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    Clinical Trial Results:
    Phase 3 Study of Ibrutinib in Combination with Venetoclax in Subjects with Mantle Cell Lymphoma

    Summary
    EudraCT number
    		 2017-000129-12
    Trial protocol
    		 GB   CZ   DE   BE   HU   ES   NL   GR   IT  
    Global end of trial date
    27 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jun 2025
    First version publication date
    27 Jun 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PCYC-1143-CA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03112174
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.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
    27 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Safety Run-in: To evaluate the occurrence of TLS and DLTs with the concurrent administration of ibrutinib and venetoclax. Randomization Phase: To evaluate whether the combination of ibrutinib and venetoclax will result in prolongation of PFS compared to ibrutinib and placebo in subjects with relapsed or refractory MCL. Treatment-naive Open-label Arm: To evaluate the complete response (CR) rate with the combination of ibrutinib and venetoclax in subjects with treatment-naive MCL.
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jun 2017
    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
    Australia: 17
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Czechia: 38
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Poland: 47
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Türkiye: 7
    Country: Number of subjects enrolled
    Ukraine: 15
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 81
    Worldwide total number of subjects
    366
    EEA total number of subjects
    205
    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)
    108
    From 65 to 84 years
    253
    85 years and over
    5

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening procedures were performed up to 28 days before the first dose of ibrutinib and venetoclax/placebo, unless otherwise specified, and may have been performed over more than 1 visit.

    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, Monitor, Subject
    Blinding implementation details
    For the Randomization Phase, subjects, investigators, and the Sponsor’s study team members remained blinded to treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Safety Run-in: Increased TLS Risk at Baseline
    Arm description
    		 Participants with an increased risk of tumor lysis syndrome (TLS) enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Arm title
    		 Safety Run-in: Low TLS Risk at Baseline
    Arm description
    		 Participants with an low risk of TLS enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Arm title
    		 Randomization Phase: Ibrutinb + Venetoclax
    Arm description
    		 Participants were randomized to ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg) for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax was discontinued after 104 weeks of treatment, regardless of response assessment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Arm title
    		 Randomization Phase: Ibrutinib + Placebo
    Arm description
    		 Participants were randomized to ibrutinib 560 mg and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo was discontinued after 104 weeks of treatment, regardless of response assessment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Arm title
    		 Treatment-naive Open-label Arm
    Arm description
    		 Participants were treated with ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once daily

    Number of subjects in period 1
    		Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo Treatment-naive Open-label Arm
    Started
    15
    6
    134
    133
    78
    On Study Treatment at Study Closure (SC)
    0 [1]
    2
    31 [2]
    21 [3]
    26 [4]
    Off Treatment + On Study Follow Up at SC
    2
    0 [5]
    22 [6]
    25 [7]
    25 [8]
    Already Off Study at Study Closure
    13
    4
    81
    87
    27 [9]
    Completed
    2
    2
    53
    46
    51
    Not completed
    13
    4
    81
    87
    27
         Consent withdrawn by subject
    3
    -
    11
    9
    7
         Death
    8
    3
    67
    73
    18
         Other, not specified
    1
    -
    1
    2
    -
         Lost to follow-up
    1
    1
    2
    3
    2
    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: Milestone data are correct as presented.
    [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: Milestone data are correct as presented.
    [3] - 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: Milestone data are correct as presented.
    [4] - 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: Milestone data are correct as presented.
    [5] - 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: Milestone data are correct as presented.
    [6] - 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: Milestone data are correct as presented.
    [7] - 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: Milestone data are correct as presented.
    [8] - 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: Milestone data are correct as presented.
    [9] - 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: Milestone data are correct as presented.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety Run-in: Increased TLS Risk at Baseline
    Reporting group description
    		 Participants with an increased risk of tumor lysis syndrome (TLS) enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.

    Reporting group title
    Safety Run-in: Low TLS Risk at Baseline
    Reporting group description
    		 Participants with an low risk of TLS enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.

    Reporting group title
    Randomization Phase: Ibrutinb + Venetoclax
    Reporting group description
    		 Participants were randomized to ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg) for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax was discontinued after 104 weeks of treatment, regardless of response assessment.

    Reporting group title
    Randomization Phase: Ibrutinib + Placebo
    Reporting group description
    		 Participants were randomized to ibrutinib 560 mg and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo was discontinued after 104 weeks of treatment, regardless of response assessment.

    Reporting group title
    Treatment-naive Open-label Arm
    Reporting group description
    		 Participants were treated with ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg).

    Reporting group values
    		 Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo Treatment-naive Open-label Arm Total
    Number of subjects
    		 15 6 134 133 78 366
    Age categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0 0 0
        Between 18 and 65 years
    		 2 5 41 47 13 108
        >=65 years
    		 13 1 93 86 65 258
    Gender categorical
    Units: Subjects
        Female
    		 6 2 31 25 25 89
        Male
    		 9 4 103 108 53 277
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 0 8 7 1 17
        Not Hispanic or Latino
    		 11 5 112 110 72 310
        Unknown or Not Reported
    		 3 1 14 16 5 39
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 0 2 3 6 11
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 0 0 1 1 1 3
        White
    		 12 6 116 115 68 317
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 3 0 15 14 3 35

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Safety Run-in: Increased TLS Risk at Baseline
    Reporting group description
    		 Participants with an increased risk of tumor lysis syndrome (TLS) enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.

    Reporting group title
    Safety Run-in: Low TLS Risk at Baseline
    Reporting group description
    		 Participants with an low risk of TLS enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.

    Reporting group title
    Randomization Phase: Ibrutinb + Venetoclax
    Reporting group description
    		 Participants were randomized to ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg) for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax was discontinued after 104 weeks of treatment, regardless of response assessment.

    Reporting group title
    Randomization Phase: Ibrutinib + Placebo
    Reporting group description
    		 Participants were randomized to ibrutinib 560 mg and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo was discontinued after 104 weeks of treatment, regardless of response assessment.

    Reporting group title
    Treatment-naive Open-label Arm
    Reporting group description
    		 Participants were treated with ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg).

    Primary: Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)

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    End point title
    		 Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in) [1] [2]
    End point description
    TLS events are defined as follows: • Clinical TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) with the following exceptions: • For the purpose of TLS assessment during the Safety Run-in Period, only those increases in serum creatinine > 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS. • In subjects with renal dysfunction at baseline (CrCl < 60 mL/min), clinical TLS is defined as the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death. • Laboratory TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) for laboratory TLS, that does not resolve within 72 hours despite protocol required management. All treated safety run-in participants
    End point type
    Primary
    End point timeframe
    After at least 3 months of treatment, with an overall median treatment duration of 20.0 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics per protocol are presented in the data table.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Safety Run-in arm only.
    End point values
    		 Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline
    Number of subjects analysed
    15
    6
    Units: participants
    1
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)

