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    Clinical Trial Results:
    An Open-label Extension Study in Patients 65 Years or Older With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Who Participated in Study PCYC-1115-CA (Ibrutinib Versus Chlorambucil)

    Summary
    EudraCT number
    		 2012-003968-44
    Trial protocol
    		 BE   GB   IE   CZ   ES   IT  
    Global end of trial date
    18 Aug 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Oct 2024
    First version publication date
    03 Aug 2024
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Clarifying text in reporting group descriptions and milestone information in participant flow.

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1116-CA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01724346
    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
    18 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To monitor progression free survival (PFS) - To continue treatment and safety assessment of patients randomized to Arm B (ibrutinib) in Study PCYC-1115-CA (the parent study) who have not progressed at the time of parent study closure - To follow patients for long-term outcome - To capture overall response rate (ORR), duration of response (DOR), PFS, and overall survival (OS), and time to next therapy - To fulfill long-term follow-up requirements of randomized patients after closure of the parent study, including OS.
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 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
    New Zealand: 13
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    United States: 61
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Türkiye: 10
    Country: Number of subjects enrolled
    Ukraine: 13
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    China: 11
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Russian Federation: 1
    Worldwide total number of subjects
    269
    EEA total number of subjects
    86
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    258
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 This extension study provided ongoing treatment and follow-up for participants previously enrolled in the parent study (PCYC-1115-CA; Study 1115; NCT01722487). Participants entered this study upon Independent Review Committee (IRC)-confirmed progressive disease (PD) or the closure of Study 1115, whichever was earlier.

    Pre-assignment
    Screening details
    		 All participants randomized to chlorambucil in Study 1115 completed or discontinued their first-line treatment prior to rollover. Participants randomized to ibrutinib in Study 1115 with no PD could continue their firstline treatment in this study. Next-line treatment with ibrutinib after PD was a subsequent-therapy option for the chlorambucil arm.

    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
    		 Ibrutinib
    Arm description
    		 Participants who received ibrutinib 420 mg daily in Study 1115 received ibrutinib orally once daily. Participants continuing in first-line ibrutinib therapy entered Study 1116 at the ibrutinib dose tolerated in Study 1115.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    PCI-32765
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib is administered orally once daily

    Arm title
    		 Chlorambucil
    Arm description
    		 Participants who received chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) Days 1 and 15 of 28-day cycle up to 12 cycles in Study 1115. In Study 1116, participants had the option to receive next-line ibrutinib 420 mg/day after PD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    PCI-32765
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib is administered orally once daily

    Number of subjects in period 1
    		Ibrutinib Chlorambucil
    Started
    136
    133
    Received Next- Line Ibrutinib After PD
    0 [1]
    78
    Completed
    57
    63
    Not completed
    79
    70
         Consent withdrawn by subject
    27
    19
         Death
    42
    42
         Eligible but didn't rollover after completing 1115
    5
    8
         Lost to follow-up
    5
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Next-line treatment with ibrutinib after PD was a subsequent-therapy option for participants enrolled in the chlorambucil arm only.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    		 Participants who received ibrutinib 420 mg daily in Study 1115 received ibrutinib orally once daily. Participants continuing in first-line ibrutinib therapy entered Study 1116 at the ibrutinib dose tolerated in Study 1115.

    Reporting group title
    Chlorambucil
    Reporting group description
    		 Participants who received chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) Days 1 and 15 of 28-day cycle up to 12 cycles in Study 1115. In Study 1116, participants had the option to receive next-line ibrutinib 420 mg/day after PD.

    Reporting group values
    		 Ibrutinib Chlorambucil Total
    Number of subjects
    		 136 133 269
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.1 ( 5.67 ) 73.4 ( 5.95 ) -
    Gender categorical
    Units: Subjects
        Female
    		 48 52 100
        Male
    		 88 81 169
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 2 5
        Not Hispanic or Latino
    		 132 129 261
        Unknown or Not Reported
    		 1 2 3
    Race
    Units: Subjects
        White
    		 120 125 245
        Asian
    		 9 4 13
        Black or African American
    		 5 3 8
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Subject declined to answer/ unknown
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    		 Participants who received ibrutinib 420 mg daily in Study 1115 received ibrutinib orally once daily. Participants continuing in first-line ibrutinib therapy entered Study 1116 at the ibrutinib dose tolerated in Study 1115.

    Reporting group title
    Chlorambucil
    Reporting group description
    		 Participants who received chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) Days 1 and 15 of 28-day cycle up to 12 cycles in Study 1115. In Study 1116, participants had the option to receive next-line ibrutinib 420 mg/day after PD.

    Primary: Progression Free Survival (PFS) Based on Investigator Assessment

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    End point title
    		 Progression Free Survival (PFS) Based on Investigator Assessment
    End point description
    PFS is defined as the time from the date of randomization to the date of disease progression determined by the investigator or date of death from any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to disease progression (PD) or death. Estimated by Kaplan-Meier method. Intent-to-Treat (ITT) Population: All randomized participants in Study 1115.
    End point type
    Primary
    End point timeframe
    Median overall follow-up of 82.7 months
    End point values
    		 Ibrutinib Chlorambucil
    Number of subjects analysed
    136 [1]
    133
    Units: months
        median (confidence interval 95%)
    106.9 (83.4 to 99999)
    15.0 (10.2 to 19.4)
    Notes
    [1] - 99999=Not estimable because there were not enough PFS events to get a reliable upper bound of 95% CI
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.155
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 0.22
    Notes
    [2] - P-value is from stratified log-rank test.

