/m^2 IV on Day 1, doxorubicin 50 mg/m^2 IV on Day 1, vincristine 1.4 mg/m^2 IV (maximum total 2 mg) on Day 1, and prednisone 100 mg orally on Days 1 to 5 until disease progression or unacceptable toxicity. After treatment unblinding at the time of the primary analysis, subjects randomised to arm "Placebo + CIT" discontinued placebo treatment.

    Serious adverse events
    		 Ibrutinib + CIT Placebo + Chemoimmunotherapy (CIT)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    113 / 201 (56.22%)
    76 / 199 (38.19%)
         number of deaths (all causes)
    64
    61
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung Neoplasm Malignant
         subjects affected / exposed
    2 / 201 (1.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute Myeloid Leukaemia
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Basal Cell Carcinoma
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder Cancer
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypopharyngeal Cancer
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myelodysplastic Syndrome
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Small Cell Lung Cancer
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Small Cell Lung Cancer Metastatic
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian Cancer
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Plasma Cell Myeloma
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of Skin
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (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 the Tongue
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional Cell Carcinoma
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal Cavity Cancer
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Venous Thrombosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity Necrosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         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 / 201 (1.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    16 / 201 (7.96%)
    5 / 199 (2.51%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Mass
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metaplasia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait Disturbance
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Cyst
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleuritic Pain
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis Chronic
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (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
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 201 (1.49%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Fibrosis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         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
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vocal Cord Leukoplakia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal Cord Polyp
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar Disorder
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disinhibition
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric Decompensation
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    3 / 201 (1.49%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand Fracture
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (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
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Related Reaction
         subjects affected / exposed
    3 / 201 (1.49%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    2 / 201 (1.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral Valve Incompetence
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    3 / 201 (1.49%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Dysfunction
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    4 / 201 (1.99%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic Valve Incompetence
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Tricuspid Valve Incompetence
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (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
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Ischaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (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
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Post Herpetic Neuralgia
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         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
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         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
    Thrombocytopenia
         subjects affected / exposed
    2 / 201 (1.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    5 / 201 (2.49%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    13 / 201 (6.47%)
    7 / 199 (3.52%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 201 (1.49%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tympanic Membrane Perforation
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear Discomfort
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual Impairment
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising Retinitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract Cortical
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal Artery Occlusion
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haemorrhoids
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Hernia
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Fissure
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Incontinence
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 201 (1.49%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's Disease
