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    Clinical Trial Results:
    A Multicenter Open-Label Phase 1b/2 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Lenalidomide and Rituximab in Subjects with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

    Summary
    EudraCT number
    		 2013-004341-17
    Trial protocol
    		 BE   GB  
    Global end of trial date
    17 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2021
    First version publication date
    16 Dec 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PCYC-1123-CA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02077166
    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
    17 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 1b: • To determine the maximum tolerated doses (MTD) and/or the recommended Phase 2 (RP2) dose of ibrutinib in combination with lenalidomide and rituximab by dose escalation of lenalidomide in subjects with relapsed or refractory DLBCL • To determine the safety and tolerability of ibrutinib in combination with lenalidomide and rituximab in subjects with relapsed or refractory DLBCL by dose escalating lenalidomide Phase 2: • To evaluate the efficacy of ibrutinib in combination with lenalidomide and rituximab by assessing the overall response rate (ORR) in subjects with relapsed or refractory non-GCB DLBCL
    Protection of trial subjects
    The Investigator or designee (designee must be listed on the Delegation of Authority log), must explain in terms understandable to the subject the purpose and nature of the study, study procedures, anticipated benefits, potential risks, possible adverse events (AEs), and any discomfort participation in the study may entail. This process must be documented in the subject’s source record. Each subject must provide a signed and dated informed consent form (ICF) before any study-related (nonstandard of care) activities are performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Mar 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    United Kingdom: 43
    Country: Number of subjects enrolled
    United States: 83
    Worldwide total number of subjects
    138
    EEA total number of subjects
    12
    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)
    70
    From 65 to 84 years
    65
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 All participants had relapsed/refractory diffuse large B-cell lymphoma (DLBCL). In the Phase 1b portion of the study, all subtypes of DLBCL and participants with transformed disease were enrolled. In the Phase 2 portion of the study, only participants with non-germinal-center B-cell-like (non-GCB) DLBCL were enrolled.

    Pre-assignment
    Screening details
    		 In the Phase 1b portion of this study, different dose levels of lenalidomide were explored, and dose escalation of lenalidomide followed the 3+3+3 dose escalation schema. Participants remained on study until disease progression or unacceptable toxicity. "Reason for non-completion" rows below display the primary reason for exiting the study.

    Pre-assignment period milestones
    Number of subjects started
    		 138
    Number of subjects completed
    		 134

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not receive any treatment: 4
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1)
    Arm description
    		 Ibrutinib 560 mg administered orally (PO) once daily (QD) beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered intravenously (IV) on Day 1 of each 28-day cycle for 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered orally daily beginning Cycle 1 Day 1.

    Investigational medicinal product name
    lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be administered orally daily on Days 1-21 of each 28-day cycle.

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Arm title
    		 Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1)
    Arm description
    		 De-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered orally daily beginning Cycle 1 Day 1.

    Investigational medicinal product name
    lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be administered orally daily on Days 1-21 of each 28-day cycle.

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Arm title
    		 Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+)
    Arm description
    		 Re-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered orally daily beginning Cycle 1 Day 1.

    Investigational medicinal product name
    lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be administered orally daily on Days 1-21 of each 28-day cycle.

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Arm title
    		 Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2)
    Arm description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered orally daily beginning Cycle 1 Day 1.

    Investigational medicinal product name
    lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be administered orally daily on Days 1-21 of each 28-day cycle.

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Arm title
    		 Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3)
    Arm description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered orally daily beginning Cycle 1 Day 1.

    Investigational medicinal product name
    lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be administered orally daily on Days 1-21 of each 28-day cycle.

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Arm title
    		 Phase 2: Enrolled at Lenalidomide Dose 20 mg
    Arm description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered orally daily beginning Cycle 1 Day 1.

    Investigational medicinal product name
    lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be administered orally daily on Days 1-21 of each 28-day cycle.

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Arm title
    		 Phase 2: Enrolled at Lenalidomide Dose 25 mg
    Arm description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered orally daily beginning Cycle 1 Day 1.

    Investigational medicinal product name
    lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be administered orally daily on Days 1-21 of each 28-day cycle.

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Number of subjects in period 1 [1]
    		Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3) Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg
    Started
    12
    7
    9
    9
    8
    55
    34
    Completed
    0
    0
    0
    0
    0
    0
    0
    Not completed
    12
    7
    9
    9
    8
    55
    34
         Consent withdrawn by subject
    3
    -
    1
    1
    1
    3
    -
         Study Closure by Sponsor
    3
    -
    2
    2
    2
    12
    4
         Death
    6
    7
    5
    6
    4
    32
    22
         Lost to follow-up
    -
    -
    -
    -
    -
    1
    -
         Other, Not Specified
    -
    -
    1
    -
    1
    7
    8
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 138 participants enrolled in the study; however, 4 participants exited the study without receiving any treatment, and are not presented in any data table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1)
    Reporting group description
    		 Ibrutinib 560 mg administered orally (PO) once daily (QD) beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered intravenously (IV) on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1)
    Reporting group description
    		 De-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+)
    Reporting group description
    		 Re-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 2: Enrolled at Lenalidomide Dose 20 mg
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 2: Enrolled at Lenalidomide Dose 25 mg
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group values
    		 Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3) Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg Total
    Number of subjects
    		 12 7 9 9 8 55 34 134
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.3 ± 13.13 58.4 ± 7.63 65.3 ± 13.44 66.0 ± 8.63 62.9 ± 14.23 63.1 ± 11.75 64.9 ± 12.52 -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 5 5 3 23 14 57
        Male
    		 8 4 4 4 5 32 20 77
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 3 1 0 0 0 5 10
        Not Hispanic or Latino
    		 11 4 8 9 8 55 29 124
    Race
    Units: Subjects
        Asian
    		 0 0 0 0 0 1 2 3
        Black or African American
    		 1 1 1 0 1 2 1 7
        White
    		 11 5 8 9 7 51 30 121
        Multiple Races
    		 0 0 0 0 0 0 1 1
        Declined to Answer/ Unknown
    		 0 1 0 0 0 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1)
    Reporting group description
    		 Ibrutinib 560 mg administered orally (PO) once daily (QD) beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered intravenously (IV) on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1)
    Reporting group description
    		 De-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+)
    Reporting group description
    		 Re-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 2: Enrolled at Lenalidomide Dose 20 mg
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 2: Enrolled at Lenalidomide Dose 25 mg
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Subject analysis set title
    All Phase 1b Participants
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10, 15, 20, or 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Subject analysis set title
    Phase 2 Total: Enrolled at Lenalidomide Dose 20 or 25 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 or 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Primary: Phase 1b: Recommended Phase 2 Dose of Lenalidomide in Combination With Fixed Doses of Ibrutinib and Rituximab in Participants With Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)

