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    Clinical Trial Results:
    Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination with Bendamustine and Rituximab (BR) in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

    Summary
    EudraCT number
    		 2012-000600-15
    Trial protocol
    		 SE   BE   ES   PT   GB   DE   GR   PL  
    Global end of trial date
    23 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2020
    First version publication date
    08 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCI-32765CLL3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01611090
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, United States, NJ 08869
    Public contact
    Janssen Research & Development, LLC, Clinical Registry Group, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen Research & Development, LLC, Clinical Registry Group, 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
    23 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study was to determine whether the addition of ibrutinib to bendamustine/rituximab (BR) significantly improved progression-free survival (PFS) compared with BR in subjects with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with good clinical practices and applicable regulatory requirements. The safety assessments included adverse events, clinical laboratory tests (hematology and chemistry), vital signs, physical examination results and electrocardiograms.
    Background therapy
    		 Bendamustine hydrochloride and Rituximab
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Sep 2012
    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: 6
    Country: Number of subjects enrolled
    Belgium: 28
    Country: Number of subjects enrolled
    Brazil: 22
    Country: Number of subjects enrolled
    Canada: 62
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Israel: 26
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Portugal: 19
    Country: Number of subjects enrolled
    Russian Federation: 100
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Turkey: 51
    Country: Number of subjects enrolled
    Ukraine: 30
    Country: Number of subjects enrolled
    United States: 64
    Worldwide total number of subjects
    578
    EEA total number of subjects
    212
    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)
    305
    From 65 to 84 years
    272
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 578 subjects were enrolled in the study. Among these, 289 subjects were randomized in each ibrutinib + bendamustine/rituximab (BR) treatment group and placebo+BR treatment group.

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ibrutinib+BR
    Arm description
    		 Subjects received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) oral once daily.

    Arm title
    		 Placebo+BR
    Arm description
    		 Subjects received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.
    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 (3 capsules) oral once daily.

    Number of subjects in period 1
    		Ibrutinib+BR Placebo+BR
    Started
    289
    289
    Crossover: Placebo to Ibrutinib
    0 [1]
    183 [2]
    Treated
    287
    287
    Completed
    259
    260
    Not completed
    30
    29
         Consent withdrawn by subject
    22
    26
         Lost to follow-up
    8
    3
    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 183 subjects from Placebo+BR group were crossed over to Ibrutinib group.
    [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 183 subjects from Placebo+BR group were crossed over to Ibrutinib group.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ibrutinib+BR
    Reporting group description
    		 Subjects received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.

    Reporting group title
    Placebo+BR
    Reporting group description
    		 Subjects received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.

    Reporting group values
    		 Ibrutinib+BR Placebo+BR Total
    Number of subjects
    		 289 289 578
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 145 160 305
        From 65 to 84 years
    		 143 129 272
        85 years and over
    		 1 0 1
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.7 ( 9.82 ) 63.3 ( 9.3 ) -
    Title for Gender
    Units: subjects
        Female
    		 96 100 196
        Male
    		 193 189 382

    End points

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    End points reporting groups
    Reporting group title
    Ibrutinib+BR
    Reporting group description
    		 Subjects received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.

    Reporting group title
    Placebo+BR
    Reporting group description
    		 Subjects received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.

    Primary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS was defined as the interval between the date of randomization and the date of disease progression or death, whichever was first reported. IWCLL 2008 criteria for PD: New enlarged nodes >1.5 cm, new hepatomegaly or splenomegaly, or other new organ infiltrates, bone lesion, ascites, or pleural effusion confirmed due to chronic lymphocytic leukemia (CLL); >=50% increase in existing lymph nodes; >=50% increase in enlargement of liver or spleen; >=50% increase from baseline in lymphocyte count (and to >=5*10^9/L) or >=50% increase from nadir count confirmed on >=2 serial assessments if absolute lymphocyte count (ALC) >=30,000 per microliter and lymphocyte doubling time is rapid, unless considered treatment-related lymphocytosis; new cytopenia (Hemoglobin b [Hgb] or platelets) attributable to CLL; and transformation to a more aggressive histology. ITT population included. Here, 99999 indicates that upper limit of CI was not evaluable due to insufficient number of events.
    End point type
    Primary
    End point timeframe
    Up to 5 years
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    289
    289
    Units: Months
        median (confidence interval 95%)
    65.12 (55.43 to 99999)
    14.32 (13.86 to 16.62)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Ibrutinib+BR v Placebo+BR
    Number of subjects included in analysis
    578
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.229
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.183
         upper limit
    		 0.286