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    End point title
    		 Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in) [3] [4]
    End point description
    DLT: any Grade (Gr) 3 or higher non-TLS adverse event (AE) at least possibly related to study drug occurring during the DLT assessment period with the following clarifications: Non-Hematologic DLTs: Gr ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum medical supportive care and persisting >5 days; Gr 3 fatigue persisting >7 days; Gr 3 infection is not a DLT, however an infection with life-threatening consequences or requiring urgent intervention (Gr 4) was considered a DLT; Treatment delay of any study drug >7 days for toxicity. Hematologic DLTs: Gr 3 neutropenia is not a DLT, however, Gr 4 neutropenia (ANC <500/mm^3) lasting for > 7 days is a DLT; Gr 3 or 4 neutropenia complicated by fever ≥38.5°C or infection; Gr 4 thrombocytopenia (<25,000/mm^3) that persists for > 7 days; Gr 3 or 4 thrombocytopenia associated with Gr 2 or greater bleeding; Gr 3 anemia is not a DLT, however, Gr 4 anemia is a DLT; Treatment delay of any study drug >7 days for hematologic toxicity.
    End point type
    Primary
    End point timeframe
    After at least 3 months of treatment, with an overall median treatment duration of 20.0 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics per protocol are presented in the data table.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Safety Run-in only.
    End point values
    		 Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline
    Number of subjects analysed
    15
    6
    Units: participants
        Any TEAE/Any Grade
    3
    0
        Any TEAE/ Grade 3+4
    3
    0
        Any TEAE/Grade 5
    0
    0
        Atrial fibrillation/Any Grade
    1
    0
        Atrial fibrillation/Grade 3+4
    1
    0
        Atrial fibrillation/Grade 5
    0
    0
        Infection/Any Grade
    1
    0
        Infection/Grade 3+4
    1
    0
        Infection/Grade 5
    0
    0
        Neutropenia/Any Grade
    1
    0
        Neutropenia/Grade 3+4
    1
    0
        Neutropenia/Grade 5
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in) [5] [6]
    End point description
    AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug (SD). Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5). All treated safety run-in participants
    End point type
    Primary
    End point timeframe
    From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 20.0 months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics per protocol are presented in the data table.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Safety Run-in only.
    End point values
    		 Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline
    Number of subjects analysed
    15
    6
    Units: participants
        Any TEAE
    15
    6
        Any TEAE, Grade 3
    15
    5
        Any Venetoclax (V) Related TEAE
    14
    6
        Any V Related TEAE Grade >=3
    13
    4
        Any Ibrutinib (I) Related TEAE
    13
    5
        Any I Related TEAE Grade >=3
    12
    4
        TEAE Leading to Discontinuation of SD (I or V)
    6
    2
        TEAE Leading to Discontinuation of SD (I only)
    1
    0
        TEAE Leading to Discontinuation of SD (V only)
    1
    0
        TEAE Leading to Discontinuation of SD (Both I + V)
    4
    2
        TEAE Leading to Dose Reduction of SD (I or V)
    7
    4
        TEAE Leading to Dose Reduction of SD (I only)
    1
    3
        TEAE Leading to Dose Reduction of SD (V only)
    3
    0
        TEAE Leading to Dose Reduction of SD (Both I + V)
    3
    1
        TEAE Leading to Dose Hold of SD (I or V)
    14
    4
        TEAE Leading to Dose Hold of SD (I Only)
    1
    1
        TEAE Leading to Dose Hold of SD (V Only)
    0
    0
        TEAE Leading to Dose Hold of SD (Both I + V)
    13
    3
        Any TESAE
    14
    3
        Any TESAE, Grade >=3
    14
    2
        Any TESAE, V Related
    9
    1
        Any TESAE, I Related
    10
    1
        Any TESAE, V or I Related
    10
    1
        Fatal TEAE
    1
    0
        Major Hemorrhage
    2
    0
        Major Hemorrhage, Grade >=3
    2
    0
        Major Hemorrhage, TESAE
    2
    0
    No statistical analyses for this end point

    Primary: Progression-free Survival (PFS) (Randomization Phase)

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    End point title
    		 Progression-free Survival (PFS) (Randomization Phase) [7]
    End point description
    PFS is defined as the time from the date of randomization to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first. All randomized participants
    End point type
    Primary
    End point timeframe
    For an overall median time on study of 61.34 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    134
    133
    Units: months
        median (confidence interval 95%)
    31.9 (22.8 to 54.5)
    22.1 (16.5 to 29.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Randomization Phase: Ibrutinb + Venetoclax v Randomization Phase: Ibrutinib + Placebo
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0024 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.629
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.465
         upper limit
    		 0.85
    Notes
    [8] - P value is from stratified log-rank test.

    Primary: Complete Response (CR) Rate (Treatment-Naive Arm)

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    End point title
    		 Complete Response (CR) Rate (Treatment-Naive Arm) [9] [10]
    End point description
    CR rate is defined as the percentage of participants with a CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
    End point type
    Primary
    End point timeframe
    For an overall median time on study of 40.51 months
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis per protocol is presented in the data table.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Treatment Naïve Arm only.
    End point values
    		 Treatment-naive Open-label Arm
    Number of subjects analysed
    78
    Units: percentage of participants
        number (confidence interval 95%)
    69.2 (57.8 to 79.2)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) (Safety Run-in)

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    End point title
    		 Overall Response Rate (ORR) (Safety Run-in) [11]
    End point description
    ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014). All enrolled safety run-in participants
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 74.78 months
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Safety Run-in only.
    End point values
    		 Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline
    Number of subjects analysed
    15
    6
    Units: percentage of participants
        number (confidence interval 95%)
    80.0 (51.9 to 95.7)
    83.3 (35.9 to 99.6)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) (Safety Run-in)

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    End point title
    		 Duration of Response (DOR) (Safety Run-in) [12]
    End point description
    DOR is defined for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma [Cheson 2014]) to disease progression or death, whichever occurs first. All enrolled safety run-in participants achieving response (partial response or better)
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 74.78 months
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Safety Run-in only.
    End point values
    		 Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline
    Number of subjects analysed
    12 [13]
    5 [14]
    Units: months
        median (confidence interval 95%)
    44.1 (12.5 to 999999)
    999999 (26.5 to 999999)
    Notes
    [13] - 999999=Not estimable due to the small number of events.
    [14] - 999999=Not estimable due to the small number of events.
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) (Safety Run-in)

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    End point title
    		 Progression-free Survival (PFS) (Safety Run-in) [15]
    End point description
    PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first. All enrolled safety run-in participants
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 74.78 months
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Safety Run-in arm only.
    End point values
    		 Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline
    Number of subjects analysed
    15 [16]
    6 [17]
    Units: months
        median (confidence interval 95%)
    46.9 (13.0 to 999999)
    35.0 (1.2 to 999999)
    Notes
    [16] - 999999=Not estimable due to the small number of events.
    [17] - 999999=Not estimable due to the small number of events.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) (Safety Run-in)

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    End point title
    		 Overall Survival (OS) (Safety Run-in) [18]
    End point description
    OS is defined as the time from the date of the first dose of study treatment to death from any cause.
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 74.78 months
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Safety Run-in only.
    End point values
    		 Safety Run-in: Increased TLS Risk at Baseline Safety Run-in: Low TLS Risk at Baseline
    Number of subjects analysed
    15 [19]
    6 [20]
    Units: months
        median (confidence interval 95%)
    52.3 (14.1 to 999999)
    999999 (1.5 to 999999)
    Notes
    [19] - 999999=not estimable due to the small number of events
    [20] - 999999=not estimable due to the small number of events
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Complete Response (CR) (Randomization Phase)

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    End point title
    		 Percentage of Participants With a Complete Response (CR) (Randomization Phase) [21]
    End point description
    Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014). All randomized participants
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 61.34 months
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    134
    133
    Units: percentage of particiapnts
        number (confidence interval 95%)
    53.7 (44.9 to 62.4)
    32.3 (24.5 to 41.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Randomization Phase: Ibrutinb + Venetoclax v Randomization Phase: Ibrutinib + Placebo
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.0004 [23]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Rate Ratio
    Point estimate
    1.658
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 2.218
    Notes
    [22] - For rate ratio, numerator is Ibrutinib + Venetoclax arm and denominator is Ibrutinib + Placebo arm.
    [23] - Estimate and p-value for rate ratio are based on Cochran-Mantel-Haenszel (CMH) test adjusted for two randomization stratification factors: number of prior lines of therapy (1-2 vs >=3) and TLS category (low risk vs increased risk) at randomization.

    Secondary: Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)

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    End point title
    		 Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm) [24]
    End point description
    ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014). All randomized participants and all treatment-naive open-label arm participants.
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase and the Treatment Naïve Arm only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo Treatment-naive Open-label Arm
    Number of subjects analysed
    134
    133
    78
    Units: percentage of participants
        number (confidence interval 95%)
    82.1 (74.5 to 88.2)
    74.4 (66.2 to 81.6)
    94.9 (87.4 to 98.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    For rate ratio, numerator is Ibrutinib + Venetoclax arm and denominator is Ibrutinib + Placebo arm.
    Comparison groups
    Randomization Phase: Ibrutinb + Venetoclax v Randomization Phase: Ibrutinib + Placebo
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1279 [25]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Rate Ratio
    Point estimate
    1.101
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.973
         upper limit
    		 1.247
    Notes
    [25] - Estimate and p-value for rate ratio are based on CMH test adjusted for two randomization stratification factors: number of prior lines of therapy (1-2 vs >=3) and TLS category (low risk vs increased risk) at randomization.