    Secondary: Progression Free Survival After Initiation of Subsequent Anticancer Therapy (PFS2)

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    End point title
    		 Progression Free Survival After Initiation of Subsequent Anticancer Therapy (PFS2)
    End point description
    PFS2 is defined as the time from the date of randomization to the earliest occurrence of the following three types of events: • PD per investigator response assessment after initiation of the first subsequent anti-cancer therapy • Initiation of second subsequent anti-cancer therapy • Death due to any cause, regardless of administration of subsequent anticancer therapy. Kaplan-Meier landmark estimate of the PFS2 rate at 60 months (that is, the estimated percentage of participants with PFS2 at Month 60) is presented. ITT Population: All randomized participants in Study 1115.
    End point type
    Secondary
    End point timeframe
    Median overall follow-up of 82.7 months
    End point values
    		 Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: percentage of participants
        number (confidence interval 95%)
    79.3 (71.1 to 85.4)
    58.4 (48.8 to 66.7)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from randomization to death due to any cause. Kaplan-Meier landmark estimate of the OS rate at 60 months (that is, the estimated percentage of participants with OS at Month 60) is presented. ITT Population: All randomized participants in Study 1115.
    End point type
    Secondary
    End point timeframe
    Median overall follow-up of 82.7 months
    End point values
    		 Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: percentage of participants
        number (confidence interval 95%)
    82.8 (75.0 to 88.3)
    68.4 (59.1 to 75.9)
    No statistical analyses for this end point

    Secondary: Time to Next Treatment (TTNT)

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    End point title
    		 Time to Next Treatment (TTNT)
    End point description
    Time from randomization to initiation of any subsequent treatment for chronic lymphocytic leukemia (CLL).
    End point type
    Secondary
    End point timeframe
    Median overall follow-up of 82.7 months
    End point values
    		 Ibrutinib Chlorambucil
    Number of subjects analysed
    136 [3]
    133
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    25.1 (21.8 to 27.9)
    Notes
    [3] - 99999=Not estimable because there were not enough TTNT events.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.087
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.054
         upper limit
    		 0.141
    Notes
    [4] - P value is from stratified log-rank test.

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR is defined as the percentage of participants who achieve complete response (CR), complete response with an incomplete marrow recovery (CRi), nodular partial response (nPR), or partial response (PR), as determined by the investigator at or prior to initiation of subsequent antineoplastic therapy according to the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy. ITT Population: All randomized participants in Study 1115.
    End point type
    Secondary
    End point timeframe
    Median overall follow-up of 82.7 months
    End point values
    		 Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: percentage of participants
        number (not applicable)
    91.2
    36.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ibrutinib v Chlorambucil
    Number of subjects included in analysis
    269
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Rate Ratio
    Point estimate
    2.496
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.99
         upper limit
    		 3.131
    Notes
    [5] - Rate ratio and p-value are based on Cochran-Mantel-Haenszel chi-square test stratified by Eastern Cooperative Oncology Group (ECOG; 0-1 vs 2) and Rai stage (0/I/II vs III/IV) at baseline.

    Secondary: Rate of Minimal Residual Disease (MRD) Negativity

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    End point title
    		 Rate of Minimal Residual Disease (MRD) Negativity
    End point description
    Percentage of participants who achieved MRD-negative response defined as < 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate and/or peripheral blood sample per central laboratory at or prior to initiation of subsequent antineoplastic therapy. ITT Population: All randomized participants in Study 1115.
    End point type
    Secondary
    End point timeframe
    Median overall follow-up of 82.7 months
    End point values
    		 Ibrutinib Chlorambucil
    Number of subjects analysed
    136
    133
    Units: percentage of participants
        number (not applicable)
    5.1
    0
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR will be calculated for the participants achieving a protocol-defined response (Halleck 2008; CR, CRi, nPR, PR) per investigator assessment and is defined as time from the date of initial response including PR with lymphocytosis to the date of disease progression or the date of death from any cause, whichever occurs first. ITT Participants Achieving Response (Partial Response or Better) per protocol definitions (Halleck 2008).
    End point type
    Secondary
    End point timeframe
    Median overall follow-up of 82.7 months
    End point values
    		 Ibrutinib Chlorambucil
    Number of subjects analysed
    124 [6]
    49
    Units: months
        median (confidence interval 95%)
    99999 (84.0 to 99999)
    29.7 (15.2 to 40.4)
    Notes
    [6] - 99999=Not estimable because there were not enough DOR events.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 1st dose of any study treatment to 30 days after last dose of study treatment or initiation of subsequent therapy, whichever was earlier. Median treatment duration: Ibrutinib=74.0 months; Chlorambucil=7.1 months; Next-line Ibrutinib=26.9 months.
    Adverse event reporting additional description
    Safety Population: participants in the ITT population who received >= 1 dose of either chlorambucil or ibrutinib as the first-line therapy in the parent Study 1115. The crossover analysis set used for next-line ibrutinib treatment included all chlorambucil arm participants who received at least 1 dose of ibrutinib as the next-line study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Ibrutinib
    Reporting group description
    		 Participants who received ibrutinib 420 mg daily in Study 1115 received ibrutinib orally once daily. Participants continuing in first-line ibrutinib therapy entered Study 1116 at the ibrutinib dose tolerated in Study 1115.