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR defined as number of subjects achieving a complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR) or partial response (PR). IWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils >1.5*10^9/liter (L), platelets >100*10^9/L, Hgb >11 gram per deciliter (g/dL) and absolute lymphocyte count <4000/microliter (mcL); CRi- CR with incomplete recovery of bone marrow; nPR- subjects meet criteria for CR, but the bone marrow biopsy shows B-lymphoid nodules, may represent a clonal infiltrate; PR-2 of the following when abnormal at baseline: >=50% decrease in ALC, >=50% decrease in sum products of up to 6 lymph nodes, >=50% decrease in enlargement of spleen or liver; and 1 of the following: neutrophils >1.5*10^9/L, Platelets >100*10^9/L and Hgb>11 g/dL or >=50% improvement over baseline in any of these; no new enlarged nodes or new hepatosplenomegaly. ITT population included.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    289
    289
    Units: Percentage of subjects
        number (not applicable)
    87.2
    66.1
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the interval between the date of randomization and the date of death from any cause. ITT population included all subjects randomized into the study regardless of treatment actually received. Here, '99999' indicates that the data was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    289
    289
    Units: Months
        median (confidence interval 95%)
    99999 (70.93 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Minimal Residual Disease (MRD)-negative Response

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    End point title
    		 Percentage of Subjects with Minimal Residual Disease (MRD)-negative Response
    End point description
    MRD-negative response was defined as the percentage of subjects who reach MRD negative disease status (less than 1 chronic lymphocytic leukemia [CLL] cell per 10,000 leukocytes) in either bone marrow or peripheral blood. All randomized subjects were included in this analysis. Subjects with missing MRD data were considered non-responders. ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    289
    289
    Units: Percentage of subjects
        number (not applicable)
    28.7
    5.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Sustained Hematologic Improvement

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    End point title
    		 Percentage of Subjects with Sustained Hematologic Improvement
    End point description
    Sustained hematologic improvement was defined as hematological improvement that was sustained continuously for greater than or equal to (>=) 56 days without blood transfusion or growth factors: 1) Platelet counts greater than (>)100* 109/liter (L) if baseline less than or equal to (<=) 100*109/L or increase >= 50 percent (%) over baseline; 2) Hemoglobin >11 gram per deciliters (g/dL) if baseline <= 11 g/dL or increase >= 2 g/dL over baseline. ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    At disease progression, up to 5 years after the last subject was randomized
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    289
    289
    Units: Percentage of subjects
    number (not applicable)
        Hemoglobin
    36.7
    29.1
        Platelets
    30.8
    21.8
    No statistical analyses for this end point

    Secondary: Median Time to Clinically Meaningful Improvement in FACIT-Fatigue Scale

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    End point title
    		 Median Time to Clinically Meaningful Improvement in FACIT-Fatigue Scale
    End point description
    Time to improvement is defined as the time interval (months) from randomization to the first observation of improvement. FACIT-Fatigue is an instrument for use as a measure of the effect of fatigue in patients with cancer and other chronic diseases. Responses to the 13-item FACIT Fatigue Scale are reported on a 5‐point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    Up to 2 years
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    289
    289
    Units: Months
        number (confidence interval 95%)
    6.5 (4.7 to 10.7)
    4.6 (2.8 to 6.4)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Relevant Shifts in Disease-Related Symptoms

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    End point title
    		 Number of Subjects With Clinically Relevant Shifts in Disease-Related Symptoms
    End point description
    The disease-related symptoms included fatigue, weight loss, fevers, night sweats, abdominal discomfort/splenomegaly and anorexia. ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to disease progression (Up to 2 years)
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    289
    289
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects who Received Subsequent Antineoplastic Therapy

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    End point title
    		 Number of Subjects who Received Subsequent Antineoplastic Therapy
    End point description
    Number of subjects who received subsequent antineoplastic therapy was reported. Safety analysis set included all the randomized subjects who received at least 1 dose of study drug or placebo.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    287
    287
    Units: Subjects
    52
    61
    No statistical analyses for this end point

    Secondary: Change from Baseline in Beta2 Microglobulin at End of Treatment (EOT)

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    End point title
    		 Change from Baseline in Beta2 Microglobulin at End of Treatment (EOT)
    End point description
    Change from baseline in beta2 microglobulin at end of treatment at time of primary analysis was reported. ITT population included all subjects randomized into the study regardless of treatment actually received. Here, 'N' (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Up to 2 years)
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    39
    106
    Units: milligram per liter (mg/L)
        arithmetic mean (standard deviation)
    -0.46 ( 1.77 )
    -0.23 ( 2.08 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in FACIT-Fatigue Scale at End of Treatment

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    End point title
    		 Change from Baseline in FACIT-Fatigue Scale at End of Treatment
    End point description
    FACIT-Fatigue is an instrument for use as a measure of the effect of fatigue in patients with cancer and other chronic diseases. Responses to the 13-item FACIT Fatigue Scale are reported on a 5‐point categorical response scale ranging from 0 (not at all) to 4 (very much). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). ITT population included all subjects randomized into the study regardless of treatment actually received. Here, 'N' (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (up to 2 years)
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    38
    104
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -0.9 ( 11.22 )
    0.0 ( 11.01 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in EORTC QLQ-C30 Physical Functioning Score at End of Treatment