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    End point title
    		 Phase 1b: Recommended Phase 2 Dose of Lenalidomide in Combination With Fixed Doses of Ibrutinib and Rituximab in Participants With Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL) [1]
    End point description
    The dose levels of lenalidomide were explored, and dose escalation of lenalidomide followed the 3+3+3 dose escalation schema. A Dose Level Review Committee evaluated safety data following completion of each dose observation period of the Phase 1b portion. All-Treated Analysis Population (Phase 1b): participants who received any dose of study drug(s).
    End point type
    Primary
    End point timeframe
    Estimated median time on study in Phase 1b was 59.6 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 are presented per protocol.
    End point values
    		 All Phase 1b Participants
    Number of subjects analysed
    45
    Units: mg
        number (not applicable)
    20
    No statistical analyses for this end point

    Primary: Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs

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    End point title
    		 Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs [2] [3]
    End point description
    An adverse event (AE) is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization > 24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. AEs that started or worsened during the treatment-emergent period and all possibly related or related AEs were considered TEAEs. Related events were those that were considered possibly related or related to study drug per investigator's judgment. Events were graded per the national Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03: Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life-threatening; grade 5=death. All-Treated Analysis Population (Phase 1).
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 30 days after last dose of study drug. Phase 1b median duration of ibrutinib exposure was 4.4 months; median duration of lenalidomide exposure was 4.4 months; median total number of doses of rituximab received was 4.0.
    Notes
    [2] - 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 are presented per protocol.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 2 data are presented as a separate endpoint.
    End point values
    		 Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3)
    Number of subjects analysed
    12
    7
    9
    9
    8
    Units: participants
        TEAE
    12
    7
    9
    9
    8
        Grade >=3 TEAE
    11
    6
    9
    9
    7
        Study Drug-Related TEAE
    12
    5
    9
    8
    8
        Grade >=3 Study Drug-Related TEAE
    10
    3
    8
    7
    7
        Ibrutinib-Related TEAE
    12
    5
    9
    8
    8
        Grade >=3 Ibrutinib-Related TEAE
    10
    3
    7
    7
    6
        Lenalidomide-Related TEAE
    12
    5
    9
    8
    8
        Grade >=3 Lenalidomide-Related TEAE
    9
    3
    8
    7
    6
        Rituximab-Related TEAE
    6
    4
    7
    6
    7
        Grade >= 3 Rituximab-Related TEAE
    1
    2
    7
    5
    3
        TEAE Leading to Dose Reduction of Any Study Drug
    4
    0
    4
    4
    5
        TEAE Leading to Dose Reduction of Ibrutinib
    3
    0
    4
    3
    3
        TEAE Leading to Dose Reduction of Lenalidomide
    2
    0
    3
    4
    4
        TEAE Leading to Dose Delay of Any Study Drug
    6
    4
    7
    8
    8
        TEAE Leading to Dose Delay of Ibrutinib
    6
    4
    7
    8
    8
        TEAE Leading to Dose Delay of Lenalidomide
    6
    3
    7
    7
    8
        TEAE Leading to Dose Delay of Rituximab
    4
    1
    6
    4
    4
        TEAE Leading to Discontinuation of Any Study Drug
    4
    2
    3
    2
    1
        TEAE Leading to Discontinuation of Ibrutinib Dose
    4
    2
    3
    2
    1
        TEAE Leading to Discontinuation of Lenalid. Dose
    4
    2
    3
    2
    1
        TEAE Leading to Discontinuation of Rituximab Dose
    3
    2
    3
    2
    1
        Serious TEAE
    4
    6
    7
    5
    6
        Grade >=3 Serious TEAE
    4
    6
    6
    4
    6
        Treatment-Related Serious TEAE
    0
    2
    4
    2
    3
        Ibrutinib-Related Serious TEAE
    0
    2
    4
    2
    3
        Lenalidomide-Related Serious TEAE
    0
    2
    4
    2
    3
        Rituximab-Related Serious TEAE
    0
    2
    2
    1
    0
        Fatal TEAE
    0
    2
    2
    1
    1
    No statistical analyses for this end point

    Primary: Phase 2: Overall Response Rate (ORR)

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    End point title
    		 Phase 2: Overall Response Rate (ORR) [4] [5]
    End point description
    The ORR was defined as the percentage of participants who achieve either a partial response (PR) or complete response (CR), according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (see Cheson, 2014 for detailed criteria), as assessed by the investigator in response-evaluable population. The 95% confidence interval (CI) was calculated using the exact method. Response-Evaluable Population: participants who had measurable disease at baseline and had at least 1 adequate post-treatment disease assessment by the investigator.
    End point type
    Primary
    End point timeframe
    Estimated median time on study in Phase 2 was 35.0 months.
    Notes
    [4] - 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 are presented per protocol.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Phase 1 data are presented as a separate endpoint.
    End point values
    		 Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg Phase 2 Total: Enrolled at Lenalidomide Dose 20 or 25 mg
    Number of subjects analysed
    53
    32
    85
    Units: percentage of participants
        number (confidence interval 95%)
    52.8 (38.6 to 66.7)
    43.8 (26.4 to 62.3)
    49.4 (38.4 to 60.5)
    No statistical analyses for this end point