    Reporting group title
    Chlorambucil Participants Crossed Over to Ibrutinib
    Reporting group description
    		 Participants who received chlorambucil treatment in Study 1115 and crossed over to next-line ibrutinib 420 mg/day in Study 1116.

    Reporting group title
    Chlorambucil
    Reporting group description
    		 Participants who received chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) Days 1 and 15 of 28-day cycle up to 12 cycles in Study 1115.

    Serious adverse events
    		 Ibrutinib Chlorambucil Participants Crossed Over to Ibrutinib Chlorambucil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    111 / 135 (82.22%)
    49 / 78 (62.82%)
    33 / 132 (25.00%)
         number of deaths (all causes)
    42
    24
    44
         number of deaths resulting from adverse events
    25
    9
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    9 / 135 (6.67%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BASOSQUAMOUS CARCINOMA OF SKIN
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLADDER CANCER
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLADDER TRANSITIONAL CELL CARCINOMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BOWEN'S DISEASE
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRAIN NEOPLASM
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHRONIC LYMPHOCYTIC LEUKAEMIA
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    COLORECTAL ADENOMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG NEOPLASM
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG CANCER METASTATIC
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    MUCINOUS ADENOCARCINOMA OF APPENDIX
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NON-SMALL CELL LUNG CANCER
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NON-SMALL CELL LUNG CANCER METASTATIC
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    4 / 135 (2.96%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RECTAL ADENOCARCINOMA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RICHTER'S SYNDROME
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINDLE CELL SARCOMA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    2 / 135 (1.48%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    AORTIC ANEURYSM
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AORTIC STENOSIS
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    4 / 135 (2.96%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ARTERY ANEURYSM
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ISCHAEMIA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    4 / 135 (2.96%)
    1 / 78 (1.28%)
    5 / 132 (3.79%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PHYSICAL DECONDITIONING
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    Immune system disorders
    HYPOGAMMAGLOBULINAEMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IMMUNODEFICIENCY
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERINEAL FISTULA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ASTHMA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHIECTASIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COUGH
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERCAPNIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG INFILTRATION
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    5 / 135 (3.70%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMOMEDIASTINUM
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY FIBROSIS
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    PULMONARY CONGESTION
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY ARTERIAL HYPERTENSION
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WHEEZING
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    CARDIOVASCULAR SOMATIC SYMPTOM DISORDER
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DELIRIUM
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PSYCHOTIC DISORDER
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    FIBRIN D DIMER INCREASED
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEART RATE IRREGULAR
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    3 / 135 (2.22%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANIMAL BITE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FRACTURED SACRUM
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEAT STROKE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPHAEMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LIMB TRAUMATIC AMPUTATION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOWER LIMB FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCLE STRAIN
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OVERDOSE
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND COMPLICATION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SHOULDER FRACTURE
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SKIN LACERATION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBCUTANEOUS HAEMATOMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TRAUMATIC HAEMATOMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ULNA FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    WRIST FRACTURE
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY RETENTION POSTOPERATIVE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    THYROGLOSSAL CYST
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AORTIC VALVE DISEASE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AORTIC VALVE DISEASE MIXED
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARRHYTHMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    11 / 135 (8.15%)
    6 / 78 (7.69%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    9 / 11
    6 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    3 / 135 (2.22%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC DYSFUNCTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    5 / 135 (3.70%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIOPULMONARY FAILURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    CARDIAC TAMPONADE
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LEFT VENTRICULAR FAILURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MITRAL VALVE INCOMPETENCE