    Secondary: MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)

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    End point title
    		 MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm) [26]
    End point description
    MRD-negative remission rate is defined as the percentage of participants with undetectable MRD at documented CR in participants who were MRD positive at screening as assessed by flow cytometry in bone marrow and/or peripheral blood, with requirement of confirmation of MRD negativity in the subsequent peripheral blood 12 weeks later. All enrolled treatment-naïve participants achieving CR who were evaluable for MRD (those who had positive MRD status at screening). Participants with a given post-screening sample.
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase and the Treatment Naïve Arm only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo Treatment-naive Open-label Arm
    Number of subjects analysed
    31 [27]
    8 [28]
    34 [29]
    Units: percentage of participants
    number (confidence interval 95%)
        Bone marrow aspirate; n=26, 7, 22
    61.5 (40.6 to 79.8)
    28.6 (3.7 to 71.0)
    59.1 (36.4 to 79.3)
        Peripheral blood; n=31, 8, 34
    77.4 (58.9 to 90.4)
    12.5 (0.3 to 52.7)
    76.5 (58.8 to 89.3)
    Notes
    [27] - n=participants with an assessment
    [28] - n=participants with an assessment
    [29] - n=participants with an assessment
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Bone marrow aspirate
    Comparison groups
    Randomization Phase: Ibrutinb + Venetoclax v Randomization Phase: Ibrutinib + Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2028
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Peripheral blood
    Comparison groups
    Randomization Phase: Ibrutinb + Venetoclax v Randomization Phase: Ibrutinib + Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)

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    End point title
    		 Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm) [30]
    End point description
    OS is defined as the time from the date of randomization (Randomization Phase) or the first dose of study treatment (Treatment-Naïve arm) to death from any cause. All randomized and all enrolled treatment-naïve participants
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase and Treatment-Naïve Arm only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo Treatment-naive Open-label Arm
    Number of subjects analysed
    134 [31]
    133
    78 [32]
    Units: months
        median (confidence interval 95%)
    44.9 (31.9 to 999999)
    38.6 (25.2 to 52.6)
    999999 (44.2 to 999999)
    Notes
    [31] - 999999=not estimable due to small number of events.
    [32] - 999999=not estimable due to the small number of events.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio is estimated using stratified Cox regression model with treatment as the only covariate.
    Comparison groups
    Randomization Phase: Ibrutinib + Placebo v Randomization Phase: Ibrutinb + Venetoclax
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2669 [33]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.832
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.602
         upper limit
    		 1.151
    Notes
    [33] - P value is from stratified log-rank test.

    Secondary: Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)

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    End point title
    		 Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm) [34]
    End point description
    DOR is defined as the time frame for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma [Cheson 2014]) to disease progression or death, whichever occurs first. All randomized participants and all enrolled treatment-naïve participants achieving response (partial response or better)
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase and Treatment-Naïve Arm only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo Treatment-naive Open-label Arm
    Number of subjects analysed
    110 [35]
    99
    74 [36]
    Units: months
        median (confidence interval 95%)
    42.1 (42.1 to 999999)
    27.6 (19.4 to 39.5)
    37.1 (30.3 to 999999)
    Notes
    [35] - 999999=Not estimable due to the small number of events.
    [36] - 999999=Not estimable due to the small number of events.
    No statistical analyses for this end point

    Secondary: Time to Next Treatment (TTNT) (Randomization Phase and Treatment-Naive Arm)

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    End point title
    		 Time to Next Treatment (TTNT) (Randomization Phase and Treatment-Naive Arm) [37]
    End point description
    TTNT is defined as the duration from the date of randomization (Randomization Phase) or date of first dose of study treatment (Treatment-Naive Arm) to the start date of any anti-lymphoma treatment subsequent to study treatment. Post-treatment stem cell transplantation, chimeric antigen receptor (CAR) T-cell therapy, or other cellular therapies were not considered subsequent anti-cancer treatments for participants responding to the study treatment (CR or PR). All randomized and all enrolled treatment-naïve participants
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase and Treatment-Naïve Arm only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo Treatment-naive Open-label Arm
    Number of subjects analysed
    134 [38]
    133
    74 [39]
    Units: months
        median (confidence interval 95%)
    999999 (48.0 to 999999)
    35.4 (24.7 to 49.8)
    999999 (999999 to 999999)
    Notes
    [38] - 999999=Not estimable due to the small number of events.
    [39] - 999999=Not estimable due to the small number of events.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio is estimated using stratified Cox regression model with treatment as the only covariate.
    Comparison groups
    Randomization Phase: Ibrutinib + Placebo v Randomization Phase: Ibrutinb + Venetoclax
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013 [40]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.541
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.369
         upper limit
    		 0.792
    Notes
    [40] - P value is from stratified log-rank test.

    Secondary: Number of Participants With TEAEs (Randomization Phase)

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    End point title
    		 Number of Participants With TEAEs (Randomization Phase) [41]
    End point description
    AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug (SD). Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5). All randomized and treated participants
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 19.5 months
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    134
    132
    Units: participants
        Any TEAE
    134
    131
        Any TEAE, Grade 3
    113
    100
        Any Venetoclax (V) Related TEAE
    112
    104
        Any V Related TEAE Grade >=3
    75
    46
        Any Ibrutinib (I) Related TEAE
    121
    114
        Any I Related TEAE Grade >=3
    83
    58
        TEAE Leading to Discontinuation of SD (I or V)
    43
    48
        TEAE Leading to Discontinuation of SD (I only)
    15
    11
        TEAE Leading to Discontinuation of SD (V only)
    2
    7
        TEAE Leading to Discontinuation of SD (Both I + V)
    26
    30
        TEAE Leading to Dose Reduction of SD (I or V)
    50
    29
        TEAE Leading to Dose Reduction of SD (I only)
    19
    14
        TEAE Leading to Dose Reduction of SD (V only)
    13
    7
        TEAE Leading to Dose Reduction of SD (Both I + V)
    18
    8
        TEAE Leading to Dose Hold of SD (I or V)
    106
    99
        TEAE Leading to Dose Hold of SD (I only)
    18
    18
        TEAE Leading to Dose Hold of Study Drug (V only)
    6
    4
        TEAE Leading to Dose Hold of SD (Both I + V)
    82
    77
        Any TESAE
    88
    80
        Any TESAE, Grade >=3
    76
    73
        Any TESAE, V Related
    31
    25
        Any TESAE, I Related
    47
    37
        Any TESAE, V or I Related
    49
    37
        Fatal TEAE
    22
    18
        Major Hemorrhage
    13
    8
        Major Hemorrhage, Grade >=3
    10
    7
        Major Hemorrhage, TESAE
    12
    6
    No statistical analyses for this end point

    Secondary: Number of Participants With TLS TEAEs (Randomization Phase)

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    End point title
    		 Number of Participants With TLS TEAEs (Randomization Phase) [42]
    End point description
    Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug (SD). Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5). All randomized and treated participants
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 19.5 months
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    134
    132
    Units: participants
        Any grade
    7
    3
        Grades 3 and 4
    6
    3
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) of Ibrutinib: Maximum Observed Plasma Concentration (Cmax) (Randomization Phase)

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    End point title
    		 Pharmacokinetics (PK) of Ibrutinib: Maximum Observed Plasma Concentration (Cmax) (Randomization Phase) [43]
    End point description
    Participants with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    106
    108
    Units: ng/mL
        arithmetic mean (standard deviation)
    195 ( 179 )
    287 ( 230 )
    No statistical analyses for this end point

    Secondary: PK of Ibrutinib: Time to Cmax (Tmax) (Randomization Phase)

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    End point title
    		 PK of Ibrutinib: Time to Cmax (Tmax) (Randomization Phase) [44]
    End point description
    Participants with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    106
    108
    Units: hours
        median (full range (min-max))
    2.00 (0.00 to 8.00)
    2.00 (0.750 to 6.00)
    No statistical analyses for this end point

    Secondary: PK of Ibrutinib: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) (Randomization Phase)

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    End point title
    		 PK of Ibrutinib: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) (Randomization Phase) [45]
    End point description
    Participants with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    102
    106
    Units: ng·h/mL
        arithmetic mean (standard deviation)
    1090 ( 870 )
    1440 ( 1060 )
    No statistical analyses for this end point

    Secondary: PK of Ibrutinib: Terminal Elimination Half-Life (t1/2,Term) (Randomization Phase)

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    End point title
    		 PK of Ibrutinib: Terminal Elimination Half-Life (t1/2,Term) (Randomization Phase) [46]
    End point description
    Participants with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    65
    73
    Units: hours
        arithmetic mean (standard deviation)
    6.29 ( 1.92 )
    6.66 ( 2.15 )
    No statistical analyses for this end point

    Secondary: PK of Ibrutinib: Time of Last Measurable Concentration (Tlast) (Randomization Phase)

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    End point title
    		 PK of Ibrutinib: Time of Last Measurable Concentration (Tlast) (Randomization Phase) [47]
    End point description
    Participants with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    102
    106
    Units: hours
        median (full range (min-max))
    24.0 (7.0 to 24.0)
    24.0 (24.0 to 24.0)
    No statistical analyses for this end point

    Secondary: PK of Ibrutinib: Area Under the Concentration-Time Curve From 0-24 Hours (AUC0-24) (Randomization Phase)

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    End point title
    		 PK of Ibrutinib: Area Under the Concentration-Time Curve From 0-24 Hours (AUC0-24) (Randomization Phase) [48]
    End point description
    Participants with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    102
    106
    Units: ng·h/mL
        arithmetic mean (standard deviation)
    1090 ( 870 )
    1440 ( 1060 )
    No statistical analyses for this end point