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 201 (1.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal Stenosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngo-Oesophageal Diverticulum
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Chronic
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Colitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         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
    3 / 201 (1.49%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 201 (1.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    3 / 201 (1.49%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile Duct Stone
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    5 / 201 (2.49%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis Noninfective
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 201 (0.00%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive Nephropathy
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvi-Ureteric Obstruction
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         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 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    3 / 201 (1.49%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis Bacterial
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus Infection
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus Chorioretinitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    4 / 201 (1.99%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronavirus Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Sinusitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    5 / 201 (2.49%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter Gastroenteritis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (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
    3 / 201 (1.49%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Bacteraemia
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Pyelonephritis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Salmonella
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1n1 Influenza
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Simplex
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    3 / 201 (1.49%)
    4 / 199 (2.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious Pleural Effusion
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective Exacerbation of Chronic Obstructive Airways Disease
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral Discitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 201 (1.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nocardiosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Endocarditis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Abscess
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         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 / 201 (0.50%)
    0 / 199 (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
    2 / 201 (1.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    20 / 201 (9.95%)
    9 / 199 (4.52%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 10
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Pneumonia Bacterial
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Cytomegaloviral
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Herpes Viral
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Klebsiella
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulpitis Dental
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    2 / 201 (1.00%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus Infection
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella Sepsis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 201 (3.98%)
    4 / 199 (2.01%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic Shock
         subjects affected / exposed
    3 / 201 (1.49%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    3 / 201 (1.49%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Sepsis
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tonsillitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 201 (1.49%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    7 / 201 (3.48%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular Neuronitis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Skin Infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (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
    2 / 201 (1.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to Thrive
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 201 (1.00%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    1 / 201 (0.50%)
    2 / 199 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ibrutinib + CIT Placebo + Chemoimmunotherapy (CIT)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    198 / 201 (98.51%)
    196 / 199 (98.49%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    19 / 201 (9.45%)
    17 / 199 (8.54%)
         occurrences all number
    37
    38
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 201 (7.96%)
    16 / 199 (8.04%)
         occurrences all number
    25
    25
    Chills
         subjects affected / exposed
    15 / 201 (7.46%)
    9 / 199 (4.52%)
         occurrences all number
    19
    15
    Fatigue
         subjects affected / exposed
    73 / 201 (36.32%)
    60 / 199 (30.15%)
         occurrences all number
    129
    120
    Influenza Like Illness
         subjects affected / exposed
    13 / 201 (6.47%)
    1 / 199 (0.50%)
         occurrences all number
    15
    1
    Malaise
         subjects affected / exposed
    16 / 201 (7.96%)
    8 / 199 (4.02%)
         occurrences all number
    26