    Secondary: Phase 1b: ORR

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    End point title
    		 Phase 1b: ORR [6]
    End point description
    The ORR was defined as the percentage of participants who achieve either a PR or CR, according to the Revised International Working Group Response Criteria for Malignant Lymphoma (Cheson 2007), as assessed by the Investigator in response-evaluable population, where CR=disappearance of all evidence of disease and PR=regression of measurable disease and no new sites. The 95% CI was calculated using the exact method. Response-Evaluable Population: participants who had measurable disease at baseline and had at least 1 adequate post-treatment disease assessment by the investigator.
    End point type
    Secondary
    End point timeframe
    Estimated median time on study in Phase 1b was 59.6 months.
    Notes
    [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: Phase 2 data are presented as a separate endpoint.
    End point values
    		 Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3) All Phase 1b Participants
    Number of subjects analysed
    9
    7
    7
    9
    8
    40
    Units: percentage of participants
        number (confidence interval 95%)
    44.4 (13.7 to 78.8)
    0 (0 to 41.0)
    71.4 (29.0 to 96.3)
    22.2 (2.8 to 60.0)
    75.0 (34.9 to 96.8)
    42.5 (27.0 to 59.1)
    No statistical analyses for this end point

    Secondary: Phase 1b: Complete Response (CR) Rate

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    End point title
    		 Phase 1b: Complete Response (CR) Rate [7]
    End point description
    The CR rate was defined as the percentage of participants who achieve a CR, according to the Revised International Working Group Response Criteria for Malignant Lymphoma (Cheson 2007), as assessed by the Investigator in response-evaluable population, where CR=disappearance of all evidence of disease, as assessed by the Investigator. Response-Evaluable Population: participants who had measurable disease at baseline and had at least 1 adequate post-treatment disease assessment by the investigator.
    End point type
    Secondary
    End point timeframe
    Estimated median time on Phase 1b study was 59.6 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: Phase 2 data are presented as a separate endpoint.
    End point values
    		 Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3) All Phase 1b Participants
    Number of subjects analysed
    9
    7
    7
    9
    8
    40
    Units: percentage of participants
        number (not applicable)
    33.3
    0
    42.9
    11.1
    50.0
    27.5
    No statistical analyses for this end point

    Secondary: Phase 2: CR Rate

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    End point title
    		 Phase 2: CR Rate [8]
    End point description
    The CR rate was defined as the percentage of participants who achieve a CR, according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (see Cheson, 2014 for detailed criteria), as assessed by the Investigator in response-evaluable population. Response-Evaluable Population: participants who had measurable disease at baseline and had at least 1 adequate post-treatment disease assessment by the investigator.
    End point type
    Secondary
    End point timeframe
    Estimated median time on study in Phase 2 was 35.0 months.
    Notes
    [8] - 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: Phase 1 data are presented as a separate endpoint.
    End point values
    		 Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg Phase 2 Total: Enrolled at Lenalidomide Dose 20 or 25 mg
    Number of subjects analysed
    53
    32
    89
    Units: percentage of participants
        number (not applicable)
    32.1
    21.9
    28.0
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response (DOR)

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    End point title
    		 Phase 2: Duration of Response (DOR) [9]
    End point description
    DOR is defined as the time from the date of the first documented response (CR or PR) to the first documented evidence of disease progression (PD) according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (Cheson 2014) or death from any cause. For participants who had achieved an overall response but did not die or progress at the time of analysis, DOR was censored on the date of the last adequate post-baseline disease assessment, or on the date of the first occurrence of response (CR or PR) if there was no disease assessment afterwards. 2-sided 95% CI is estimated by Kaplan-Meier method. All-Treated Analysis Population (Phase 2): participants who received any dose of study drug(s). Participants who achieved Overall Response.
    End point type
    Secondary
    End point timeframe
    Estimated median time on study in Phase 2 was 35.0 months.
    Notes
    [9] - 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 addresses Phase 2 only.
    End point values
    		 Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg Phase 2 Total: Enrolled at Lenalidomide Dose 20 or 25 mg
    Number of subjects analysed
    28 [10]
    14
    42 [11]
    Units: months
        median (confidence interval 95%)
    38.3 (3.7 to 99999)
    28.6 (2.8 to 28.6)
    38.3 (9.5 to 99999)
    Notes
    [10] - 99999=The 95% Confidence limit cannot be estimated.
    [11] - 99999=The 95% Confidence limit cannot be estimated.
    No statistical analyses for this end point

    Secondary: Phase 2: Progression Free Survival (PFS)

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    End point title
    		 Phase 2: Progression Free Survival (PFS) [12]
    End point description
    PFS is defined as the time from the date of the first dose of study drug to confirmed PD according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (Cheson 2014) or death from any cause, whichever occurred first. For participants without disease progression or death, PFS data was censored at the date of the last tumor assessment. 2 sided 95% CI is estimated by Kaplan-Meier method. All-Treated Analysis Population (Phase 2): participants who received any dose of study drug(s).
    End point type
    Secondary
    End point timeframe
    Estimated median time on study in Phase 2 was 35.0 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 addresses Phase 2 only.
    End point values
    		 Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg Phase 2 Total: Enrolled at Lenalidomide Dose 20 or 25 mg
    Number of subjects analysed
    55
    34
    89
    Units: months
        median (confidence interval 95%)
    5.4 (3.4 to 11.3)
    4.7 (2.6 to 24.8)
    5.4 (3.4 to 6.3)
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival (OS)

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    End point title
    		 Phase 2: Overall Survival (OS) [13]
    End point description
    OS is defined as the time from the date of the first dose of study drug to the date of death due to any cause. For participants not known to have died at or prior to the database lock date, OS data was censored at the date last known alive. Participants who withdrew consent prior to study closure were censored on the date of the consent withdrawal. 2-sided 95% CI was estimated by Kaplan-Meier method. All-Treated Analysis Population (Phase 2): participants who received any dose of study drug(s).
    End point type
    Secondary
    End point timeframe
    Estimated median time on study in Phase 2 was 35.0 months.
    Notes
    [13] - 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 addresses Phase 2 only.
    End point values
    		 Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg Phase 2 Total: Enrolled at Lenalidomide Dose 20 or 25 mg
    Number of subjects analysed
    55
    34 [14]
    89
    Units: months
        median (confidence interval 95%)
    14.7 (9.7 to 32.8)
    11.6 (5.7 to 99999)
    14.2 (9.7 to 28.1)
    Notes
    [14] - 99999=The 95% Confidence limit cannot be estimated.
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Participants With TEAEs, Serious TEAEs, and Discontinuations Due to TEAEs