    Secondary: PK of Ibrutinib: Terminal Elimination Rate Constant (λz) (Randomization Phase)

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    End point title
    		 PK of Ibrutinib: Terminal Elimination Rate Constant (λz) (Randomization Phase) [49]
    End point description
    Participants with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    65
    73
    Units: 1/hour
        arithmetic mean (standard deviation)
    0.123 ( 0.0556 )
    0.114 ( 0.0332 )
    No statistical analyses for this end point

    Secondary: PK of Ibrutinib: Apparent Total Clearance at Steady State (CLss/F) (Randomization Phase)

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    End point title
    		 PK of Ibrutinib: Apparent Total Clearance at Steady State (CLss/F) (Randomization Phase) [50]
    End point description
    Participants with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    102
    106
    Units: L/hour
        arithmetic mean (standard deviation)
    1020 ( 1130 )
    709 ( 651 )
    No statistical analyses for this end point

    Secondary: PK of Venetoclax: Cmax (Randomization Phase)

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    End point title
    		 PK of Venetoclax: Cmax (Randomization Phase) [51]
    End point description
    Participants receiving venetoclax with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax
    Number of subjects analysed
    102
    Units: ng/mL
        arithmetic mean (standard deviation)
    3620 ( 1650 )
    No statistical analyses for this end point

    Secondary: PK of Venetoclax: AUC0-24 (Randomization Phase)

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    End point title
    		 PK of Venetoclax: AUC0-24 (Randomization Phase) [52]
    End point description
    Participants receiving venetoclax with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax
    Number of subjects analysed
    98
    Units: ng·h/mL
        arithmetic mean (standard deviation)
    65000 ( 32900 )
    No statistical analyses for this end point

    Secondary: PK of Venetoclax: Time to Cmax (Tmax) (Randomization Phase)

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    End point title
    		 PK of Venetoclax: Time to Cmax (Tmax) (Randomization Phase) [53]
    End point description
    Participants receiving venetoclax with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax
    Number of subjects analysed
    102
    Units: hours
        median (full range (min-max))
    6.00 (0.00 to 8.03)
    No statistical analyses for this end point

    Secondary: PK of Venetoclax: CLss/F (Randomization Phase)

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    End point title
    		 PK of Venetoclax: CLss/F (Randomization Phase) [54]
    End point description
    Participants receiving venetoclax with an evaluable PK assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour) post-dose
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax
    Number of subjects analysed
    98
    Units: L/hour
        geometric mean (standard deviation)
    8.09 ( 4.82 )
    No statistical analyses for this end point

    Secondary: Time to Worsening in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale of the Health-Related Quality of Life (Randomization Phase)

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    End point title
    		 Time to Worsening in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale of the Health-Related Quality of Life (Randomization Phase) [55]
    End point description
    The FACT-Lym lymphoma-specific additional concerns subscale responses to all items are rated on a 5-point scale ranging from 0 “not at all” to 4 “very much”. The lymphoma subscale includes 15 items and scores range from 0 to 60, with higher scores representing better functional status and well-being. Worsening is defined by a >=5 points reduction from baseline in FACT-Lym Subscale or death due to any cause, whichever occurs first. All randomized participants
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 61.34 months
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Randomization Phase only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax Randomization Phase: Ibrutinib + Placebo
    Number of subjects analysed
    134
    133
    Units: months
        median (confidence interval 95%)
    9.3 (6.5 to 12.7)
    12.5 (8.3 to 17.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio is estimated using stratified Cox regression model with treatment as the only covariate.
    Comparison groups
    Randomization Phase: Ibrutinb + Venetoclax v Randomization Phase: Ibrutinib + Placebo
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2861 [56]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.169
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.879
         upper limit
    		 1.554
    Notes
    [56] - P value is from stratified log-rank test.

    Secondary: Duration of CR (Treatment-Naive Arm)

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    End point title
    		 Duration of CR (Treatment-Naive Arm) [57]
    End point description
    Duration of CR, defined for subjects who achieve CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014) as the time from the first occurrence of CR to disease progression or death, whichever occurs first. All Enrolled Treatment-Naïve Subjects Achieving Response (Partial Response or Better)
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 40.51 months
    Notes
    [57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Treatment Naïve Arm only.
    End point values
    		 Treatment-naive Open-label Arm
    Number of subjects analysed
    74 [58]
    Units: months
        median (confidence interval 95%)
    37.1 (34.0 to 999999)
    Notes
    [58] - 999999=Not estimable due to the small number of events.
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) (Treatment-Naive Arm)

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    End point title
    		 Progression-free Survival (PFS) (Treatment-Naive Arm) [59]
    End point description
    PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first. All enrolled treatment-naïve participants
    End point type
    Secondary
    End point timeframe
    For an overall median time on study of 40.51 months
    Notes
    [59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, this endpoint was specified for the Treatment Naïve Arm only.
    End point values
    		 Randomization Phase: Ibrutinb + Venetoclax
    Number of subjects analysed
    78 [60]
    Units: months
        median (full range (min-max))
    40.2 (29.4 to 999999)
    Notes
    [60] - 999999=not estimable due to the low number of events.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For an overall median duration of 69.6 months (Safety Run-in: Increased TLS Risk), 77.9 months (Safety Run-in: Low TLS Risk), 61.0 months (Randomization Phase: Ibrutinb + Venetoclax), 61.7 months (Randomization Phase: Ibrutinb + Placebo), 40.5 months (Tre
    Adverse event reporting additional description
    All treated participants
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Safety Run-in: Low TLS Risk at Baseline
    Reporting group description
    		 Participants with an low risk of TLS enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.

    Reporting group title
    Safety Run-in: Increased TLS Risk at Baseline
    Reporting group description
    		 Participants with an increased risk of TLS enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.

    Reporting group title
    Treatment-naive Open-label Arm
    Reporting group description
    		 Participants were treated with ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg).

    Reporting group title
    Randomization Phase: Ibrutinib + Placebo
    Reporting group description
    		 Participants were randomized to ibrutinib 560 mg and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo was discontinued after 104 weeks of treatment, regardless of response assessment.

    Reporting group title
    Randomization Phase: Ibrutinb + Venetoclax
    Reporting group description
    		 Participants were randomized to ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg) for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax was discontinued after 104 weeks of treatment, regardless of response assessment.