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PALPITATIONS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SINUS NODE DYSFUNCTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CAUDA EQUINA SYNDROME
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBELLAR INFARCTION
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COGNITIVE DISORDER
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    3 / 135 (2.22%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    CEREBRAL INFARCTION
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    DEMENTIA
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEMENTIA ALZHEIMER'S TYPE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSARTHRIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    METABOLIC ENCEPHALOPATHY
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST HERPETIC NEURALGIA
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEMIANOPIA HOMONYMOUS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PRESYNCOPE
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    5 / 135 (3.70%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    5 / 135 (3.70%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    HAEMOLYTIC ANAEMIA
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    4 / 135 (2.96%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    AUTOIMMUNE HAEMOLYTIC ANAEMIA
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    3 / 135 (2.22%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LYMPHADENOPATHY
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    EYE OEDEMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CATARACT
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLINDNESS UNILATERAL
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GLAUCOMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VITREOUS HAEMORRHAGE
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RETINAL VEIN OCCLUSION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RETINAL DETACHMENT
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RETINAL VASCULAR OCCLUSION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 135 (0.74%)
    3 / 78 (3.85%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL WALL HAEMATOMA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIVERTICULUM
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    3 / 135 (2.22%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HIATUS HERNIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ILEUS PARALYTIC
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MELAENA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL STENOSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OVERFLOW DIARRHOEA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 135 (0.74%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STONE
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLANGITIS
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    JAUNDICE CHOLESTATIC
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATITIS TOXIC
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    PSORIASIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYTHEMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ECZEMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DERMATITIS ALLERGIC
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DERMAL CYST
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RASH MACULAR
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SKIN ULCER
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBCUTANEOUS EMPHYSEMA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    4 / 135 (2.96%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLADDER CYST
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLADDER TAMPONADE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CALCULUS BLADDER
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CYSTITIS HAEMORRHAGIC
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    4 / 135 (2.96%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYDRONEPHROSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL HAEMORRHAGE
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URETEROLITHIASIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARTHRITIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATOMA MUSCLE
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUMBAR SPINAL STENOSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NECK PAIN
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL PAIN
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RHABDOMYOLYSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    ARTHRITIS BACTERIAL
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANAL ABSCESS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ACUTE HEPATITIS B
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    ABSCESS LIMB
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACTERIAL SEPSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BILIARY SEPSIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CANDIDA SEPSIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    3 / 135 (2.22%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CAMPYLOBACTER GASTROENTERITIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 PNEUMONIA
         subjects affected / exposed
    4 / 135 (2.96%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    CHOLANGITIS INFECTIVE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CORONAVIRUS INFECTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EAR INFECTION
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHRONIC SINUSITIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENDOCARDITIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ESCHERICHIA BACTERAEMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ESCHERICHIA INFECTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ESCHERICHIA SEPSIS
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFECTED SKIN ULCER
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    KLEBSIELLA INFECTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION VIRAL
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    4 / 135 (2.96%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORCHITIS
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORAL HERPES
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMOCOCCAL SEPSIS
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    27 / 135 (20.00%)
    7 / 78 (8.97%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    8 / 38
    2 / 14
    1 / 2
         deaths causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA FUNGAL
         subjects affected / exposed
    0 / 135 (0.00%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA LEGIONELLA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA PSEUDOMONAL
         subjects affected / exposed
    1 / 135 (0.74%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA STREPTOCOCCAL
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL PNEUMONIA
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PSEUDOMONAL BACTERAEMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PSEUDOMONAL SEPSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    5 / 135 (3.70%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY SEPSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    2 / 135 (1.48%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    6 / 135 (4.44%)
    5 / 78 (6.41%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 11
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    2 / 135 (1.48%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    3 / 135 (2.22%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DIABETES MELLITUS INADEQUATE CONTROL
         subjects affected / exposed
    0 / 135 (0.00%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FAILURE TO THRIVE
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    5 / 135 (3.70%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOVOLAEMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    1 / 135 (0.74%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ibrutinib Chlorambucil Participants Crossed Over to Ibrutinib Chlorambucil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    134 / 135 (99.26%)
    75 / 78 (96.15%)
    120 / 132 (90.91%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    14 / 135 (10.37%)
    5 / 78 (6.41%)
    2 / 132 (1.52%)
         occurrences all number
    22
    6
    3
    SEBORRHOEIC KERATOSIS
         subjects affected / exposed
    7 / 135 (5.19%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences all number
    8
    1
    0
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    8 / 135 (5.93%)
    1 / 78 (1.28%)
    2 / 132 (1.52%)
         occurrences all number
    10
    1
    2
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    37 / 135 (27.41%)
    10 / 78 (12.82%)
    0 / 132 (0.00%)
         occurrences all number
    64
    26
    0
    HYPOTENSION
         subjects affected / exposed
    6 / 135 (4.44%)
    4 / 78 (5.13%)
    6 / 132 (4.55%)
         occurrences all number
    6
    8
    8
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    39 / 135 (28.89%)
    15 / 78 (19.23%)
    11 / 132 (8.33%)
         occurrences all number
    71
    21
    11
    FATIGUE
         subjects affected / exposed
    55 / 135 (40.74%)
    18 / 78 (23.08%)
    51 / 132 (38.64%)
         occurrences all number
    110
    35
    85
    CHEST PAIN
         subjects affected / exposed
    10 / 135 (7.41%)
    4 / 78 (5.13%)
    0 / 132 (0.00%)
         occurrences all number
    11
    6
    0
    ASTHENIA
         subjects affected / exposed
    17 / 135 (12.59%)
    9 / 78 (11.54%)
    5 / 132 (3.79%)
         occurrences all number
    20
    12
    7
    PYREXIA
         subjects affected / exposed
    36 / 135 (26.67%)
    9 / 78 (11.54%)
    14 / 132 (10.61%)
         occurrences all number
    59
    20
    23
    PERIPHERAL SWELLING
         subjects affected / exposed
    7 / 135 (5.19%)
    4 / 78 (5.13%)
    2 / 132 (1.52%)
         occurrences all number
    10
    5
    2
    PAIN
         subjects affected / exposed
    7 / 135 (5.19%)
    3 / 78 (3.85%)
    0 / 132 (0.00%)
         occurrences all number
    7
    4
    0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    8 / 135 (5.93%)
    4 / 78 (5.13%)
    6 / 132 (4.55%)
         occurrences all number
    8
    4
    7
    DYSPNOEA
         subjects affected / exposed
    21 / 135 (15.56%)
    11 / 78 (14.10%)
    13 / 132 (9.85%)
         occurrences all number
    37
    20
    16
    COUGH
         subjects affected / exposed
    52 / 135 (38.52%)
    19 / 78 (24.36%)
    20 / 132 (15.15%)
         occurrences all number
    79
    25
    24
    EPISTAXIS
         subjects affected / exposed
    21 / 135 (15.56%)
    7 / 78 (8.97%)
    5 / 132 (3.79%)
         occurrences all number
    26
    8
    8
    NASAL CONGESTION
         subjects affected / exposed
    8 / 135 (5.93%)
    3 / 78 (3.85%)
    2 / 132 (1.52%)
         occurrences all number
    9
    3
    2
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    16 / 135 (11.85%)
    3 / 78 (3.85%)
    5 / 132 (3.79%)
         occurrences all number
    23
    3
    5
    PLEURAL EFFUSION
         subjects affected / exposed
    11 / 135 (8.15%)
    4 / 78 (5.13%)
    1 / 132 (0.76%)
         occurrences all number
    17
    5
    1
    PRODUCTIVE COUGH
         subjects affected / exposed
    8 / 135 (5.93%)
    3 / 78 (3.85%)
    2 / 132 (1.52%)
         occurrences all number
    8
    3
    2
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    16 / 135 (11.85%)
    4 / 78 (5.13%)
    2 / 132 (1.52%)
         occurrences all number
    21
    5
    2
    INSOMNIA
         subjects affected / exposed
    18 / 135 (13.33%)
    6 / 78 (7.69%)
    9 / 132 (6.82%)
         occurrences all number
    22
    11
    11
    DEPRESSION
         subjects affected / exposed
    11 / 135 (8.15%)
    7 / 78 (8.97%)
    5 / 132 (3.79%)
         occurrences all number
    11
    10
    5
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    34 / 135 (25.19%)
    12 / 78 (15.38%)
    16 / 132 (12.12%)
         occurrences all number
    47
    16
    16
    PLATELET COUNT DECREASED
         subjects affected / exposed
    7 / 135 (5.19%)