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    End point title
    		 Phase 2: Number of Participants With TEAEs, Serious TEAEs, and Discontinuations Due to TEAEs [15]
    End point description
    An AE is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization > 24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. AEs that started or worsened during the treatment-emergent period and all possibly related or related AEs were considered TEAEs. Related events were those that were considered possibly related or related to study drug per investigator's judgment. Events were graded per the national Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03: Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life-threatening; grade 5=death. All-Treated Analysis Population (Phase 2): participants who received any dose of study drug(s).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days after last dose of study drug. Phase 2 median duration of ibrutinib exposure=4.9 months; median duration of lenalidomide exposure=4.7 months; median total number of doses of rituximab received=5.0.
    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: Phase 1 data are presented as a separate endpoint.
    End point values
    		 Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg Phase 2 Total: Enrolled at Lenalidomide Dose 20 or 25 mg
    Number of subjects analysed
    55
    34
    89
    Units: participants
        TEAE
    55
    34
    89
        Grade >=3 TEAE
    51
    30
    81
        Study Drug-Related TEAE
    52
    33
    85
        Grade >=3 Study Drug-Related TEAE
    41
    25
    66
        Ibrutinib-Related TEAE
    50
    32
    82
        Grade >=3 Ibrutinib-Related TEAE
    36
    24
    60
        Lenalidomide-Related TEAE
    51
    32
    83
        Grade >=3 Lenalidomide-Related TEAE
    40
    25
    65
        Rituximab-Related TEAE
    37
    25
    62
        Grade >= 3 Rituximab-Related TEAE
    18
    13
    31
        TEAE Leading to Dose Reduction of Any Study Drug
    23
    14
    37
        TEAE Leading to Dose Reduction of Ibrutinib
    12
    9
    21
        TEAE Leading to Dose Reduction of Lenalidomide
    21
    14
    35
        TEAE Leading to Dose Delay of Any Study Drug
    40
    29
    69
        TEAE Leading to Dose Delay of Ibrutinib
    38
    28
    66
        TEAE Leading to Dose Delay of Lenalidomide
    37
    26
    63
        TEAE Leading to Dose Delay of Rituximab
    10
    6
    16
        TEAE Leading to Discontinuation of Any Study Drug
    11
    7
    18
        TEAE Leading to Discontinuation of Ibrutinib Dose
    11
    5
    16
        TEAE Leading to Discontinuation of Lenalid. Dose
    11
    7
    18
        TEAE Leading to Discontinuation of Rituximab Dose
    6
    4
    10
        Serious TEAE
    32
    25
    57
        Grade >=3 Serious TEAE
    29
    21
    50
        Treatment-Related Serious TEAE
    16
    12
    28
        Ibrutinib-Related Serious TEAE
    14
    12
    26
        Lenalidomide-Related Serious TEAE
    16
    10
    26
        Rituximab-Related Serious TEAE
    4
    5
    9
        Fatal TEAE
    8
    4
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after last dose of study drug. Phase 1b median duration of ibrutinib exposure was 4.4 months; median duration of lenalidomide exposure was 4.4 months; median total number of doses of rituximab received was 4.0
    Adverse event reporting additional description
    Phase 2 median duration of ibrutinib exposure was 4.9 months; median duration of lenalidomide exposure was 4.7 months; median total number of doses of rituximab received was 5.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3)
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 2: Enrolled at Lenalidomide Dose 20 mg
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Reporting group title
    Phase 2: Enrolled at Lenalidomide Dose 25 mg
    Reporting group description
    		 Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m^2 administered IV on Day 1 of each 28-day cycle for 6 cycles.