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    End point title
    		 Change from Baseline in EORTC QLQ-C30 Physical Functioning Score at End of Treatment
    End point description
    EORTC QLQ-C30 Physical Functioning Score is a questionnaire to assess quality of life of cancer patients. It is composed of 30 items, multi-item measure (28 items) and 2 single-item measures. For the multiple item measure, 4-point scale is used and the score for each item range from "1 = not at all" to "4 = very much". Higher scores indicate worsening. The 2 single-item measure involves question about the overall health and overall quality of life which was rated on a 7-point scale ranging from "1 = very poor" to "7 = excellent". Lower scores indicate worsening. All scale and item scores were linearly transformed to be in range from 0-100. A higher score represents a higher (better) level of functioning, or a higher (worse) level of symptoms. ITT population included all subjects randomized into the study regardless of treatment actually received. Here, 'N' (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (up to 2 years)
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    38
    104
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -2.1 ( 16.34 )
    -4.1 ( 22.52 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in EORTC QLQ-CLL 16 Domain Scores at End of Treatment

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    End point title
    		 Change from Baseline in EORTC QLQ-CLL 16 Domain Scores at End of Treatment
    End point description
    The EORTC QLQ-CLL 16 is a 16-item disease specific module that comprises 5 domains of patient-reported health status important in CLL. There are three multi-item scales that include fatigue (2 items), treatment side effects and disease symptoms (8 items), and infection (4 items), and 2 single-item scales on social activities and future health worries. Responses are measured on a 4 point scale ranging from 1 (not at all) to 4 (very much). ITT population included all subjects randomized into the study regardless of treatment actually received. Here, 'N' (number of subjects analyzed) signifies number of subjects evaluable for this endpoint. Here, 'n' signifies the number of subjects analyzed at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (up to 2 years)
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    38
    104
    Units: Units on the scale
    arithmetic mean (standard deviation)
        Lost weight (n=38,104)
    0.1 ( 0.86 )
    0.0 ( 0.74 )
        Dry mouth (n=38,104)
    0.3 ( 0.96 )
    0.1 ( 0.85 )
        Bruises (n=38,104)
    0.1 ( 0.61 )
    0.0 ( 0.65 )
        Abdominal discomfort (n=37,104)
    0.1 ( 0.81 )
    0.0 ( 0.76 )
        Temperature going up and down (n=38,104)
    0.1 ( 0.93 )
    0.0 ( 0.72 )
        Night sweats (n=38,103)
    -0.6 ( 0.92 )
    -0.3 ( 1.07 )
        Skin problems (n=37,104)
    0.4 ( 1.14 )
    0.3 ( 0.96 )
        Feel ill (n=38,104)
    0.1 ( 1.08 )
    0.2 ( 0.98 )
        Feel lethargic (n=38,104)
    0.1 ( 1.01 )
    0.0 ( 0.91 )
        Felt slowed down (n=38,103)
    0.3 ( 0.80 )
    0.0 ( 0.97 )
        Limited in planning activities (n=38,103)
    0.2 ( 0.97 )
    0.1 ( 0.90 )
        Worried about health in the future (n=38,103)
    0.0 ( 0.94 )
    0.0 ( 0.97 )
        Trouble with chest infections (n=38,104)
    0.2 ( 1.05 )
    0.0 ( 0.82 )
        Trouble with other infections (n=38,104)
    0.7 ( 1.07 )
    0.1 ( 0.86 )
        Repeated courses of antibiotics (n=38,104)
    0.9 ( 1.22 )
    0.0 ( 0.97 )
        Worried about picking up infection (n=38,103)
    0.3 ( 0.96 )
    0.2 ( 1.00 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Visual Analog Scale at End of Treatment

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    End point title
    		 Change from Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Visual Analog Scale at End of Treatment
    End point description
    The EQ-5D questionnaire is a brief, generic health-related quality of life assessment (HRQOL) that can also be used to incorporate subject preferences into health economic evaluations. The EQ-5D questionnaire assesses HRQOL in terms of degree of limitation on 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and as overall health using a visual analog scale with response options ranging from 0 (worst imaginable health) to 100 (best imaginable health). ITT population included all subjects randomized into the study regardless of treatment actually received. Here, 'N' (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (up to 2 years)
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    38
    110
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -4.3 ( 19.58 )
    4.0 ( 18.21 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Utility Score Scale at End of Treatment

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    End point title
    		 Change from Baseline in EuroQol-5 Dimension-5 Level (EQ-5D-5L) Utility Score Scale at End of Treatment
    End point description
    The EuroQol-5 is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1. High score indicating a high level of utility. ITT population included all subjects randomized into the study regardless of treatment actually received. Here, 'N' (number of subjects analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (up to 2 years)
    End point values
    		 Ibrutinib+BR Placebo+BR
    Number of subjects analysed
    38
    110
    Units: Units on a scale
        arithmetic mean (standard deviation)
    0.0 ( 0.28 )
    0.0 ( 0.24 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time a signed and dated informed consent form is obtained until 30 days following the last dose of study treatment or until the start of a subsequent systemic antineoplastic therapy, if earlier (up to 5 years)
    Adverse event reporting additional description
    Safety analysis set included all the randomized subjects who received at least 1 dose of study drug or placebo.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Ibrutinib+BR
    Reporting group description
    		 Subjects received ibrutinib 420 milligram (mg) (3 * 140 mg capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles ibrutinib alone was administered until disease progression or unacceptable toxicity.