    1 / 78 (1.28%)
    6 / 132 (4.55%)
         occurrences all number
    62
    6
    10
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    11 / 135 (8.15%)
    5 / 78 (6.41%)
    2 / 132 (1.52%)
         occurrences all number
    16
    5
    3
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    26 / 135 (19.26%)
    4 / 78 (5.13%)
    2 / 132 (1.52%)
         occurrences all number
    40
    4
    2
    FALL
         subjects affected / exposed
    25 / 135 (18.52%)
    9 / 78 (11.54%)
    3 / 132 (2.27%)
         occurrences all number
    45
    14
    5
    PROCEDURAL PAIN
         subjects affected / exposed
    8 / 135 (5.93%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
         occurrences all number
    8
    1
    1
    SKIN ABRASION
         subjects affected / exposed
    9 / 135 (6.67%)
    1 / 78 (1.28%)
    1 / 132 (0.76%)
         occurrences all number
    10
    2
    1
    SKIN LACERATION
         subjects affected / exposed
    5 / 135 (3.70%)
    4 / 78 (5.13%)
    4 / 132 (3.03%)
         occurrences all number
    10
    4
    5
    TRAUMATIC HAEMATOMA
         subjects affected / exposed
    6 / 135 (4.44%)
    4 / 78 (5.13%)
    2 / 132 (1.52%)
         occurrences all number
    9
    5
    2
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    21 / 135 (15.56%)
    6 / 78 (7.69%)
    0 / 132 (0.00%)
         occurrences all number
    23
    7
    0
    PALPITATIONS
         subjects affected / exposed
    11 / 135 (8.15%)
    5 / 78 (6.41%)
    1 / 132 (0.76%)
         occurrences all number
    13
    6
    1
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    25 / 135 (18.52%)
    10 / 78 (12.82%)
    16 / 132 (12.12%)
         occurrences all number
    29
    14
    22
    HEADACHE
         subjects affected / exposed
    19 / 135 (14.07%)
    9 / 78 (11.54%)
    13 / 132 (9.85%)
         occurrences all number
    32
    17
    23
    HYPOAESTHESIA
         subjects affected / exposed
    7 / 135 (5.19%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    10
    0
    1
    PARAESTHESIA
         subjects affected / exposed
    7 / 135 (5.19%)
    4 / 78 (5.13%)
    1 / 132 (0.76%)
         occurrences all number
    8
    6
    1
    SYNCOPE
         subjects affected / exposed
    7 / 135 (5.19%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
         occurrences all number
    7
    4
    2
    Blood and lymphatic system disorders
    INCREASED TENDENCY TO BRUISE
         subjects affected / exposed
    22 / 135 (16.30%)
    8 / 78 (10.26%)
    5 / 132 (3.79%)
         occurrences all number
    29
    8
    5
    ANAEMIA
         subjects affected / exposed
    33 / 135 (24.44%)
    14 / 78 (17.95%)
    25 / 132 (18.94%)
         occurrences all number
    86
    29
    53
    SPONTANEOUS HAEMATOMA
         subjects affected / exposed
    7 / 135 (5.19%)
    4 / 78 (5.13%)
    0 / 132 (0.00%)
         occurrences all number
    13
    4
    0
    THROMBOCYTOPENIA
         subjects affected / exposed
    20 / 135 (14.81%)
    8 / 78 (10.26%)
    17 / 132 (12.88%)
         occurrences all number
    49
    9
    29
    NEUTROPENIA
         subjects affected / exposed
    24 / 135 (17.78%)
    7 / 78 (8.97%)
    28 / 132 (21.21%)
         occurrences all number
    43
    17
    50
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    6 / 135 (4.44%)
    4 / 78 (5.13%)
    0 / 132 (0.00%)
         occurrences all number
    9
    4
    0
    Eye disorders
    CATARACT
         subjects affected / exposed
    22 / 135 (16.30%)
    5 / 78 (6.41%)
    2 / 132 (1.52%)
         occurrences all number
    27
    7
    2
    CONJUNCTIVAL HAEMORRHAGE
         subjects affected / exposed
    14 / 135 (10.37%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences all number
    14
    1
    0
    DRY EYE
         subjects affected / exposed
    27 / 135 (20.00%)
    5 / 78 (6.41%)
    6 / 132 (4.55%)
         occurrences all number
    40
    6
    7
    EYE IRRITATION
         subjects affected / exposed
    13 / 135 (9.63%)
    4 / 78 (5.13%)
    5 / 132 (3.79%)
         occurrences all number
    23
    7
    5
    EYE PAIN
         subjects affected / exposed
    10 / 135 (7.41%)
    3 / 78 (3.85%)
    2 / 132 (1.52%)
         occurrences all number
    14
    4
    2
    LACRIMATION INCREASED
         subjects affected / exposed
    20 / 135 (14.81%)
    6 / 78 (7.69%)
    8 / 132 (6.06%)
         occurrences all number
    47
    10
    10
    VITREOUS FLOATERS
         subjects affected / exposed
    13 / 135 (9.63%)
    2 / 78 (2.56%)
    7 / 132 (5.30%)
         occurrences all number
    19
    4
    8
    VISUAL ACUITY REDUCED
         subjects affected / exposed
    17 / 135 (12.59%)
    3 / 78 (3.85%)
    3 / 132 (2.27%)
         occurrences all number
    24
    3
    3
    VISION BLURRED
         subjects affected / exposed
    23 / 135 (17.04%)
    8 / 78 (10.26%)
    11 / 132 (8.33%)
         occurrences all number
    33
    11
    11
    PHOTOPHOBIA
         subjects affected / exposed
    8 / 135 (5.93%)
    4 / 78 (5.13%)
    2 / 132 (1.52%)
         occurrences all number
    10
    8
    2
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    10 / 135 (7.41%)
    4 / 78 (5.13%)
    6 / 132 (4.55%)
         occurrences all number
    13
    6
    7
    ABDOMINAL PAIN
         subjects affected / exposed
    22 / 135 (16.30%)
    6 / 78 (7.69%)
    13 / 132 (9.85%)
         occurrences all number
    30
    8
    13
    HAEMORRHOIDS
         subjects affected / exposed
    8 / 135 (5.93%)
    2 / 78 (2.56%)
    3 / 132 (2.27%)
         occurrences all number
    9
    2
    3
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    17 / 135 (12.59%)
    3 / 78 (3.85%)
    2 / 132 (1.52%)
         occurrences all number
    17
    3
    2
    DYSPEPSIA
         subjects affected / exposed
    21 / 135 (15.56%)
    11 / 78 (14.10%)
    3 / 132 (2.27%)
         occurrences all number
    26
    11
    3
    DIARRHOEA
         subjects affected / exposed
    67 / 135 (49.63%)
    27 / 78 (34.62%)
    22 / 132 (16.67%)
         occurrences all number
    145
    60
    33