    Serious adverse events
    		 Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3) Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 12 (33.33%)
    6 / 7 (85.71%)
    7 / 9 (77.78%)
    5 / 9 (55.56%)
    6 / 8 (75.00%)
    32 / 55 (58.18%)
    25 / 34 (73.53%)
         number of deaths (all causes)
    7
    7
    5
    7
    5
    33
    22
         number of deaths resulting from adverse events
    0
    2
    2
    1
    1
    8
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    BOWEN'S DISEASE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    DIFFUSE LARGE B-CELL LYMPHOMA
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    5 / 55 (9.09%)
    3 / 34 (8.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 2
    0 / 1
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    0 / 1
    0 / 4
    0 / 3
    INTRADUCTAL PROLIFERATIVE BREAST LESION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    MYELODYSPLASTIC SYNDROME
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    OCULAR LYMPHOMA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    CATHETER SITE PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    CHILLS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    5 / 55 (9.09%)
    4 / 34 (11.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    1 / 1
    0 / 0
    2 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    PROSTATIC OBSTRUCTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    COUGH
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURISY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    DELIRIUM
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Investigations
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    FIBULA FRACTURE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    3 / 3
    3 / 4
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    1 / 1
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    EMBOLIC CEREBRAL INFARCTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMOLYTIC ANAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROSPLENIC FISTULA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    INCARCERATED INGUINAL HERNIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STENOSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS CHRONIC
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    GALLBLADDER ENLARGEMENT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    PURPURA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    HYDRONEPHROSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT OBSTRUCTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MOBILITY DECREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    SPINAL OSTEOARTHRITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Infections and infestations
    ACUTE SINUSITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    CANDIDA INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 3
    0 / 0
    0 / 3
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS ORBITAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    ESCHERICHIA SEPSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FOLLICULITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMATOMA INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION BACTERIAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    LYMPHANGITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    PARAINFLUENZAE VIRUS INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
    0 / 0
    0 / 0
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    1 / 1
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SALMONELLA BACTERAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    1 / 1
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND SEPSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FAILURE TO THRIVE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    TUMOUR LYSIS SYNDROME
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3) Phase 2: Enrolled at Lenalidomide Dose 20 mg Phase 2: Enrolled at Lenalidomide Dose 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    7 / 7 (100.00%)
    9 / 9 (100.00%)
    9 / 9 (100.00%)
    8 / 8 (100.00%)
    54 / 55 (98.18%)
    34 / 34 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    CANCER PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    LIPOMA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    TUMOUR PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    HOT FLUSH
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    HYPERTENSION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    5 / 34 (14.71%)
         occurrences all number
    0
    0
    2
    0
    3
    21
    15
    HYPOTENSION
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    3 / 34 (8.82%)
         occurrences all number
    2
    0
    2
    1
    0
    3
    3
    PERIPHERAL COLDNESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    VARICOSE VEIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    ADVERSE DRUG REACTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    ASTHENIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    1 / 55 (1.82%)
    4 / 34 (11.76%)
         occurrences all number
    1
    0
    2
    0
    2
    2
    4
    CHEST DISCOMFORT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    CHEST PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    2
    CHILLS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    1
    FACE OEDEMA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    FATIGUE
         subjects affected / exposed
    6 / 12 (50.00%)
    3 / 7 (42.86%)
    5 / 9 (55.56%)
    2 / 9 (22.22%)
    3 / 8 (37.50%)
    22 / 55 (40.00%)
    16 / 34 (47.06%)
         occurrences all number
    8
    3
    9
    3
    4
    34
    22
    GAIT DISTURBANCE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    2
    0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    INFUSION SITE EXTRAVASATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    INFUSION SITE SWELLING
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    INJECTION SITE PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    MALAISE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    3 / 55 (5.45%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    1
    0
    4
    3
    3
    NODULE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    OEDEMA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    3 / 9 (33.33%)
    3 / 9 (33.33%)
    4 / 8 (50.00%)
    21 / 55 (38.18%)
    8 / 34 (23.53%)
         occurrences all number
    2
    1
    3
    3
    5
    30
    10
    PAIN
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 7 (28.57%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    3 / 8 (37.50%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    2
    0
    3
    2
    2
    PERIPHERAL SWELLING
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    4 / 55 (7.27%)
    4 / 34 (11.76%)
         occurrences all number
    1
    0
    0
    0
    0
    5
    4
    PYREXIA
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    3 / 8 (37.50%)
    2 / 55 (3.64%)
    3 / 34 (8.82%)
         occurrences all number
    0
    2
    4
    0
    3
    2
    3
    VESSEL PUNCTURE SITE BRUISE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    HYPOGAMMAGLOBULINAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    SEASONAL ALLERGY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Social circumstances
    PHYSICAL ASSAULT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    GENITAL RASH
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    OEDEMA GENITAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    ALLERGIC SINUSITIS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    APHONIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    COUGH
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    3 / 8 (37.50%)
    18 / 55 (32.73%)
    13 / 34 (38.24%)
         occurrences all number
    3
    0
    4
    0
    5
    27
    19
    DYSPHONIA
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    0
    2
    1
    2
    3
    DYSPNOEA
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    3 / 9 (33.33%)
    3 / 8 (37.50%)
    17 / 55 (30.91%)
    7 / 34 (20.59%)
         occurrences all number
    2
    3
    2
    3
    3
    23
    9
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    5 / 55 (9.09%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    7
    0
    EPISTAXIS
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    5 / 55 (9.09%)
    3 / 34 (8.82%)
         occurrences all number
    4
    1
    0
    2
    0
    7
    4
    HICCUPS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    HYPOXIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    LUNG DISORDER
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    NASAL CONGESTION
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    4 / 55 (7.27%)
    5 / 34 (14.71%)
         occurrences all number
    2
    1
    1
    1
    1
    5
    5
    NASAL DRYNESS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    NASAL SEPTUM PERFORATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    6 / 55 (10.91%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    1
    1
    9
    2
    PARANASAL SINUS HYPERSECRETION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    4 / 55 (7.27%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    7
    0
    PNEUMONITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    PRODUCTIVE COUGH
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
    4 / 55 (7.27%)
    5 / 34 (14.71%)
         occurrences all number
    0
    1
    1
    1
    3
    6
    5
    RESPIRATORY DISORDER