    Reporting group title
    Placebo+BR
    Reporting group description
    		 Subjects received placebo (3 capsules) orally once daily starting on Cycle 1 Day 2 for a maximum of 6 cycles (each cycle of 28 days except Cycle 1 which was of 29 days) along with BR. After 6 cycles placebo alone was administered until disease progression or unacceptable toxicity.

    Reporting group title
    Crossover Ibrutinib
    Reporting group description
    		 Subjects in the placebo+BR treatment group could cross over to receive next-line ibrutinib treatment (420 mg [3 * 140 mg capsules] orally once daily on a 28-day cycle) at the discretion of the investigator at the time of disease progression or if IWCLL criteria for treatment were met.

    Serious adverse events
    		 Ibrutinib+BR Placebo+BR Crossover Ibrutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    198 / 287 (68.99%)
    127 / 287 (44.25%)
    105 / 183 (57.38%)
         number of deaths (all causes)
    74
    107
    57
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute Lymphocytic Leukaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenosquamous Cell Lung Cancer
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    5 / 287 (1.74%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    13 / 13
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Cancer
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchioloalveolar Carcinoma
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Myelomonocytic Leukaemia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Intestinal Adenocarcinoma
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraductal Papilloma of Breast
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Adenocarcinoma
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Malignant Melanoma
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma in Situ
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Maxillofacial Sinus Neoplasm
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to Central Nervous System
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Metastatic Renal Cell Carcinoma
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic Syndrome
         subjects affected / exposed
    2 / 287 (0.70%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Myeloproliferative Neoplasm
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Neuroendocrine Carcinoma
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Cancer
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Cancer Stage I
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Oncocytoma
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    3 / 287 (1.05%)
    1 / 287 (0.35%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma of Skin
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superficial Spreading Melanoma Stage Unspecified
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic Aneurysm Rupture
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Arterial Stenosis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 287 (0.35%)
    3 / 287 (1.05%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular Vein Thrombosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Artery Occlusion
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Artery Thrombosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complication Associated with Device
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Condition Aggravated
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    Disease Progression
         subjects affected / exposed
    1 / 287 (0.35%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 287 (1.05%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza Like Illness
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion Site Extravasation
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal Inflammation
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    1 / 287 (0.35%)
    3 / 287 (1.05%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
    5 / 5
         deaths causally related to treatment / all
    1 / 1
    3 / 3
    3 / 3
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 287 (3.83%)
    7 / 287 (2.44%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    13 / 13
    11 / 11
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden Cardiac Death
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Systemic Inflammatory Response Syndrome
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibrocystic Breast Disease
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Genital Rash
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic Floor Muscle Weakness
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Penile Dysplasia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine Prolapse
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 287 (0.35%)
    3 / 287 (1.05%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Infiltration
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    3 / 287 (1.05%)
    2 / 287 (0.70%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Congestion
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Mass
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Sarcoidosis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    Respiratory Tract Oedema
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sleep Apnoea Syndrome
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute Stress Disorder
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcoholic Psychosis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Confusional State
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Biopsy
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Body Temperature Increased
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic Specific Antigen Increased
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal Injury
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incision Site Haemorrhage
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion Related Reaction
         subjects affected / exposed
    4 / 287 (1.39%)
    5 / 287 (1.74%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumoconiosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax Traumatic
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Post Procedural Swelling
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic Vertebral Fracture
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 287 (0.00%)
    3 / 287 (1.05%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Angina Pectoris
         subjects affected / exposed
    4 / 287 (1.39%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia Supraventricular
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    16 / 287 (5.57%)
    2 / 287 (0.70%)