    CONSTIPATION
         subjects affected / exposed
    30 / 135 (22.22%)
    12 / 78 (15.38%)
    21 / 132 (15.91%)
         occurrences all number
    48
    14
    21
    APHTHOUS ULCER
         subjects affected / exposed
    7 / 135 (5.19%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences all number
    7
    0
    0
    MOUTH ULCERATION
         subjects affected / exposed
    9 / 135 (6.67%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences all number
    9
    2
    0
    NAUSEA
         subjects affected / exposed
    43 / 135 (31.85%)
    13 / 78 (16.67%)
    52 / 132 (39.39%)
         occurrences all number
    60
    22
    75
    VOMITING
         subjects affected / exposed
    29 / 135 (21.48%)
    10 / 78 (12.82%)
    27 / 132 (20.45%)
         occurrences all number
    37
    17
    42
    STOMATITIS
         subjects affected / exposed
    13 / 135 (9.63%)
    2 / 78 (2.56%)
    5 / 132 (3.79%)
         occurrences all number
    22
    3
    5
    Hepatobiliary disorders
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    7 / 135 (5.19%)
    3 / 78 (3.85%)
    0 / 132 (0.00%)
         occurrences all number
    24
    11
    0
    Skin and subcutaneous tissue disorders
    DECUBITUS ULCER
         subjects affected / exposed
    2 / 135 (1.48%)
    5 / 78 (6.41%)
    0 / 132 (0.00%)
         occurrences all number
    2
    8
    0
    ACTINIC KERATOSIS
         subjects affected / exposed
    12 / 135 (8.89%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
         occurrences all number
    19
    2
    2
    DRY SKIN
         subjects affected / exposed
    12 / 135 (8.89%)
    4 / 78 (5.13%)
    3 / 132 (2.27%)
         occurrences all number
    13
    7
    3
    PETECHIAE
         subjects affected / exposed
    7 / 135 (5.19%)
    5 / 78 (6.41%)
    1 / 132 (0.76%)
         occurrences all number
    8
    5
    1
    NIGHT SWEATS
         subjects affected / exposed
    14 / 135 (10.37%)
    3 / 78 (3.85%)
    10 / 132 (7.58%)
         occurrences all number
    16
    3
    12
    ECCHYMOSIS
         subjects affected / exposed
    3 / 135 (2.22%)
    9 / 78 (11.54%)
    1 / 132 (0.76%)
         occurrences all number
    5
    12
    1
    PRURITUS
         subjects affected / exposed
    19 / 135 (14.07%)
    5 / 78 (6.41%)
    7 / 132 (5.30%)
         occurrences all number
    29
    10
    13
    SKIN LESION
         subjects affected / exposed
    11 / 135 (8.15%)
    4 / 78 (5.13%)
    1 / 132 (0.76%)
         occurrences all number
    13
    5
    1
    RASH MACULO-PAPULAR
         subjects affected / exposed
    13 / 135 (9.63%)
    6 / 78 (7.69%)
    5 / 132 (3.79%)
         occurrences all number
    19
    17
    7
    PURPURA
         subjects affected / exposed
    7 / 135 (5.19%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences all number
    8
    3
    0
    RASH
         subjects affected / exposed
    9 / 135 (6.67%)
    3 / 78 (3.85%)
    3 / 132 (2.27%)
         occurrences all number
    22
    3
    8
    RASH ERYTHEMATOUS
         subjects affected / exposed
    17 / 135 (12.59%)
    4 / 78 (5.13%)
    6 / 132 (4.55%)
         occurrences all number
    30
    4
    6
    Renal and urinary disorders
    POLLAKIURIA
         subjects affected / exposed
    8 / 135 (5.93%)
    0 / 78 (0.00%)
    4 / 132 (3.03%)
         occurrences all number
    8
    0
    4
    HAEMATURIA
         subjects affected / exposed
    13 / 135 (9.63%)
    6 / 78 (7.69%)
    3 / 132 (2.27%)
         occurrences all number
    14
    8
    3
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    8 / 135 (5.93%)
    0 / 78 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    12
    0
    1
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    9 / 135 (6.67%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences all number
    13
    2
    0
    Musculoskeletal and connective tissue disorders
    JOINT SWELLING
         subjects affected / exposed
    7 / 135 (5.19%)
    3 / 78 (3.85%)
    1 / 132 (0.76%)
         occurrences all number
    9
    4
    1
    BACK PAIN
         subjects affected / exposed
    27 / 135 (20.00%)
    10 / 78 (12.82%)
    9 / 132 (6.82%)
         occurrences all number
    38
    12
    9
    ARTHRALGIA
         subjects affected / exposed
    41 / 135 (30.37%)
    22 / 78 (28.21%)
    10 / 132 (7.58%)
         occurrences all number
    75
    40
    18
    MUSCLE SPASMS
         subjects affected / exposed
    28 / 135 (20.74%)
    13 / 78 (16.67%)
    7 / 132 (5.30%)
         occurrences all number
    40
    20
    7
    MUSCULAR WEAKNESS
         subjects affected / exposed
    9 / 135 (6.67%)
    2 / 78 (2.56%)
    2 / 132 (1.52%)
         occurrences all number
    10
    2
    2
    MYALGIA
         subjects affected / exposed
    11 / 135 (8.15%)
    3 / 78 (3.85%)
    4 / 132 (3.03%)
         occurrences all number
    17
    3
    6
    NECK PAIN
         subjects affected / exposed
    8 / 135 (5.93%)
    2 / 78 (2.56%)
    4 / 132 (3.03%)
         occurrences all number
    11
    3
    5
    OSTEOPOROSIS
         subjects affected / exposed
    8 / 135 (5.93%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences all number
    8
    1
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    23 / 135 (17.04%)
    8 / 78 (10.26%)
    7 / 132 (5.30%)
         occurrences all number
    27
    10
    7
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    17 / 135 (12.59%)
    5 / 78 (6.41%)
    4 / 132 (3.03%)
         occurrences all number
    34
    7
    5
    COVID-19
         subjects affected / exposed
    15 / 135 (11.11%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences all number
    18
    0
    0
    CELLULITIS
         subjects affected / exposed
    13 / 135 (9.63%)
    3 / 78 (3.85%)
    1 / 132 (0.76%)
         occurrences all number
    17
    3
    1
    EYE INFECTION
         subjects affected / exposed
    8 / 135 (5.93%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences all number
    9
    1
    0
    CYSTITIS
         subjects affected / exposed
    7 / 135 (5.19%)
    1 / 78 (1.28%)
    0 / 132 (0.00%)