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    RESPIRATORY TRACT CONGESTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    RHINITIS ALLERGIC
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    1
    RHINORRHOEA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    4 / 55 (7.27%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    3
    0
    4
    4
    4
    SINUS CONGESTION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    2
    0
    1
    0
    0
    UPPER RESPIRATORY TRACT CONGESTION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    WHEEZING
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    0
    YAWNING
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    DEPRESSION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    DISORIENTATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    INSOMNIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    5 / 55 (9.09%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    1
    0
    1
    5
    2
    IRRITABILITY
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    STRESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    1
    2
    3
    5
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    3
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    0
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    1
    BLOOD CREATINE INCREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    8
    0
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    BLOOD URINE PRESENT
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    BODY TEMPERATURE FLUCTUATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    CARDIAC MURMUR
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    4
    0
    CREATININE RENAL CLEARANCE DECREASED
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
    6 / 55 (10.91%)
    6 / 34 (17.65%)
         occurrences all number
    2
    0
    2
    1
    3
    11
    12
    LYMPHOCYTE COUNT DECREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    2
    0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    7 / 55 (12.73%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    0
    0
    7
    53
    2
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    5 / 55 (9.09%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    1
    14
    5
    STAPHYLOCOCCUS TEST POSITIVE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    1
    0
    VITAMIN D DECREASED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    WEIGHT DECREASED
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 7 (28.57%)
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
    8 / 55 (14.55%)
    4 / 34 (11.76%)
         occurrences all number
    2
    2
    2
    1
    3
    11
    8
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    0
    4
    0
    0
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    6 / 55 (10.91%)
    5 / 34 (14.71%)
         occurrences all number
    3
    0
    1
    0
    1
    7
    8
    EYE CONTUSION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    FALL
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    4 / 34 (11.76%)
         occurrences all number
    4
    0
    0
    0
    0
    3
    4
    IMPACTED FRACTURE
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    INFUSION RELATED REACTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    1
    LIMB INJURY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    MOUTH INJURY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    NAIL INJURY
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    POST PROCEDURAL HAEMATOMA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    PROCEDURAL PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    RIB FRACTURE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    SCRATCH
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    SKIN ABRASION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    SKIN LACERATION
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    3
    0
    0
    0
    1
    3
    1
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    1
    WOUND
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    1
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    1
    0
    0
    2
    2
    PALPITATIONS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    4 / 34 (11.76%)
         occurrences all number
    0
    0
    1
    0
    2
    1
    4
    SINUS BRADYCARDIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    1
    SINUS TACHYCARDIA
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    1
    TACHYCARDIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    0
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    ATAXIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    BALANCE DISORDER
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    DIZZINESS
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    3 / 9 (33.33%)
    1 / 8 (12.50%)
    11 / 55 (20.00%)
    7 / 34 (20.59%)
         occurrences all number
    5
    0
    2
    5
    2
    16
    7
    DIZZINESS POSTURAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    DYSARTHRIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    DYSGEUSIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    4 / 55 (7.27%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    HEAD DISCOMFORT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    HEADACHE
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    3 / 9 (33.33%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
    3 / 55 (5.45%)
    4 / 34 (11.76%)
         occurrences all number
    2
    0
    3
    1
    3
    4
    6
    HYPOAESTHESIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    2
    PARAESTHESIA
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    5 / 55 (9.09%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    0
    0
    1
    5
    2
    PARKINSON'S DISEASE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    6
    0
    PERIPHERAL SENSORIMOTOR NEUROPATHY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    1
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    11 / 55 (20.00%)
    7 / 34 (20.59%)
         occurrences all number
    1
    1
    0
    1
    1
    20
    14
    PRESYNCOPE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    RESTLESS LEGS SYNDROME
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    SCIATICA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    2
    0
    SPEECH DISORDER
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    SYNCOPE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    2
    TREMOR
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    4 / 55 (7.27%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    4
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 7 (0.00%)
    3 / 9 (33.33%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
    17 / 55 (30.91%)
    11 / 34 (32.35%)
         occurrences all number
    6
    0
    6
    22
    6
    88
    16
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    INCREASED TENDENCY TO BRUISE
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    8 / 55 (14.55%)
    5 / 34 (14.71%)
         occurrences all number
    3
    1
    3
    0
    2
    13
    6
    LEUKOCYTOSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    LEUKOPENIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    3 / 55 (5.45%)
    3 / 34 (8.82%)
         occurrences all number
    7
    0
    0
    4
    2
    35
    6
    LYMPHADENOPATHY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    LYMPHOCYTOSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    LYMPHOPENIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    0
    0
    NEUTROPENIA
         subjects affected / exposed
    5 / 12 (41.67%)
    0 / 7 (0.00%)
    6 / 9 (66.67%)
    3 / 9 (33.33%)
    5 / 8 (62.50%)
    25 / 55 (45.45%)
    14 / 34 (41.18%)
         occurrences all number
    13
    0
    46
    22
    41
    126
    68
    PANCYTOPENIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    SPONTANEOUS HAEMATOMA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    1
    THROMBOCYTOPENIA
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 7 (28.57%)
    4 / 9 (44.44%)
    4 / 9 (44.44%)
    3 / 8 (37.50%)
    11 / 55 (20.00%)
    10 / 34 (29.41%)
         occurrences all number
    8
    5
    9
    21
    10
    61
    36
    Ear and labyrinth disorders
    DEAFNESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    EAR PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    3
    HYPOACUSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    VERTIGO
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    Eye disorders
    CATARACT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    3
    0
    CHALAZION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    DRY AGE-RELATED MACULAR DEGENERATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    DRY EYE
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    6 / 55 (10.91%)
    6 / 34 (17.65%)
         occurrences all number
    1
    0
    0
    1
    0
    7
    8
    EXOPHTHALMOS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    EYE OEDEMA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    EYE PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    0
    EYE PRURITUS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    LACRIMATION INCREASED
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    4 / 55 (7.27%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    0
    0
    0
    4
    2
    METAMORPHOPSIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    OCULAR HYPERAEMIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    OPTIC NERVE COMPRESSION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    PERIORBITAL SWELLING