    6 / 183 (3.28%)
         occurrences causally related to treatment / all
    16 / 19
    2 / 2
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    Cardiac Failure
         subjects affected / exposed
    3 / 287 (1.05%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Cardiovascular Insufficiency
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Carditis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Occlusion
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    2 / 287 (0.70%)
    2 / 287 (0.70%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Myocarditis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    2 / 287 (0.70%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular Fibrillation
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular Flutter
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Ventricular Tachycardia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid Sinus Syndrome
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral Disorder
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    3 / 287 (1.05%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cognitive Disorder
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed Level of Consciousness
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Facial Paresis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Stroke
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of Consciousness
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningism
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post Herpetic Neuralgia
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient Global Amnesia
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular Encephalopathy
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 287 (1.05%)
    7 / 287 (2.44%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    2 / 3
    10 / 11
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aplasia Pure Red Cell
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aplastic Anaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune Haemolytic Anaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    5 / 287 (1.74%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone Marrow Failure
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytopenia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    30 / 287 (10.45%)
    22 / 287 (7.67%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    22 / 33
    20 / 28
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Haemolytic Anaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune Thrombocytopenic Purpura
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    7 / 287 (2.44%)
    6 / 287 (2.09%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    8 / 9
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    4 / 287 (1.39%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 287 (1.05%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Maculopathy
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal Haemorrhage
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scleral Disorder
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous Adhesions
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous Haemorrhage
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Incarcerated Hernia
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal Fistula
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 287 (0.35%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 287 (1.39%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer Perforation
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    3 / 287 (1.05%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Disorder
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Inflammation
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    4 / 287 (1.39%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intra-Abdominal Haemorrhage
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth Ulceration
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal Ulcer
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 287 (0.35%)
    2 / 287 (0.70%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Gallbladder Obstruction
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic Cirrhosis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Hepatitis Toxic
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular Injury
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hepatosplenomegaly
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute Febrile Neutrophilic Dermatosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug Eruption
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Excessive Granulation Tissue
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity Vasculitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pemphigoid
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pemphigus
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash Erythematous
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash Maculo-Papular
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Necrosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    2 / 287 (0.70%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus Bladder
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy Toxic
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    2 / 287 (0.70%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric Stenosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urge Incontinence
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Incontinence
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Addison's Disease
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chondrocalcinosis Pyrophosphate
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoroacetabular Impingement
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin Pain
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar Spinal Stenosis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle Haemorrhage
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 287 (1.05%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Jaw
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Actinomycotic Pulmonary Infection
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute Sinusitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis Bacterial
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascariasis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain Abscess
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast Abscess
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast Cellulitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    8 / 287 (2.79%)
    5 / 287 (1.74%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    8 / 10