    15
    Oedema Peripheral
         subjects affected / exposed
    18 / 201 (8.96%)
    18 / 199 (9.05%)
         occurrences all number
    24
    21
    Pyrexia
         subjects affected / exposed
    60 / 201 (29.85%)
    45 / 199 (22.61%)
         occurrences all number
    117
    79
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    20 / 201 (9.95%)
    7 / 199 (3.52%)
         occurrences all number
    24
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    57 / 201 (28.36%)
    40 / 199 (20.10%)
         occurrences all number
    99
    58
    Dyspnoea
         subjects affected / exposed
    19 / 201 (9.45%)
    21 / 199 (10.55%)
         occurrences all number
    28
    31
    Epistaxis
         subjects affected / exposed
    16 / 201 (7.96%)
    5 / 199 (2.51%)
         occurrences all number
    24
    6
    Oropharyngeal Pain
         subjects affected / exposed
    18 / 201 (8.96%)
    20 / 199 (10.05%)
         occurrences all number
    27
    23
    Productive Cough
         subjects affected / exposed
    15 / 201 (7.46%)
    17 / 199 (8.54%)
         occurrences all number
    21
    20
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 201 (8.46%)
    16 / 199 (8.04%)
         occurrences all number
    26
    17
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    27 / 201 (13.43%)
    23 / 199 (11.56%)
         occurrences all number
    57
    41
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    19 / 201 (9.45%)
    20 / 199 (10.05%)
         occurrences all number
    25
    40
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    15 / 201 (7.46%)
    3 / 199 (1.51%)
         occurrences all number
    37
    6
    Blood Bilirubin Increased
         subjects affected / exposed
    9 / 201 (4.48%)
    13 / 199 (6.53%)
         occurrences all number
    15
    19
    Blood Creatinine Increased
         subjects affected / exposed
    20 / 201 (9.95%)
    10 / 199 (5.03%)
         occurrences all number
    43
    15
    Lymphocyte Count Decreased
         subjects affected / exposed
    17 / 201 (8.46%)
    14 / 199 (7.04%)
         occurrences all number
    85
    77
    Neutrophil Count Decreased
         subjects affected / exposed
    32 / 201 (15.92%)
    27 / 199 (13.57%)
         occurrences all number
    134
    166
    Platelet Count Decreased
         subjects affected / exposed
    35 / 201 (17.41%)
    17 / 199 (8.54%)
         occurrences all number
    155
    89
    Weight Decreased
         subjects affected / exposed
    25 / 201 (12.44%)
    11 / 199 (5.53%)
         occurrences all number
    50
    19
    White Blood Cell Count Decreased
         subjects affected / exposed
    31 / 201 (15.42%)
    29 / 199 (14.57%)
         occurrences all number
    168
    211
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    12 / 201 (5.97%)
    3 / 199 (1.51%)
         occurrences all number
    16
    4
    Infusion Related Reaction
         subjects affected / exposed
    15 / 201 (7.46%)
    18 / 199 (9.05%)
         occurrences all number
    19
    23
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    12 / 201 (5.97%)
    5 / 199 (2.51%)
         occurrences all number
    14
    7
    Nervous system disorders
    Dizziness Postural
         subjects affected / exposed
    14 / 201 (6.97%)
    13 / 199 (6.53%)
         occurrences all number
    14
    17
    Headache
         subjects affected / exposed
    35 / 201 (17.41%)
    34 / 199 (17.09%)
         occurrences all number
    67
    61
    Neuropathy Peripheral
         subjects affected / exposed
    12 / 201 (5.97%)
    10 / 199 (5.03%)
         occurrences all number
    18
    12
    Paraesthesia
         subjects affected / exposed
    6 / 201 (2.99%)
    12 / 199 (6.03%)
         occurrences all number
    7
    16
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    12 / 201 (5.97%)
    8 / 199 (4.02%)
         occurrences all number
    20
    11
    Dysgeusia
         subjects affected / exposed
    12 / 201 (5.97%)
    3 / 199 (1.51%)
         occurrences all number
    15
    4
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    75 / 201 (37.31%)
    69 / 199 (34.67%)
         occurrences all number
    402
    342
    Lymphopenia
         subjects affected / exposed
    18 / 201 (8.96%)
    23 / 199 (11.56%)
         occurrences all number
    90
    68
    Leukopenia
         subjects affected / exposed
    27 / 201 (13.43%)
    26 / 199 (13.07%)
         occurrences all number
    199
    107
    Anaemia
         subjects affected / exposed
    50 / 201 (24.88%)
    39 / 199 (19.60%)
         occurrences all number
    154
    93
    Thrombocytopenia
         subjects affected / exposed
    46 / 201 (22.89%)
    28 / 199 (14.07%)
         occurrences all number
    187
    90
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    12 / 201 (5.97%)
    15 / 199 (7.54%)
         occurrences all number
    14
    16
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    102 / 201 (50.75%)
    69 / 199 (34.67%)
         occurrences all number
    225
    123
    Dry Mouth
         subjects affected / exposed
    13 / 201 (6.47%)
    6 / 199 (3.02%)
         occurrences all number
    19
    9
    Dyspepsia
         subjects affected / exposed
    25 / 201 (12.44%)
    15 / 199 (7.54%)
         occurrences all number
    36
    16
    Nausea
         subjects affected / exposed
    103 / 201 (51.24%)
    78 / 199 (39.20%)
         occurrences all number
    225
    180
    Vomiting
         subjects affected / exposed
    57 / 201 (28.36%)
    40 / 199 (20.10%)
         occurrences all number
    115
    76
    Constipation