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    PHOTOPHOBIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    TRICHIASIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    VISION BLURRED
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    1
    1
    1
    2
    3
    VISUAL ACUITY REDUCED
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    VISUAL IMPAIRMENT
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    1
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    ABDOMINAL DISTENSION
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    1
    1
    1
    2
    0
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
    9 / 55 (16.36%)
    7 / 34 (20.59%)
         occurrences all number
    2
    2
    0
    3
    2
    11
    10
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    0
    1
    0
    4
    2
    CONSTIPATION
         subjects affected / exposed
    5 / 12 (41.67%)
    2 / 7 (28.57%)
    4 / 9 (44.44%)
    4 / 9 (44.44%)
    3 / 8 (37.50%)
    11 / 55 (20.00%)
    10 / 34 (29.41%)
         occurrences all number
    5
    2
    4
    4
    5
    17
    13
    DEFAECATION URGENCY
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    DIARRHOEA
         subjects affected / exposed
    9 / 12 (75.00%)
    3 / 7 (42.86%)
    3 / 9 (33.33%)
    4 / 9 (44.44%)
    7 / 8 (87.50%)
    32 / 55 (58.18%)
    13 / 34 (38.24%)
         occurrences all number
    22
    4
    3
    8
    16
    83
    29
    DRY MOUTH
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    2 / 8 (25.00%)
    8 / 55 (14.55%)
    8 / 34 (23.53%)
         occurrences all number
    0
    0
    0
    1
    2
    9
    8
    DYSPEPSIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    7 / 55 (12.73%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    1
    0
    2
    7
    3
    EPIGASTRIC DISCOMFORT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    FAECES DISCOLOURED
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    FLATULENCE
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    GASTRITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    5 / 55 (9.09%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    0
    1
    9
    1
    GINGIVAL BLEEDING
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    GINGIVAL PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    GINGIVAL SWELLING
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    GLOSSODYNIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    HAEMATEMESIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    HAEMORRHOIDAL HAEMORRHAGE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    HAEMORRHOIDS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    0
    HYPERCHLORHYDRIA
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    MELAENA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    MOUTH ULCERATION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    1
    NAUSEA
         subjects affected / exposed
    7 / 12 (58.33%)
    3 / 7 (42.86%)
    3 / 9 (33.33%)
    3 / 9 (33.33%)
    4 / 8 (50.00%)
    17 / 55 (30.91%)
    9 / 34 (26.47%)
         occurrences all number
    10
    4
    4
    5
    8
    20
    15
    ORAL DISORDER
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    ORAL PAIN
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    3 / 8 (37.50%)
    4 / 55 (7.27%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    0
    0
    3
    4
    2
    PARAESTHESIA ORAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    SALIVARY GLAND CALCULUS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    STOMATITIS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    7 / 55 (12.73%)
    5 / 34 (14.71%)
         occurrences all number
    1
    0
    0
    2
    1
    7
    17
    TONGUE ULCERATION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    TOOTH LOSS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    TOOTHACHE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    VOMITING
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
    12 / 55 (21.82%)
    5 / 34 (14.71%)
         occurrences all number
    3
    1
    1
    6
    3
    19
    8
    Hepatobiliary disorders
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    HEPATIC CYST
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    3
    0
    HEPATOMEGALY
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    ACTINIC KERATOSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    BLISTER
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    BLOOD BLISTER
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    0
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    DERMATITIS CONTACT
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    DRY SKIN
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    13 / 55 (23.64%)
    7 / 34 (20.59%)
         occurrences all number
    0
    1
    0
    1
    1
    15
    7
    ECCHYMOSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    3
    ECZEMA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    4
    ERYTHEMA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    6 / 55 (10.91%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    0
    0
    9
    2
    HYPERHIDROSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    0
    0
    1
    1
    INGROWING NAIL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    MACULE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    NIGHT SWEATS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    4 / 55 (7.27%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    2
    1
    0
    9
    3
    ONYCHOCLASIS
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    PETECHIAE
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    4 / 9 (44.44%)
    2 / 8 (25.00%)
    5 / 55 (9.09%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    0
    5
    3
    10
    3
    PRURITUS
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    3 / 9 (33.33%)
    0 / 8 (0.00%)
    7 / 55 (12.73%)
    6 / 34 (17.65%)
         occurrences all number
    2
    0
    1
    3
    0
    11
    8
    PURPURA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    RASH
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    5 / 55 (9.09%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    0
    0
    5
    1
    RASH ERYTHEMATOUS
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    4 / 55 (7.27%)
    7 / 34 (20.59%)
         occurrences all number
    2
    0
    0
    0
    2
    4
    7
    RASH MACULAR
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    7 / 55 (12.73%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    1
    0
    0
    11
    3
    RASH MACULO-PAPULAR
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    5 / 9 (55.56%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
    15 / 55 (27.27%)
    12 / 34 (35.29%)
         occurrences all number
    5
    2
    11
    5
    3
    40
    35
    RASH PRURITIC
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    SCAB
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    SKIN DISCOLOURATION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    SKIN EXFOLIATION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    SKIN FISSURES
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    2
    SKIN HYPERPIGMENTATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    SKIN IRRITATION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    SKIN LESION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    3 / 34 (8.82%)
         occurrences all number
    1
    0
    1
    1
    0
    2
    4
    STASIS DERMATITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Renal and urinary disorders
    BLADDER TRABECULATION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    DYSURIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    1
    HAEMATURIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    RENAL IMPAIRMENT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    1
    2
    11
    1
    URETHRAL STENOSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    URINARY INCONTINENCE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    URINARY RETENTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    2 / 8 (25.00%)
    9 / 55 (16.36%)
    5 / 34 (14.71%)
         occurrences all number
    4
    0
    4
    4
    2
    12
    7
    BACK PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    3 / 9 (33.33%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    10 / 55 (18.18%)
    4 / 34 (11.76%)
         occurrences all number
    0
    1
    4
    0
    4
    12
    4
    BONE PAIN
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    0
    0
    2
    3
    2
    FLANK PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    1
    GROIN PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    JOINT SWELLING
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    5 / 55 (9.09%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    MUSCLE ATROPHY
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    MUSCLE SPASMS
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    3 / 8 (37.50%)
    12 / 55 (21.82%)
    7 / 34 (20.59%)
         occurrences all number
    2
    2
    3
    0
    3
    18
    10
    MUSCLE TIGHTNESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    6 / 34 (17.65%)
         occurrences all number
    0
    1
    0
    1
    1
    2
    6
    MUSCULOSKELETAL DISCOMFORT
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    MUSCULOSKELETAL STIFFNESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    4 / 55 (7.27%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    0
    MYALGIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    4 / 55 (7.27%)