    Serious adverse events
    		 Safety Run-in: Low TLS Risk at Baseline Safety Run-in: Increased TLS Risk at Baseline Treatment-naive Open-label Arm Randomization Phase: Ibrutinib + Placebo Randomization Phase: Ibrutinb + Venetoclax
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    15 / 15 (100.00%)
    48 / 78 (61.54%)
    86 / 132 (65.15%)
    92 / 134 (68.66%)
         number of deaths (all causes)
    3
    8
    20
    78
    70
         number of deaths resulting from adverse events
    1
    1
    10
    29
    34
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MANTLE CELL LYMPHOMA RECURRENT
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MANTLE CELL LYMPHOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    18 / 132 (13.64%)
    15 / 134 (11.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 27
    0 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 14
    0 / 12
    LYMPHOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    LUNG ADENOCARCINOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRADUCTAL PROLIFERATIVE BREAST LESION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BENIGN LUNG NEOPLASM
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ADRENAL NEOPLASM
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    METASTATIC MALIGNANT MELANOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    THYROID CANCER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NON-SMALL CELL LUNG CANCER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    MYELODYSPLASTIC SYNDROME
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Vascular disorders
    AORTIC ANEURYSM
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    AORTIC STENOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CIRCULATORY COLLAPSE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    3 / 132 (2.27%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ILIAC ARTERY STENOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ISCHAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EMBOLISM
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC DEATH
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    CHEST PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    PYREXIA
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 15 (20.00%)
    3 / 78 (3.85%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    5 / 5
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GAIT DISTURBANCE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEROSITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    GRAFT VERSUS HOST DISEASE IN GASTROINTESTINAL TRACT
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY POSITIVE VASCULITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GRAFT VERSUS HOST DISEASE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    LOSS OF PERSONAL INDEPENDENCE IN DAILY ACTIVITIES
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    COUGH
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    4 / 132 (3.03%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY HYPERTENSION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    6 / 132 (4.55%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 6
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    1 / 2
    UPPER AIRWAY OBSTRUCTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOCAL CORD POLYP
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    4 / 132 (3.03%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COMPLETED SUICIDE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    SKULL FRACTURE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CRANIOCEREBRAL INJURY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACCIDENTAL OVERDOSE
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
    7 / 134 (5.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    2 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPLENIC RUPTURE
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    3 / 132 (2.27%)
    6 / 134 (4.48%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    3 / 3
    4 / 4
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARTERIOSCLEROSIS CORONARY ARTERY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    5 / 134 (3.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 2
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 3
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    3 / 132 (2.27%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LEFT VENTRICULAR FAILURE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR EXTRASYSTOLES
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MITRAL VALVE DISEASE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR FIBRILLATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    AMNESIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRADYKINESIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMORRHAGIC STROKE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    EPILEPSY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    CEREBRAL HAEMATOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TREMOR
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPEECH DISORDER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRAVENTRICULAR HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    6 / 134 (4.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEBRILE BONE MARROW APLASIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    3 / 132 (2.27%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPHADENOPATHY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    4 / 132 (3.03%)
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 4
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPONTANEOUS HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    CATARACT
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UVEITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DUODENAL ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOLITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC ULCER PERFORATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GINGIVAL BLEEDING
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL ISCHAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PROCTITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RETROPERITONEAL HAEMORRHAGE
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUBILEUS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UMBILICAL HERNIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMATOSIS INTESTINALIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STONE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BILIARY COLIC
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLANGITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    CUTANEOUS VASCULITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ECCHYMOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URTICARIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL FAILURE
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
    3 / 134 (2.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARTHRALGIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POLYARTHRITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECK PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ABDOMINAL ABSCESS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ABSCESS LIMB
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS PERFORATED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARTHRITIS BACTERIAL
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CENTRAL NERVOUS SYSTEM INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BACTERIAL SEPSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BRONCHOPULMONARY ASPERGILLOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 3
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ARTHRITIS INFECTIVE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CLOSTRIDIUM COLITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    COVID-19
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    8 / 78 (10.26%)
    1 / 132 (0.76%)
    6 / 134 (4.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 11
    0 / 1
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    1 / 4
    COVID-19 PNEUMONIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    6 / 78 (7.69%)
    2 / 132 (1.52%)
    5 / 134 (3.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 7
    2 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
    0 / 2
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DISSEMINATED CRYPTOCOCCOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FUNGAL ABSCESS CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EMPYEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MEDIASTINITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECROTISING FASCIITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    ORCHITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA CHLAMYDIAL
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    5 / 78 (6.41%)
    15 / 132 (11.36%)
    17 / 134 (12.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 6
    6 / 17
    13 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERIORBITAL CELLULITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA MORAXELLA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA STREPTOCOCCAL
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY SEPSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION VIRAL
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    5 / 132 (3.79%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SKIN INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TOOTH INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    4 / 132 (3.03%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND SEPSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL PHARYNGITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GOUT
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METABOLIC ACIDOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    LACTIC ACIDOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERPHOSPHATAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPERURICAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUMOUR LYSIS SYNDROME
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    2 / 132 (1.52%)
    4 / 134 (2.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    3 / 3
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Run-in: Low TLS Risk at Baseline Safety Run-in: Increased TLS Risk at Baseline Treatment-naive Open-label Arm Randomization Phase: Ibrutinib + Placebo Randomization Phase: Ibrutinb + Venetoclax
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    15 / 15 (100.00%)
    77 / 78 (98.72%)
    127 / 132 (96.21%)
    131 / 134 (97.76%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    0
    0
    2
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    5 / 132 (3.79%)
    7 / 134 (5.22%)
         occurrences all number
    0
    1
    1
    5
    10
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    4 / 132 (3.03%)
    7 / 134 (5.22%)
         occurrences all number
    0
    1
    3
    6
    7
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    HAEMATOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    HYPERTENSION
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    15 / 78 (19.23%)
    23 / 132 (17.42%)
    20 / 134 (14.93%)
         occurrences all number
    5
    4
    23
    28
    32
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    4 / 132 (3.03%)
    6 / 134 (4.48%)
         occurrences all number
    0
    1
    1
    5
    7
    ADVERSE DRUG REACTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    ASTHENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    6 / 78 (7.69%)
    18 / 132 (13.64%)
    26 / 134 (19.40%)
         occurrences all number
    0
    3
    12
    24
    38
    CATHETER SITE BRUISE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    1
    0
    1
    CHILLS