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Campylobacter Infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 287 (1.39%)
    2 / 287 (0.70%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis Staphylococcal
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central Nervous System Infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic Sinusitis
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Infection
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus Colitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus Infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dacryocystitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermo-Hypodermitis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated Cryptococcosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr Virus Infection
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    3 / 183 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia Urinary Tract Infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal Infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemophilus Infection
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B Reactivation
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 287 (0.35%)
    2 / 287 (0.70%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 287 (1.05%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious Pleural Effusion
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 287 (0.70%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    3 / 287 (1.05%)
    3 / 287 (1.05%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis Bacterial
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle Abscess
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nocardiosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral Candidiasis
         subjects affected / exposed
    0 / 287 (0.00%)
    2 / 287 (0.70%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis Media
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital Cellulitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar Abscess
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal Abscess
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis Streptococcal
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    48 / 287 (16.72%)
    26 / 287 (9.06%)
    34 / 183 (18.58%)
         occurrences causally related to treatment / all
    59 / 64
    38 / 38
    42 / 46
         deaths causally related to treatment / all
    1 / 1
    3 / 3
    4 / 4
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Haemophilus
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Progressive Multifocal Leukoencephalopathy
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    Pseudomembranous Colitis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Tuberculoma
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash Pustular
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    5 / 287 (1.74%)
    2 / 287 (0.70%)
    5 / 183 (2.73%)
         occurrences causally related to treatment / all
    6 / 6
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 287 (2.79%)
    4 / 287 (1.39%)
    4 / 183 (2.19%)
         occurrences causally related to treatment / all
    9 / 9
    5 / 7
    6 / 6
         deaths causally related to treatment / all
    1 / 1
    2 / 3
    2 / 2
    Septic Shock
         subjects affected / exposed
    6 / 287 (2.09%)
    2 / 287 (0.70%)
    5 / 183 (2.73%)
         occurrences causally related to treatment / all
    9 / 9
    1 / 3
    7 / 7
         deaths causally related to treatment / all
    4 / 4
    0 / 1
    5 / 5
    Sinusitis
         subjects affected / exposed
    1 / 287 (0.35%)
    2 / 287 (0.70%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Candida
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    2 / 287 (0.70%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic Abscess
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    2 / 287 (0.70%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Skin Infection
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous Abscess
         subjects affected / exposed
    3 / 287 (1.05%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth Abscess
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis of Central Nervous System
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 287 (1.05%)
    3 / 287 (1.05%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    6 / 287 (2.09%)
    1 / 287 (0.35%)
    2 / 183 (1.09%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 287 (0.35%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicella Zoster Virus Infection
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 287 (0.70%)
    1 / 287 (0.35%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    1 / 287 (0.35%)
    0 / 287 (0.00%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    0 / 287 (0.00%)
    1 / 183 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 287 (0.00%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    6 / 287 (2.09%)
    1 / 287 (0.35%)
    0 / 183 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ibrutinib+BR Placebo+BR Crossover Ibrutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    268 / 287 (93.38%)
    271 / 287 (94.43%)
    157 / 183 (85.79%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    26 / 287 (9.06%)
    3 / 287 (1.05%)
    14 / 183 (7.65%)
         occurrences all number
    58
    3
    18
    Hypertension
         subjects affected / exposed
    47 / 287 (16.38%)
    14 / 287 (4.88%)
    27 / 183 (14.75%)
         occurrences all number
    70
    17
    38
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    26 / 287 (9.06%)
    24 / 287 (8.36%)
    5 / 183 (2.73%)
         occurrences all number
    39
    36
    5
    Chills
         subjects affected / exposed
    33 / 287 (11.50%)
    31 / 287 (10.80%)
    5 / 183 (2.73%)
         occurrences all number
    45
    35
    6
    Fatigue
         subjects affected / exposed
    69 / 287 (24.04%)
    66 / 287 (23.00%)
    32 / 183 (17.49%)
         occurrences all number
    145
    121
    45
    Influenza Like Illness
         subjects affected / exposed
    9 / 287 (3.14%)
    10 / 287 (3.48%)
    12 / 183 (6.56%)
         occurrences all number
    11
    14
    16
    Mucosal Inflammation
         subjects affected / exposed
    15 / 287 (5.23%)
    7 / 287 (2.44%)
    3 / 183 (1.64%)
         occurrences all number
    27
    11
    3
    Non-Cardiac Chest Pain
         subjects affected / exposed
    17 / 287 (5.92%)
    13 / 287 (4.53%)
    3 / 183 (1.64%)
         occurrences all number
    22
    16
    3
    Oedema Peripheral