         occurrences all number
    11
    2
    0
    CONJUNCTIVITIS
         subjects affected / exposed
    22 / 135 (16.30%)
    8 / 78 (10.26%)
    3 / 132 (2.27%)
         occurrences all number
    37
    11
    3
    FOLLICULITIS
         subjects affected / exposed
    7 / 135 (5.19%)
    0 / 78 (0.00%)
    0 / 132 (0.00%)
         occurrences all number
    7
    0
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    15 / 135 (11.11%)
    5 / 78 (6.41%)
    6 / 132 (4.55%)
         occurrences all number
    27
    11
    6
    INFLUENZA
         subjects affected / exposed
    7 / 135 (5.19%)
    7 / 78 (8.97%)
    4 / 132 (3.03%)
         occurrences all number
    11
    9
    4
    HERPES ZOSTER
         subjects affected / exposed
    13 / 135 (9.63%)
    1 / 78 (1.28%)
    7 / 132 (5.30%)
         occurrences all number
    14
    1
    8
    SKIN INFECTION
         subjects affected / exposed
    13 / 135 (9.63%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
         occurrences all number
    16
    1
    3
    SINUSITIS
         subjects affected / exposed
    9 / 135 (6.67%)
    3 / 78 (3.85%)
    1 / 132 (0.76%)
         occurrences all number
    14
    3
    1
    RHINITIS
         subjects affected / exposed
    7 / 135 (5.19%)
    0 / 78 (0.00%)
    2 / 132 (1.52%)
         occurrences all number
    14
    0
    2
    PHARYNGITIS
         subjects affected / exposed
    8 / 135 (5.93%)
    2 / 78 (2.56%)
    0 / 132 (0.00%)
         occurrences all number
    9
    2
    0
    PNEUMONIA
         subjects affected / exposed
    12 / 135 (8.89%)
    5 / 78 (6.41%)
    3 / 132 (2.27%)
         occurrences all number
    16
    9
    3
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    6 / 135 (4.44%)
    4 / 78 (5.13%)
    2 / 132 (1.52%)
         occurrences all number
    8
    9
    3
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    38 / 135 (28.15%)
    20 / 78 (25.64%)
    23 / 132 (17.42%)
         occurrences all number
    73
    31
    30
    URINARY TRACT INFECTION
         subjects affected / exposed
    29 / 135 (21.48%)
    10 / 78 (12.82%)
    10 / 132 (7.58%)
         occurrences all number
    87
    14
    15
    Metabolism and nutrition disorders
    HYPERURICAEMIA
         subjects affected / exposed
    23 / 135 (17.04%)
    2 / 78 (2.56%)
    1 / 132 (0.76%)
         occurrences all number
    37
    5
    1
    DECREASED APPETITE
         subjects affected / exposed
    24 / 135 (17.78%)
    7 / 78 (8.97%)
    19 / 132 (14.39%)
         occurrences all number
    38
    10
    26
    HYPOCALCAEMIA
         subjects affected / exposed
    7 / 135 (5.19%)
    1 / 78 (1.28%)
    3 / 132 (2.27%)
         occurrences all number
    25
    1
    3
    IRON DEFICIENCY
         subjects affected / exposed
    12 / 135 (8.89%)
    5 / 78 (6.41%)
    0 / 132 (0.00%)
         occurrences all number
    14
    5
    0
    HYPONATRAEMIA
         subjects affected / exposed
    7 / 135 (5.19%)
    5 / 78 (6.41%)
    1 / 132 (0.76%)
         occurrences all number
    15
    10
    1
    HYPOKALAEMIA
         subjects affected / exposed
    16 / 135 (11.85%)
    6 / 78 (7.69%)
    2 / 132 (1.52%)
         occurrences all number
    26
    9
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2014
    • Provide a clarification to broaden the eligible timeframe to receive second-line PCI-32765 by removing the 12 month time limit after last chlorambucil dose to obtain second-line PCI-32765 • Allow subjects receiving non-PCI-32765 as second-line therapy are now eligible to receive next-line PCI-32765 but must have recovered from any toxicity from non-PCI-32765 therapy prior to receiving PCI-32765 therapy. • Update safety language and to ensure consistency across PCI-32765 protocols. • All AEs will be collected to strengthen safety monitoring.
    29 Sep 2016
    • Revised study duration • Clarified assessment for MRD-possitive and MRD-negative subjects. • Aligned current protocol language with updated protocol template. • Updated safety language per updated Investigator's Brochure version 10. • Allowed for discontinuation and re-initiation of ibrutinib in subjects receiving second-line ibrutinib who reach MRD-negative status.
    12 Jul 2018
    • Revised study duration • Revised study objective • Revised study design: o Subjects randomized to first-line chlorambucil once progressed post their first-line therapy will exit the study and the initiation of second-line treatment with ibrutinib will not be available for these subjects on Study 1116. Note, with the implementation of Amendment 3, first-line chlorambucil subjects, who have withdrawn partial consent and are being followed up for overall survival only, will also exit the study. o Subjects randomized to first-line ibrutinib who have withdrawn partial consent and are being followed up for overall survival only will continue their participation in the study. o Subjects randomized to first-line chlorambucil who are receiving ibrutinib on study will exit and will be given the opportunity to enroll into a separate long-term ibrutinib extension study if they meet the eligibility criteria of that study or can continue therapy from commercial source. o Subjects who were randomized to ibrutinib and have progressed will continue to be followed in the study. • Revised second-line ibrutinib criteria. • Revised first-line therapy continuation. • Revised statistical methods. NOTE: after implementation of amendment 3, at a median follow-up of 60 months, post-PD follow-up for Chlorambucil arm was terminated. Subjects in the chlorambucil arm were to exit the study after PD, and those who had crossed over to next-line ibrutinib had the opportunity to roll over to another long-term ibrutinib study (PCYC-1145-CA).
    10 Oct 2022
    • Updated the recommendations that are intended to improve tolerability for continued ibrutinib treatment in the study protocol. • Update risks to Cardiac Arrhythmia section.

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

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

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