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    4 / 78 (5.13%)
    4 / 132 (3.03%)
    8 / 134 (5.97%)
         occurrences all number
    2
    2
    6
    4
    8
    FATIGUE
         subjects affected / exposed
    4 / 6 (66.67%)
    5 / 15 (33.33%)
    30 / 78 (38.46%)
    36 / 132 (27.27%)
    39 / 134 (29.10%)
         occurrences all number
    12
    12
    78
    77
    66
    GENERALISED OEDEMA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    IMPAIRED HEALING
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    5 / 132 (3.79%)
    10 / 134 (7.46%)
         occurrences all number
    0
    1
    4
    6
    11
    INJECTION SITE BRUISING
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    1
    1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    OEDEMA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 15 (13.33%)
    14 / 78 (17.95%)
    21 / 132 (15.91%)
    16 / 134 (11.94%)
         occurrences all number
    4
    2
    15
    28
    20
    PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    6 / 78 (7.69%)
    4 / 132 (3.03%)
    3 / 134 (2.24%)
         occurrences all number
    0
    1
    6
    4
    3
    PERIPHERAL SWELLING
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    9 / 132 (6.82%)
    11 / 134 (8.21%)
         occurrences all number
    1
    1
    9
    11
    19
    PYREXIA
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    16 / 78 (20.51%)
    28 / 132 (21.21%)
    28 / 134 (20.90%)
         occurrences all number
    1
    1
    20
    56
    51
    SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    EXTRAVASATION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Immune system disorders
    HYPOGAMMAGLOBULINAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    3 / 132 (2.27%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    0
    4
    2
    ALLERGY TO ARTHROPOD BITE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    PRODUCTIVE COUGH
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    6 / 132 (4.55%)
    5 / 134 (3.73%)
         occurrences all number
    0
    3
    2
    7
    8
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    COUGH
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 15 (33.33%)
    13 / 78 (16.67%)
    35 / 132 (26.52%)
    28 / 134 (20.90%)
         occurrences all number
    2
    5
    17
    55
    46
    DYSPHONIA
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    2 / 78 (2.56%)
    3 / 132 (2.27%)
    4 / 134 (2.99%)
         occurrences all number
    0
    2
    2
    3
    4
    PLEURITIC PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    3 / 132 (2.27%)
    4 / 134 (2.99%)
         occurrences all number
    0
    1
    0
    3
    4
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    15 / 132 (11.36%)
    14 / 134 (10.45%)
         occurrences all number
    1
    1
    3
    21
    15
    NASAL DRYNESS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    1
    1
    NASAL CONGESTION
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    6 / 132 (4.55%)
    7 / 134 (5.22%)
         occurrences all number
    2
    1
    5
    6
    8
    EPISTAXIS
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 15 (6.67%)
    6 / 78 (7.69%)
    14 / 132 (10.61%)
    9 / 134 (6.72%)
         occurrences all number
    7
    1
    6
    23
    14
    DYSPNOEA
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    14 / 78 (17.95%)
    15 / 132 (11.36%)
    17 / 134 (12.69%)
         occurrences all number
    3
    4
    23
    24
    24
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    RESPIRATORY TRACT CONGESTION
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    SINUS CONGESTION
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    6 / 132 (4.55%)
    3 / 134 (2.24%)
         occurrences all number
    1
    0
    0
    7
    3
    SINUS DISORDER
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    UPPER-AIRWAY COUGH SYNDROME
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
    3 / 134 (2.24%)
         occurrences all number
    0
    1
    1
    3
    4
    VOCAL CORD POLYP
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    WHEEZING
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    2
    1
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    4 / 78 (5.13%)
    6 / 132 (4.55%)
    5 / 134 (3.73%)
         occurrences all number
    1
    2
    5
    7
    6
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    3 / 134 (2.24%)
         occurrences all number
    0
    1
    0
    1
    3
    INSOMNIA
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    9 / 78 (11.54%)
    13 / 132 (9.85%)
    12 / 134 (8.96%)
         occurrences all number
    2
    0
    10
    14
    12
    DISORIENTATION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    0
    1
    DEPRESSION
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences all number
    1
    0
    1
    1
    2
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    3 / 132 (2.27%)
    4 / 134 (2.99%)
         occurrences all number
    3
    2
    9
    5
    4
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    5 / 78 (6.41%)
    2 / 132 (1.52%)
    5 / 134 (3.73%)
         occurrences all number
    3
    3
    11
    2
    5
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    4 / 134 (2.99%)
         occurrences all number
    3
    0
    3
    1
    7
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    2 / 132 (1.52%)
    3 / 134 (2.24%)
         occurrences all number
    6
    2
    19
    4
    4
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 15 (20.00%)
    7 / 78 (8.97%)
    13 / 132 (9.85%)
    7 / 134 (5.22%)
         occurrences all number
    3
    6
    9
    27
    8
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    BLOOD PHOSPHORUS INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    5
    1
    BLOOD PRESSURE INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
    7 / 134 (5.22%)
         occurrences all number
    0
    0
    2
    2
    9
    BLOOD UREA INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    7
    0
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    2 / 132 (1.52%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    3
    2
    4
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    6 / 78 (7.69%)
    7 / 132 (5.30%)
    15 / 134 (11.19%)
         occurrences all number
    0
    4
    7
    7
    17
    TROPONIN T INCREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    6 / 78 (7.69%)
    5 / 132 (3.79%)
    3 / 134 (2.24%)
         occurrences all number
    0
    2
    10
    11
    3
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    10 / 78 (12.82%)
    5 / 132 (3.79%)
    2 / 134 (1.49%)
         occurrences all number
    0
    2
    32
    12
    2
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    6 / 78 (7.69%)
    3 / 132 (2.27%)
    8 / 134 (5.97%)
         occurrences all number
    3
    2
    7
    3
    8
    FALL
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 15 (26.67%)
    6 / 78 (7.69%)
    7 / 132 (5.30%)
    11 / 134 (8.21%)
         occurrences all number
    1
    6
    9
    7
    11
    INFUSION RELATED REACTION
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    1
    2
    LIMB INJURY
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    1 / 78 (1.28%)
    6 / 132 (4.55%)
    0 / 134 (0.00%)
         occurrences all number
    0
    2
    1
    6
    0
    SCRATCH
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    1
    1
    SKIN ABRASION
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
    3 / 134 (2.24%)
         occurrences all number
    1
    0
    5
    0
    3
    SKIN LACERATION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
    5 / 134 (3.73%)
         occurrences all number
    0
    1
    2
    2
    6
    THERMAL BURN
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    TRAUMATIC HAEMATOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    5 / 132 (3.79%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    2
    7
    2
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    10 / 78 (12.82%)
    12 / 132 (9.09%)
    12 / 134 (8.96%)
         occurrences all number
    0
    1
    10
    16
    14
    BRADYCARDIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    4 / 134 (2.99%)
         occurrences all number
    0
    1
    0
    2
    4
    PALPITATIONS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    7 / 78 (8.97%)
    3 / 132 (2.27%)
    5 / 134 (3.73%)
         occurrences all number
    0
    0
    10
    3
    8
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 15 (6.67%)
    15 / 78 (19.23%)
    22 / 132 (16.67%)
    15 / 134 (11.19%)
         occurrences all number
    4
    1
    21
    43
    19
    DYSKINESIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    DYSGEUSIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    4 / 78 (5.13%)
    2 / 132 (1.52%)
    6 / 134 (4.48%)
         occurrences all number
    0
    0
    4
    2
    6
    DYSARTHRIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    1
    0
    1
    DIZZINESS
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 15 (13.33%)
    17 / 78 (21.79%)
    20 / 132 (15.15%)
    16 / 134 (11.94%)
         occurrences all number
    21
    2
    23
    35
    22
    PARESIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    HYPOAESTHESIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    7 / 78 (8.97%)
    6 / 132 (4.55%)
    8 / 134 (5.97%)
         occurrences all number
    4
    0
    19
    9
    10
    MEMORY IMPAIRMENT
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    2 / 78 (2.56%)
    4 / 132 (3.03%)
    1 / 134 (0.75%)
         occurrences all number
    1
    3
    2
    10
    3
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    1
    1
    1
    PARAESTHESIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    9 / 78 (11.54%)
    14 / 132 (10.61%)
    5 / 134 (3.73%)
         occurrences all number
    3
    0
    19
    23
    9
    VASCULAR ENCEPHALOPATHY
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    TREMOR
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences all number
    0
    3
    2
    1
    4
    SYNCOPE
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
    6 / 134 (4.48%)
         occurrences all number
    1
    0
    1
    4
    7
    SENSORY DISTURBANCE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    SCIATICA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    3 / 132 (2.27%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    2
    5
    3
    RESTLESS LEGS SYNDROME
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    0
    1
    PRESYNCOPE
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences all number
    1
    2
    0
    2
    2
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    6 / 78 (7.69%)
    7 / 132 (5.30%)
    4 / 134 (2.99%)
         occurrences all number
    1
    0
    8
    13
    4
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 15 (26.67%)
    17 / 78 (21.79%)
    17 / 132 (12.88%)
    27 / 134 (20.15%)
         occurrences all number
    2
    20
    27
    32
    40
    LEUKOPENIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
    12 / 134 (8.96%)
         occurrences all number
    0
    1
    2
    2
    53
    LYMPHADENOPATHY
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    4 / 132 (3.03%)
    2 / 134 (1.49%)
         occurrences all number
    1
    0
    2
    4
    2
    NEUTROPENIA
         subjects affected / exposed
    1 / 6 (16.67%)
    7 / 15 (46.67%)
    26 / 78 (33.33%)
    19 / 132 (14.39%)
    46 / 134 (34.33%)
         occurrences all number
    2
    33
    67
    25
    207
    SPLENOMEGALY
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    SPONTANEOUS HAEMATOMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
    3 / 134 (2.24%)
         occurrences all number