         subjects affected / exposed
    49 / 287 (17.07%)
    34 / 287 (11.85%)
    21 / 183 (11.48%)
         occurrences all number
    82
    40
    24
    Pyrexia
         subjects affected / exposed
    74 / 287 (25.78%)
    60 / 287 (20.91%)
    22 / 183 (12.02%)
         occurrences all number
    140
    93
    29
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    74 / 287 (25.78%)
    75 / 287 (26.13%)
    27 / 183 (14.75%)
         occurrences all number
    116
    106
    41
    Dyspnoea
         subjects affected / exposed
    22 / 287 (7.67%)
    29 / 287 (10.10%)
    11 / 183 (6.01%)
         occurrences all number
    30
    43
    13
    Epistaxis
         subjects affected / exposed
    22 / 287 (7.67%)
    10 / 287 (3.48%)
    15 / 183 (8.20%)
         occurrences all number
    46
    15
    16
    Nasal Congestion
         subjects affected / exposed
    16 / 287 (5.57%)
    9 / 287 (3.14%)
    4 / 183 (2.19%)
         occurrences all number
    21
    14
    5
    Oropharyngeal Pain
         subjects affected / exposed
    30 / 287 (10.45%)
    20 / 287 (6.97%)
    8 / 183 (4.37%)
         occurrences all number
    42
    23
    8
    Productive Cough
         subjects affected / exposed
    21 / 287 (7.32%)
    18 / 287 (6.27%)
    9 / 183 (4.92%)
         occurrences all number
    30
    31
    12
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    30 / 287 (10.45%)
    20 / 287 (6.97%)
    13 / 183 (7.10%)
         occurrences all number
    47
    27
    19
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    22 / 287 (7.67%)
    11 / 287 (3.83%)
    9 / 183 (4.92%)
         occurrences all number
    30
    12
    10
    Depression
         subjects affected / exposed
    18 / 287 (6.27%)
    8 / 287 (2.79%)
    4 / 183 (2.19%)
         occurrences all number
    18
    9
    5
    Insomnia
         subjects affected / exposed
    27 / 287 (9.41%)
    21 / 287 (7.32%)
    10 / 183 (5.46%)
         occurrences all number
    36
    26
    10
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    15 / 287 (5.23%)
    12 / 287 (4.18%)
    3 / 183 (1.64%)
         occurrences all number
    17
    19
    4
    Blood Creatinine Increased
         subjects affected / exposed
    17 / 287 (5.92%)
    7 / 287 (2.44%)
    6 / 183 (3.28%)
         occurrences all number
    24
    7
    7
    Neutrophil Count Decreased
         subjects affected / exposed
    21 / 287 (7.32%)
    16 / 287 (5.57%)
    3 / 183 (1.64%)
         occurrences all number
    47
    60
    5
    Platelet Count Decreased
         subjects affected / exposed
    17 / 287 (5.92%)
    9 / 287 (3.14%)
    2 / 183 (1.09%)
         occurrences all number
    38
    23
    2
    Weight Decreased
         subjects affected / exposed
    18 / 287 (6.27%)
    18 / 287 (6.27%)
    5 / 183 (2.73%)
         occurrences all number
    24
    28
    5
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    30 / 287 (10.45%)
    9 / 287 (3.14%)
    15 / 183 (8.20%)
         occurrences all number
    56
    13
    27
    Infusion Related Reaction
         subjects affected / exposed
    45 / 287 (15.68%)
    64 / 287 (22.30%)
    1 / 183 (0.55%)
         occurrences all number
    66
    111
    2
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    23 / 287 (8.01%)
    5 / 287 (1.74%)
    19 / 183 (10.38%)
         occurrences all number
    35
    6
    23
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    15 / 287 (5.23%)
    15 / 287 (5.23%)
    3 / 183 (1.64%)
         occurrences all number
    16
    15
    3
    Headache
         subjects affected / exposed
    49 / 287 (17.07%)
    47 / 287 (16.38%)
    18 / 183 (9.84%)
         occurrences all number
    81
    74
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    73 / 287 (25.44%)
    79 / 287 (27.53%)
    33 / 183 (18.03%)
         occurrences all number
    154
    200
    56
    Leukopenia
         subjects affected / exposed
    15 / 287 (5.23%)
    18 / 287 (6.27%)
    2 / 183 (1.09%)
         occurrences all number
    26
    62
    3
    Neutropenia
         subjects affected / exposed
    170 / 287 (59.23%)
    159 / 287 (55.40%)
    40 / 183 (21.86%)
         occurrences all number
    659
    722
    82
    Thrombocytopenia
         subjects affected / exposed
    90 / 287 (31.36%)
    69 / 287 (24.04%)
    24 / 183 (13.11%)
         occurrences all number
    273
    223
    51
    Eye disorders
    Cataract
         subjects affected / exposed
    20 / 287 (6.97%)
    3 / 287 (1.05%)
    8 / 183 (4.37%)
         occurrences all number
    32
    3
    9
    Dry Eye
         subjects affected / exposed
    15 / 287 (5.23%)
    9 / 287 (3.14%)
    6 / 183 (3.28%)
         occurrences all number
    15
    12
    7
    Vision Blurred
         subjects affected / exposed
    19 / 287 (6.62%)
    19 / 287 (6.62%)
    3 / 183 (1.64%)
         occurrences all number
    21
    20
    3
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    39 / 287 (13.59%)
    24 / 287 (8.36%)
    3 / 183 (1.64%)
         occurrences all number
    45
    35
    3
    Abdominal Pain Upper
         subjects affected / exposed
    23 / 287 (8.01%)
    16 / 287 (5.57%)
    11 / 183 (6.01%)
         occurrences all number
    33
    23
    12
    Constipation
         subjects affected / exposed
    61 / 287 (21.25%)
    50 / 287 (17.42%)
    15 / 183 (8.20%)
         occurrences all number
    97
    71
    23
    Diarrhoea
         subjects affected / exposed
    115 / 287 (40.07%)
    68 / 287 (23.69%)
    47 / 183 (25.68%)
         occurrences all number
    248
    115
    87
    Dyspepsia
         subjects affected / exposed
    24 / 287 (8.36%)
    21 / 287 (7.32%)
    8 / 183 (4.37%)
         occurrences all number
    31
    30
    15
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    15 / 287 (5.23%)
    12 / 287 (4.18%)
    4 / 183 (2.19%)
         occurrences all number
    19
    12
    4
    Nausea
         subjects affected / exposed
    108 / 287 (37.63%)
    101 / 287 (35.19%)
    16 / 183 (8.74%)
         occurrences all number
    192
    204
    22
    Toothache
         subjects affected / exposed
    15 / 287 (5.23%)
    5 / 287 (1.74%)
    3 / 183 (1.64%)
         occurrences all number
    15
    8
    3
    Vomiting
         subjects affected / exposed
    42 / 287 (14.63%)
    45 / 287 (15.68%)
    15 / 183 (8.20%)
         occurrences all number
    63
    86
    26
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    27 / 287 (9.41%)
    17 / 287 (5.92%)
    7 / 183 (3.83%)
         occurrences all number
    32
    17
    8
    Ecchymosis
         subjects affected / exposed
    14 / 287 (4.88%)
    2 / 287 (0.70%)