         subjects affected / exposed
    33 / 201 (16.42%)
    54 / 199 (27.14%)
         occurrences all number
    53
    84
    Abdominal Pain Upper
         subjects affected / exposed
    19 / 201 (9.45%)
    13 / 199 (6.53%)
         occurrences all number
    26
    14
    Abdominal Pain
         subjects affected / exposed
    16 / 201 (7.96%)
    18 / 199 (9.05%)
         occurrences all number
    26
    23
    Stomatitis
         subjects affected / exposed
    27 / 201 (13.43%)
    12 / 199 (6.03%)
         occurrences all number
    58
    17
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    11 / 201 (5.47%)
    6 / 199 (3.02%)
         occurrences all number
    13
    6
    Dry Skin
         subjects affected / exposed
    13 / 201 (6.47%)
    9 / 199 (4.52%)
         occurrences all number
    17
    9
    Pruritus
         subjects affected / exposed
    25 / 201 (12.44%)
    30 / 199 (15.08%)
         occurrences all number
    33
    39
    Rash
         subjects affected / exposed
    68 / 201 (33.83%)
    33 / 199 (16.58%)
         occurrences all number
    120
    51
    Rash Maculo-Papular
         subjects affected / exposed
    16 / 201 (7.96%)
    12 / 199 (6.03%)
         occurrences all number
    32
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    28 / 201 (13.93%)
    36 / 199 (18.09%)
         occurrences all number
    49
    55
    Back Pain
         subjects affected / exposed
    21 / 201 (10.45%)
    21 / 199 (10.55%)
         occurrences all number
    28
    25
    Muscle Spasms
         subjects affected / exposed
    33 / 201 (16.42%)
    16 / 199 (8.04%)
         occurrences all number
    60
    23
    Myalgia
         subjects affected / exposed
    23 / 201 (11.44%)
    13 / 199 (6.53%)
         occurrences all number
    28
    18
    Pain in Extremity
         subjects affected / exposed
    17 / 201 (8.46%)
    21 / 199 (10.55%)
         occurrences all number
    26
    26
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    10 / 201 (4.98%)
    11 / 199 (5.53%)
         occurrences all number
    13
    12
    Bronchitis
         subjects affected / exposed
    21 / 201 (10.45%)
    25 / 199 (12.56%)
         occurrences all number
    38
    33
    Cellulitis
         subjects affected / exposed
    16 / 201 (7.96%)
    2 / 199 (1.01%)
         occurrences all number
    20
    4
    Conjunctivitis
         subjects affected / exposed
    11 / 201 (5.47%)
    6 / 199 (3.02%)
         occurrences all number
    17
    8
    Covid-19
         subjects affected / exposed
    15 / 201 (7.46%)
    4 / 199 (2.01%)
         occurrences all number
    16
    4
    Folliculitis
         subjects affected / exposed
    12 / 201 (5.97%)
    3 / 199 (1.51%)
         occurrences all number
    14
    3
    Herpes Zoster
         subjects affected / exposed
    15 / 201 (7.46%)
    22 / 199 (11.06%)
         occurrences all number
    21
    24
    Influenza
         subjects affected / exposed
    17 / 201 (8.46%)
    16 / 199 (8.04%)
         occurrences all number
    18
    18
    Nasopharyngitis
         subjects affected / exposed
    23 / 201 (11.44%)
    31 / 199 (15.58%)
         occurrences all number
    51
    82
    Pneumonia
         subjects affected / exposed
    25 / 201 (12.44%)
    11 / 199 (5.53%)
         occurrences all number
    38
    18
    Respiratory Tract Infection
         subjects affected / exposed
    9 / 201 (4.48%)
    12 / 199 (6.03%)
         occurrences all number
    13
    18
    Sinusitis
         subjects affected / exposed
    15 / 201 (7.46%)
    12 / 199 (6.03%)
         occurrences all number
    24
    16
    Skin Infection
         subjects affected / exposed
    15 / 201 (7.46%)
    4 / 199 (2.01%)
         occurrences all number
    24
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    47 / 201 (23.38%)
    49 / 199 (24.62%)
         occurrences all number
    94
    93
    Urinary Tract Infection
         subjects affected / exposed
    28 / 201 (13.93%)
    10 / 199 (5.03%)
         occurrences all number
    82
    11
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    44 / 201 (21.89%)
    33 / 199 (16.58%)
         occurrences all number
    73
    51
    Hyperglycaemia
         subjects affected / exposed
    6 / 201 (2.99%)
    11 / 199 (5.53%)
         occurrences all number
    18
    18
    Hyperuricaemia
         subjects affected / exposed
    16 / 201 (7.96%)
    4 / 199 (2.01%)
         occurrences all number
    25
    4
    Hypoalbuminaemia
         subjects affected / exposed
    12 / 201 (5.97%)
    2 / 199 (1.01%)
         occurrences all number
    21
    2
    Hypokalaemia
         subjects affected / exposed
    36 / 201 (17.91%)
    12 / 199 (6.03%)
         occurrences all number
    89
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2014
    The purpose of this amendment was to remove requirement that only ~70% of subjects can receive 1 of the background chemotherapies as well as to implement several administrative clarifications. Updates on safety related information (eg, monitoring for ocular symptoms and atrial fibrillation; potential risks; and guidance on co-administration with certain concomitant medications) had been implemented to align with the current Investigator’s Brochure (IB).
    29 Aug 2022
    The purpose of this amendment was to update the dose modification guidance and the data that was being collected after the clinical cutoff for the primary analysis.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    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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