    0
    1
    2
    3
    3
    THROMBOCYTOPENIA
         subjects affected / exposed
    4 / 6 (66.67%)
    4 / 15 (26.67%)
    8 / 78 (10.26%)
    20 / 132 (15.15%)
    22 / 134 (16.42%)
         occurrences all number
    5
    6
    23
    46
    74
    INCREASED TENDENCY TO BRUISE
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 15 (20.00%)
    17 / 78 (21.79%)
    10 / 132 (7.58%)
    12 / 134 (8.96%)
         occurrences all number
    4
    4
    25
    12
    17
    Ear and labyrinth disorders
    EAR PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    2
    1
    2
    TINNITUS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    3 / 132 (2.27%)
    4 / 134 (2.99%)
         occurrences all number
    1
    0
    0
    3
    4
    VERTIGO
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    3 / 78 (3.85%)
    5 / 132 (3.79%)
    6 / 134 (4.48%)
         occurrences all number
    1
    0
    5
    5
    6
    Eye disorders
    ASTIGMATISM
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    CATARACT
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    3 / 78 (3.85%)
    9 / 132 (6.82%)
    5 / 134 (3.73%)
         occurrences all number
    0
    2
    5
    9
    6
    VISUAL ACUITY REDUCED
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    9 / 78 (11.54%)
    16 / 132 (12.12%)
    20 / 134 (14.93%)
         occurrences all number
    1
    3
    13
    32
    42
    DIPLOPIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    3 / 132 (2.27%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    2
    5
    2
    DRY EYE
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 15 (26.67%)
    8 / 78 (10.26%)
    20 / 132 (15.15%)
    18 / 134 (13.43%)
         occurrences all number
    3
    4
    14
    45
    25
    EYE DISCHARGE
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    5 / 132 (3.79%)
    2 / 134 (1.49%)
         occurrences all number
    1
    1
    2
    5
    3
    EYE IRRITATION
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    6 / 78 (7.69%)
    21 / 132 (15.91%)
    13 / 134 (9.70%)
         occurrences all number
    2
    5
    6
    27
    16
    EYE PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    7 / 132 (5.30%)
    6 / 134 (4.48%)
         occurrences all number
    0
    1
    1
    10
    10
    HYPERMETROPIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    LACRIMATION INCREASED
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    9 / 78 (11.54%)
    16 / 132 (12.12%)
    18 / 134 (13.43%)
         occurrences all number
    6
    2
    15
    25
    30
    MACULAR DEGENERATION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    0
    1
    MACULOPATHY
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    OCULAR HYPERAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    1
    3
    1
    PHOTOPHOBIA
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    3 / 78 (3.85%)
    12 / 132 (9.09%)
    11 / 134 (8.21%)
         occurrences all number
    3
    3
    4
    19
    14
    PHOTOPSIA
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
    5 / 134 (3.73%)
         occurrences all number
    0
    2
    1
    3
    8
    VISION BLURRED
         subjects affected / exposed
    3 / 6 (50.00%)
    4 / 15 (26.67%)
    8 / 78 (10.26%)
    23 / 132 (17.42%)
    25 / 134 (18.66%)
         occurrences all number
    10
    5
    17
    50
    47
    CONJUNCTIVAL HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    0
    3
    2
    VITREOUS FLOATERS
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    5 / 78 (6.41%)
    10 / 132 (7.58%)
    5 / 134 (3.73%)
         occurrences all number
    3
    2
    6
    12
    7
    Gastrointestinal disorders
    FLATULENCE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
    6 / 134 (4.48%)
         occurrences all number
    0
    1
    1
    3
    6
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    11 / 78 (14.10%)
    12 / 132 (9.09%)
    14 / 134 (10.45%)
         occurrences all number
    1
    4
    20
    17
    22
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    7 / 78 (8.97%)
    9 / 132 (6.82%)
    6 / 134 (4.48%)
         occurrences all number
    1
    2
    8
    11
    8
    ANAL HAEMORRHAGE
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    APHTHOUS ULCER
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    5 / 78 (6.41%)
    4 / 132 (3.03%)
    2 / 134 (1.49%)
         occurrences all number
    1
    0
    10
    9
    2
    CHRONIC GASTRITIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    CONSTIPATION
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 15 (20.00%)
    13 / 78 (16.67%)
    23 / 132 (17.42%)
    19 / 134 (14.18%)
         occurrences all number
    5
    3
    19
    59
    23
    DIARRHOEA
         subjects affected / exposed
    5 / 6 (83.33%)
    10 / 15 (66.67%)
    37 / 78 (47.44%)
    48 / 132 (36.36%)
    84 / 134 (62.69%)
         occurrences all number
    21
    24
    196
    89
    243
    DRY MOUTH
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    3 / 78 (3.85%)
    10 / 132 (7.58%)
    7 / 134 (5.22%)
         occurrences all number
    1
    2
    4
    11
    9
    DUODENITIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences all number
    1
    0
    0
    0
    2
    DYSPEPSIA
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 15 (6.67%)
    8 / 78 (10.26%)
    11 / 132 (8.33%)
    19 / 134 (14.18%)
         occurrences all number
    3
    1
    12
    13
    28
    DYSPHAGIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
    3 / 134 (2.24%)
         occurrences all number
    0
    1
    1
    7
    5
    ENTERITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    FAECES SOFT
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    0
    1
    FEMORAL HERNIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    4 / 132 (3.03%)
    4 / 134 (2.99%)
         occurrences all number
    0
    1
    4
    4
    4
    GASTRITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    3 / 78 (3.85%)
    5 / 132 (3.79%)
    7 / 134 (5.22%)
         occurrences all number
    0
    0
    3
    6
    8
    GLOSSODYNIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    HAEMORRHOIDS
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    4 / 78 (5.13%)
    3 / 132 (2.27%)
    7 / 134 (5.22%)
         occurrences all number
    0
    2
    4
    3
    10
    HYPOAESTHESIA ORAL
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    MOUTH ULCERATION
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    7 / 78 (8.97%)
    6 / 132 (4.55%)
    11 / 134 (8.21%)
         occurrences all number
    3
    0
    13
    6
    15
    NAUSEA
         subjects affected / exposed
    5 / 6 (83.33%)
    5 / 15 (33.33%)
    24 / 78 (30.77%)
    21 / 132 (15.91%)
    43 / 134 (32.09%)
         occurrences all number
    16
    15
    75
    36
    78
    OESOPHAGITIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    2 / 134 (1.49%)
         occurrences all number
    1
    0
    0
    2
    2
    PEPTIC ULCER
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    STOMATITIS
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    12 / 78 (15.38%)
    11 / 132 (8.33%)
    12 / 134 (8.96%)
         occurrences all number
    3
    2
    31
    20
    16
    TONGUE ERYTHEMA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    TONGUE HAEMORRHAGE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    TOOTHACHE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    5 / 78 (6.41%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    5
    1
    1
    VOMITING
         subjects affected / exposed
    1 / 6 (16.67%)
    5 / 15 (33.33%)
    18 / 78 (23.08%)
    14 / 132 (10.61%)
    27 / 134 (20.15%)
         occurrences all number
    11
    9
    35
    24
    59
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    11 / 78 (14.10%)
    5 / 132 (3.79%)
    11 / 134 (8.21%)
         occurrences all number
    0
    2
    12
    5
    15
    Hepatobiliary disorders
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    6 / 78 (7.69%)
    1 / 132 (0.76%)
    3 / 134 (2.24%)
         occurrences all number
    0
    0
    8
    1
    7
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    2 / 134 (1.49%)
         occurrences all number
    7
    2
    0
    3
    10
    HEPATITIS CHOLESTATIC
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    1
    0
    0
    0
    1
    PORTAL FIBROSIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    ONYCHOCLASIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    7 / 132 (5.30%)
    11 / 134 (8.21%)
         occurrences all number
    0
    0
    1
    9
    13
    PETECHIAE
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    7 / 78 (8.97%)
    5 / 132 (3.79%)
    6 / 134 (4.48%)
         occurrences all number
    0
    0
    11
    10
    8
    ALOPECIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    4
    0
    0
    BLOOD BLISTER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    4 / 78 (5.13%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    0
    0
    5
    1
    1
    DECUBITUS ULCER
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    3
    0
    0
    1
    1
    DRY SKIN
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    5 / 132 (3.79%)
    6 / 134 (4.48%)
         occurrences all number
    1
    1
    4
    5
    7
    ECCHYMOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    1
    2
    2
    ERYTHEMA
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    3 / 132 (2.27%)
    7 / 134 (5.22%)
         occurrences all number
    2
    1
    3
    3
    8
    HYPERHIDROSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    4 / 132 (3.03%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    6
    1
    NIGHT SWEATS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    5 / 132 (3.79%)
    9 / 134 (6.72%)
         occurrences all number
    1
    0
    2
    6
    10
    PRURITUS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    11 / 78 (14.10%)
    15 / 132 (11.36%)
    15 / 134 (11.19%)
         occurrences all number
    1
    0
    13
    26
    18
    RASH
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
    5 / 134 (3.73%)
         occurrences all number
    1
    1
    2
    3
    7
    RASH ERYTHEMATOUS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    5 / 78 (6.41%)
    5 / 132 (3.79%)
    8 / 134 (5.97%)
         occurrences all number
    0
    1
    5
    6
    9
    RASH MACULO-PAPULAR
         subjects affected / exposed
    2 / 6 (33.33%)
    4 / 15 (26.67%)
    13 / 78 (16.67%)
    12 / 132 (9.09%)
    18 / 134 (13.43%)
         occurrences all number
    6
    5
    19
    14
    33
    SKIN LESION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    1 / 132 (0.76%)
    4 / 134 (2.99%)
         occurrences all number
    0
    1
    4
    1
    7
    URTICARIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    4 / 78 (5.13%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences all number
    0
    0
    4
    0
    2
    SKIN ULCER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    5 / 78 (6.41%)
    1 / 132 (0.76%)
    5 / 134 (3.73%)
         occurrences all number
    0
    0
    12
    2
    6
    Renal and urinary disorders
    DYSURIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    6 / 78 (7.69%)
    4 / 132 (3.03%)
    5 / 134 (3.73%)
         occurrences all number
    0
    0
    8
    5
    7
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    BLADDER HYPERTROPHY
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    3 / 132 (2.27%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    4
    2
    HAEMATURIA
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    11 / 78 (14.10%)
    5 / 132 (3.79%)
    4 / 134 (2.99%)
         occurrences all number
    1
    2
    13
    7
    5
    POLLAKIURIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
    4 / 134 (2.99%)
         occurrences all number
    0
    1
    1
    2
    4
    RENAL FAILURE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    3 / 134 (2.24%)
         occurrences all number
    0
    1
    0
    3
    5
    URINARY INCONTINENCE
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    0
    2
    URINARY RETENTION
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    2 / 78 (2.56%)
    4 / 132 (3.03%)
    2 / 134 (1.49%)
         occurrences all number
    0
    2
    2
    4
    3
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    3 / 78 (3.85%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    8 / 78 (10.26%)
    12 / 132 (9.09%)
    11 / 134 (8.21%)
         occurrences all number
    1
    2
    14
    18
    18
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    4 / 132 (3.03%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    2
    4
    2
    NECK PAIN
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    4 / 132 (3.03%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    2
    4
    2
    MYALGIA
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 15 (13.33%)
    16 / 78 (20.51%)
    17 / 132 (12.88%)
    13 / 134 (9.70%)
         occurrences all number
    13
    3
    34
    34
    18
    MUSCULOSKELETAL STIFFNESS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    3 / 78 (3.85%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    6 / 134 (4.48%)
         occurrences all number
    0
    1
    2
    5
    7
    MUSCLE SPASMS
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 15 (6.67%)
    6 / 78 (7.69%)
    32 / 132 (24.24%)
    12 / 134 (8.96%)
         occurrences all number
    3
    1
    10
    56
    16
    LIMB DISCOMFORT
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    JOINT SWELLING
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    3 / 78 (3.85%)
    4 / 132 (3.03%)
    4 / 134 (2.99%)
         occurrences all number
    0
    3
    3
    10
    6
    BACK PAIN
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 15 (0.00%)
    14 / 78 (17.95%)
    15 / 132 (11.36%)
    12 / 134 (8.96%)
         occurrences all number
    2
    0
    26
    20
    18
    ARTHRALGIA
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 15 (20.00%)
    12 / 78 (15.38%)
    23 / 132 (17.42%)
    22 / 134 (16.42%)
         occurrences all number
    8
    5
    26
    47
    29
    ROTATOR CUFF SYNDROME
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    SPONDYLITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    HERPES ZOSTER
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    5 / 78 (6.41%)
    8 / 132 (6.06%)
    3 / 134 (2.24%)
         occurrences all number
    0
    0
    6
    10
    3
    BRONCHITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    4 / 78 (5.13%)
    9 / 132 (6.82%)
    7 / 134 (5.22%)
         occurrences all number
    0
    0
    5
    15
    10
    CANDIDA INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    CELLULITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
    7 / 134 (5.22%)
         occurrences all number
    0
    0
    1
    0
    10
    CONJUNCTIVITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    3 / 78 (3.85%)
    11 / 132 (8.33%)
    8 / 134 (5.97%)
         occurrences all number
    0
    3
    3
    15
    10
    COVID-19
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    19 / 78 (24.36%)
    16 / 132 (12.12%)
    16 / 134 (11.94%)
         occurrences all number
    1
    4
    22
    22
    20
    COVID-19 PNEUMONIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    1
    1
    CYSTITIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    5 / 132 (3.79%)
    2 / 134 (1.49%)
         occurrences all number
    13
    0
    2
    5
    3
    DEMODICIDOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    EPIDIDYMITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    ERYSIPELAS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    ESCHERICHIA URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    1
    1
    FOLLICULITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    3 / 134 (2.24%)
         occurrences all number
    0
    2
    2
    1
    4
    FUNGAL INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    INFLUENZA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    7 / 134 (5.22%)
         occurrences all number
    0
    1
    0
    2
    12
    VULVOVAGINAL CANDIDIASIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    0
    1
    NASAL ABSCESS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    4 / 78 (5.13%)
    8 / 132 (6.06%)
    8 / 134 (5.97%)
         occurrences all number
    1
    0
    4
    9
    11
    ORAL HERPES
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    7 / 132 (5.30%)
    8 / 134 (5.97%)
         occurrences all number
    0
    0
    1
    9
    10
    PARONYCHIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    1 / 78 (1.28%)
    7 / 132 (5.30%)
    5 / 134 (3.73%)
         occurrences all number
    2
    0
    1
    12
    6
    PNEUMONIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    2 / 78 (2.56%)
    7 / 132 (5.30%)
    7 / 134 (5.22%)
         occurrences all number
    0
    1
    3
    9
    7
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    7 / 132 (5.30%)
    6 / 134 (4.48%)
         occurrences all number
    0
    0
    3
    18
    11
    RHINITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    2 / 78 (2.56%)
    9 / 132 (6.82%)
    3 / 134 (2.24%)
         occurrences all number
    0
    2
    2
    10
    3
    SINUSITIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    6 / 132 (4.55%)
    11 / 134 (8.21%)
         occurrences all number
    0
    2
    8
    8
    14
    SKIN CANDIDA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    TINEA CRURIS
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    0 / 134 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    9 / 78 (11.54%)
    14 / 132 (10.61%)
    23 / 134 (17.16%)
         occurrences all number
    2
    3
    13
    16
    42
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 15 (26.67%)
    7 / 78 (8.97%)
    10 / 132 (7.58%)
    14 / 134 (10.45%)
         occurrences all number
    4
    14
    21
    12
    22
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    0
    0
    4
    LOCALISED INFECTION
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
    5 / 134 (3.73%)
         occurrences all number
    1
    0
    4
    1
    8
    WOUND INFECTION
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    1
    3
    0
    Metabolism and nutrition disorders
    HYPOKALAEMIA
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 15 (33.33%)
    16 / 78 (20.51%)
    8 / 132 (6.06%)
    21 / 134 (15.67%)
         occurrences all number
    2
    11
    24
    13
    31
    HYPERVOLAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    1 / 134 (0.75%)
         occurrences all number
    0
    1
    0
    0
    1
    HYPERURICAEMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    5 / 78 (6.41%)
    11 / 132 (8.33%)
    9 / 134 (6.72%)
         occurrences all number
    3
    3
    5
    15
    12
    HYPERPHOSPHATAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 15 (0.00%)
    9 / 78 (11.54%)
    3 / 132 (2.27%)
    2 / 134 (1.49%)
         occurrences all number
    0
    0
    12
    3
    3
    HYPERNATRAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    HYPERKALAEMIA
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 15 (0.00%)
    8 / 78 (10.26%)
    3 / 132 (2.27%)
    5 / 134 (3.73%)
         occurrences all number
    1
    0
    8
    4
    5
    DEHYDRATION
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 15 (13.33%)
    1 / 78 (1.28%)
    4 / 132 (3.03%)
    4 / 134 (2.99%)
         occurrences all number
    1
    2
    1
    4
    4
    DECREASED APPETITE
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 15 (20.00%)
    8 / 78 (10.26%)
    15 / 132 (11.36%)
    24 / 134 (17.91%)
         occurrences all number
    1
    4
    9
    18
    33
    ACIDOSIS
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
    0 / 134 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    HYPOGLYCAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    1
    1
    2
    VITAMIN B12 DEFICIENCY
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
    2 / 134 (1.49%)
         occurrences all number
    0
    1
    0
    1
    2
    IRON DEFICIENCY
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    3 / 132 (2.27%)
    4 / 134 (2.99%)
         occurrences all number
    0
    2
    4
    3
    5
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 15 (6.67%)
    4 / 78 (5.13%)
    4 / 132 (3.03%)
    4 / 134 (2.99%)
         occurrences all number
    0
    2
    7
    6
    5
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 15 (13.33%)
    1 / 78 (1.28%)
    4 / 132 (3.03%)
    2 / 134 (1.49%)
         occurrences all number
    0
    2
    4
    5
    3
    HYPOMAGNESAEMIA
         subjects affected / exposed
    4 / 6 (66.67%)
    3 / 15 (20.00%)
    16 / 78 (20.51%)
    4 / 132 (3.03%)
    14 / 134 (10.45%)
         occurrences all number
    6
    5
    21
    13
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2017
    • Included 560 mg tablet to decrease the pill burden for subjects participating in the study • Included that a prior rituximab/anti-CD20-containing regimen was required • Extended the ECOG performance status to include subjects with ECOG performance status of 2 in order to expand study eligibility to a broader population of subjects • Updated the ibrutinib and venetoclax overview and safety sections according to current IB version and labeling information • Updated the rationale for ibrutinib and venetoclax combination to include current results and reference based on ICML 2017 data • Excluded subjects who could not tolerate study treatment due to hypersensitivity to 1 or more study drug components • Included a 24-hour time window for the investigator to notify the sponsor in case subject discontinued study treatment.
    07 Nov 2019
    • Removed the planned Interim Analysis for the SRI and Randomization Phase • Added the treatment-naive arm, including subjects with a TP53 mutation • Added the rationale for the treatment-naive arm, including subjects with a TP53 mutation • Removed the now obsolete ibrutinib Lead-in Schedule of treatment • Added further clarity regarding the maximum dose of ibrutinib tablets and capsules.
    25 Mar 2021
    • Changed eligibility to adults ≥ 18 years with a TP53 mutation for the treatment naive cohort • Removed the requirement of 25 subjects less than 65 years of age with a TP53 mutation • Updated the MRD analysis population • Added the OS assumptions • Added an interim analysis for OS at the time of the primary analysis for PFS at 134 events • Added cardiac failure as a risk per IB update • Clarified that dose reductions are an option to manage Grade 2 AEs • Removed required sequencing of PET first then CT if on the same day • Clarification that only post-dose laboratory assessments will be considered for TLS when applying Howard Criteria • Made corrections regarding MRD testing in text and schedule of activities (SoA).
    16 Sep 2022
    • Included updated recommendations intended to improve tolerability for continued ibrutinib treatment in the study protocol • Included a new Protocol Table 2: Ibrutinib Dose Modifications for Cardiac Failure or Cardiac Arrhythmias • Clarified that all patients need to have adequate response assessments per schedule of assessment until the end of study • Clarified that all patients need to have adequate patient-reported outcomes per schedule of assessments until the end of study.

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

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