    10 / 183 (5.46%)
         occurrences all number
    20
    2
    15
    Onychoclasis
         subjects affected / exposed
    10 / 287 (3.48%)
    0 / 287 (0.00%)
    10 / 183 (5.46%)
         occurrences all number
    11
    0
    10
    Pruritus
         subjects affected / exposed
    34 / 287 (11.85%)
    33 / 287 (11.50%)
    9 / 183 (4.92%)
         occurrences all number
    43
    56
    10
    Rash
         subjects affected / exposed
    63 / 287 (21.95%)
    35 / 287 (12.20%)
    15 / 183 (8.20%)
         occurrences all number
    104
    61
    18
    Rash Maculo-Papular
         subjects affected / exposed
    17 / 287 (5.92%)
    11 / 287 (3.83%)
    7 / 183 (3.83%)
         occurrences all number
    25
    16
    7
    Skin Lesion
         subjects affected / exposed
    30 / 287 (10.45%)
    5 / 287 (1.74%)
    11 / 183 (6.01%)
         occurrences all number
    40
    8
    14
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    47 / 287 (16.38%)
    29 / 287 (10.10%)
    25 / 183 (13.66%)
         occurrences all number
    81
    41
    43
    Back Pain
         subjects affected / exposed
    41 / 287 (14.29%)
    22 / 287 (7.67%)
    23 / 183 (12.57%)
         occurrences all number
    55
    31
    30
    Muscle Spasms
         subjects affected / exposed
    44 / 287 (15.33%)
    14 / 287 (4.88%)
    17 / 183 (9.29%)
         occurrences all number
    75
    19
    26
    Myalgia
         subjects affected / exposed
    28 / 287 (9.76%)
    15 / 287 (5.23%)
    9 / 183 (4.92%)
         occurrences all number
    42
    24
    12
    Pain in Extremity
         subjects affected / exposed
    21 / 287 (7.32%)
    15 / 287 (5.23%)
    12 / 183 (6.56%)
         occurrences all number
    32
    20
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    51 / 287 (17.77%)
    29 / 287 (10.10%)
    19 / 183 (10.38%)
         occurrences all number
    75
    41
    28
    Cellulitis
         subjects affected / exposed
    16 / 287 (5.57%)
    8 / 287 (2.79%)
    10 / 183 (5.46%)
         occurrences all number
    21
    12
    11
    Conjunctivitis
         subjects affected / exposed
    20 / 287 (6.97%)
    15 / 287 (5.23%)
    10 / 183 (5.46%)
         occurrences all number
    28
    20
    14
    Herpes Zoster
         subjects affected / exposed
    24 / 287 (8.36%)
    17 / 287 (5.92%)
    7 / 183 (3.83%)
         occurrences all number
    31
    23
    7
    Influenza
         subjects affected / exposed
    22 / 287 (7.67%)
    16 / 287 (5.57%)
    7 / 183 (3.83%)
         occurrences all number
    30
    19
    11
    Oral Herpes
         subjects affected / exposed
    15 / 287 (5.23%)
    18 / 287 (6.27%)
    7 / 183 (3.83%)
         occurrences all number
    26
    27
    13
    Pharyngitis
         subjects affected / exposed
    18 / 287 (6.27%)
    13 / 287 (4.53%)
    2 / 183 (1.09%)
         occurrences all number
    19
    13
    3
    Pneumonia
         subjects affected / exposed
    40 / 287 (13.94%)
    25 / 287 (8.71%)
    21 / 183 (11.48%)
         occurrences all number
    55
    29
    34
    Respiratory Tract Infection
         subjects affected / exposed
    19 / 287 (6.62%)
    10 / 287 (3.48%)
    15 / 183 (8.20%)
         occurrences all number
    30
    12
    31
    Sinusitis
         subjects affected / exposed
    38 / 287 (13.24%)
    24 / 287 (8.36%)
    25 / 183 (13.66%)
         occurrences all number
    67
    34
    33
    Upper Respiratory Tract Infection
         subjects affected / exposed
    69 / 287 (24.04%)
    50 / 287 (17.42%)
    36 / 183 (19.67%)
         occurrences all number
    135
    79
    61
    Urinary Tract Infection
         subjects affected / exposed
    28 / 287 (9.76%)
    15 / 287 (5.23%)
    26 / 183 (14.21%)
         occurrences all number
    56
    20
    39
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    42 / 287 (14.63%)
    42 / 287 (14.63%)
    16 / 183 (8.74%)
         occurrences all number
    58
    65
    20
    Hyperuricaemia
         subjects affected / exposed
    36 / 287 (12.54%)
    20 / 287 (6.97%)
    7 / 183 (3.83%)
         occurrences all number
    60
    24
    12
    Hypokalaemia
         subjects affected / exposed
    24 / 287 (8.36%)
    12 / 287 (4.18%)
    8 / 183 (4.37%)
         occurrences all number
    40
    18
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2012
    • Clarified management of study drug with concomitant cytochrome (CYP) CYP3A4/5 inhibitors/inducers and warfarin or other anticoagulants during the study to reflect updated standard language across the ibrutinib development program • Removed the eligibility restriction for subjects requiring treatment with strong CYP2D6 inhibitors in the exclusion criteria • Clarified management of study drug during the perioperative periods • Incorporated feedback from investigators, health authorities, and the study steering committee with regard to the platelet cutoff eligibility criteria, and bone marrow and MRD sampling for subjects reaching CR
    13 Sep 2013
    • Updated the protocol with safety information in the investigator’s brochure • Implemented a recommendation from the DMC to use anti-microbial prophylaxis • Added that data related to the occurrence of other malignancies or transformation to a more aggressive histology (Richter’s transformation) during the follow-up phase should be collected
    30 Jan 2014
    • Provided access to next-line treatment with ibrutinib for subjects initially assigned to placebo who had IRC-confirmed disease progression (that is each subject had met the primary endpoint), at investigator’s discretion, and with medical monitor approval
    13 Apr 2015
    • Unblinded study and removed the Amendment 3 requirement for IRC-confirmed disease progression providing access to next-line treatment with ibrutinib for subjects initially assigned to placebo at the discretion of the investigator at the time the subject had progression or met IWCLL criteria for treatment • End of study definition was revised to change the length of time from last subject in study from 4 years to 5 years so that estimated median PFS could be reached • Clarified that all responding subjects were to have peripheral blood MRD evaluations performed every 12 weeks until PD

    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.
    Study was planned to end when 80% of randomized participants died or 5 years after last participant randomized, whichever was first. Sponsor terminated study on 23-Jan-2019 (5 year after last participant randomized) and study was considered completed
    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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