    6 / 34 (17.65%)
         occurrences all number
    0
    0
    2
    0
    4
    8
    8
    NECK PAIN
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    1
    OSTEOARTHRITIS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    5 / 55 (9.09%)
    5 / 34 (14.71%)
         occurrences all number
    2
    1
    5
    1
    1
    5
    8
    PAIN IN JAW
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    RHABDOMYOLYSIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    ARTHRITIS BACTERIAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    BLISTER INFECTED
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    BRONCHITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    1
    CHRONIC SINUSITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    CLOSTRIDIUM COLITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    CONJUNCTIVITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    4 / 55 (7.27%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    2
    1
    4
    1
    CONJUNCTIVITIS BACTERIAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    CORONAVIRUS INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    CYSTITIS KLEBSIELLA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    ESCHERICHIA URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    EYE INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    FOLLICULITIS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    3
    FUNGAL SKIN INFECTION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    FURUNCLE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    1
    0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    IMPETIGO
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    INFLUENZA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    NAIL INFECTION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    7 / 55 (12.73%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    0
    0
    10
    1
    ONYCHOMYCOSIS
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    ORAL CANDIDIASIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    5
    OTITIS EXTERNA
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    OTITIS MEDIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    1
    PHARYNGITIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    PNEUMONIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    0
    0
    2
    3
    2
    PSEUDOMONAS INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    PUSTULE
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    RASH PUSTULAR
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    1
    7
    5
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    RHINOVIRUS INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    3
    SINUSITIS
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    4 / 55 (7.27%)
    4 / 34 (11.76%)
         occurrences all number
    2
    2
    2
    0
    2
    5
    6
    SINUSITIS BACTERIAL
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    TINEA PEDIS
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    12 / 55 (21.82%)
    4 / 34 (11.76%)
         occurrences all number
    3
    0
    2
    0
    9
    22
    6
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    3 / 8 (37.50%)
    7 / 55 (12.73%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    0
    1
    3
    8
    4
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    1
    WOUND ABSCESS
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    WOUND INFECTION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    3 / 55 (5.45%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    WOUND INFECTION STAPHYLOCOCCAL
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 7 (14.29%)
    4 / 9 (44.44%)
    2 / 9 (22.22%)
    2 / 8 (25.00%)
    8 / 55 (14.55%)
    5 / 34 (14.71%)
         occurrences all number
    2
    1
    7
    5
    3
    11
    7
    DEHYDRATION
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    0
    3
    1
    0
    ENZYME ABNORMALITY
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    HYPERCALCAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    2 / 55 (3.64%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    6
    0
    5
    2
    5
    HYPERKALAEMIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    7
    0
    0
    0
    1
    1
    1
    HYPERURICAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    3 / 55 (5.45%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    6
    3
    1
    HYPOALBUMINAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    1
    HYPOCALCAEMIA
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    5 / 55 (9.09%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    0
    1
    0
    5
    2
    HYPOKALAEMIA
         subjects affected / exposed
    4 / 12 (33.33%)
    1 / 7 (14.29%)
    3 / 9 (33.33%)
    3 / 9 (33.33%)
    3 / 8 (37.50%)
    16 / 55 (29.09%)
    4 / 34 (11.76%)
         occurrences all number
    8
    1
    7
    3
    6
    22
    7
    HYPOMAGNESAEMIA
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    11 / 55 (20.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    4
    2
    6
    19
    2
    HYPONATRAEMIA
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    2 / 8 (25.00%)
    1 / 55 (1.82%)
    1 / 34 (2.94%)
         occurrences all number
    4
    0
    1
    1
    5
    1
    2
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    2 / 55 (3.64%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    3
    MALNUTRITION
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 55 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jan 2014
    - Updating of safety language for Other Malignancies safety observation. - Study Objectives were updated to provide clarification to the Phase 1 and 2 Primary Objectives, the Phase 2 Secondary Objectives, and the Exploratory Objectives. - Relapsed and refractory disease definitions were clarified. - Ibrutinib and lenalidomide administration was updated to remove dosing restrictions. - Phase 1b Dosing Levels was updated to include cohort information. - Collection of subsequent anti-cancer therapy was updated from all subsequent anticancer therapies to only the first anti-cancer therapy after discontinuation of treatment. - Subject Completion and Withdrawal section was updated to include DLT as a reason for treatment discontinuation.
    03 Feb 2015
    - Include the dose re-escalation strategy and rationale to a higher dose level after Dose Level -1 and a dose escalation to 25 mg of lenalidomide since DLBCL is a more aggressive lymphoma (than follicular lymphoma) and may require higher doses. - Clarify the DLT definition in regard to the adverse event of rash and to allow transfusional support during the DLT observation period. - Update the Study Design to allow over-enrollment while keeping the same DLT and cohort expansion criteria in the Phase 1b cohort and update the expected subjects number. - Update the Inclusion and Exclusion Criteria. - Add rash management guidelines. - Add the analysis of serum immunoglobulins as an exploratory objective. - Provide clarity to the lenalidomide prescribing information for US and Ex-US sites per Celgene Corporation’s REMS and PPP requirements. - Provide updated reporting requirements on “Other Malignancies” and “Pregnancy”. - Update the response criteria for Phase 2 subjects only to reflect the revised criteria being used in the scientific community, updated response criteria were published in 2014 (Cheson et al, 2014).
    13 Jul 2015
    - Clarify the DLT definition in regard to TLS, neutropenia, and deep venous thrombosis. - Allow subjects with a DLT to continue study treatment if the treating physician and sponsor expect clinical benefit for the subject. - Modify overdose instructions to align with Pharmacyclics updated safety language. - Update ibrutinib dose reduction guideline for concomitant use of strong or moderate CYP3A inhibitors.
    10 Nov 2015
    - As the use of rituximab in the DLBCL salvage setting is considered standard and to maximize potential efficacy in a patient population with relapsed/refractory and aggressive DLBCL, the Phase 2 study design was amended to remove the randomization and the arm with the 2-drug combination of ibrutinib and lenalidomide without rituximab. - Based on efficacy and safety considerations outlined in the protocol, the dose of 20 mg lenalidomide was proposed as the recommended Phase 2 dose, if determined to be safe and tolerated in Phase 1b. Additional subjects may receive 25 mg lenalidomide as outlined. - Updates per the revised Ibrutinib Investigator’s Brochure version 9.0 have been implemented.
    01 Jun 2016
    - Included preliminary safety data from the Phase 1b into the protocol to support initiation of the Phase 2 portion of the trial. - Amended that the primary analysis for all efficacy endpoints will be conducted based on the response-evaluable population with de novo non-GCB subtype DLBCL, and not the All-treated population. - Revised based on the updated Imbruvica® label and statistical analysis plan. - Updated to include that a Celgene designee may provide counseling to subjects per Celgene’s guidance. - Added Currently active, clinically significant hepatic impairment Child-Pugh class B or C according to the Child-Pugh classification as an exclusion criterion. - Update the use of concomitant medications including that use of QT prolonging agents is no longer restricted. - Updated to specify the number of subjects that will be included for PK collection in the 20 mg and 25 mg lenalidomide cohorts in Phase 2.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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