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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab versus Placebo in Combination with Rituximab in Treatment Naïve Subjects with Follicular Lymphoma (PERSPECTIVE)

    Summary
    EudraCT number
    		 2016-003202-14
    Trial protocol
    		 GB   ES   CZ   HU   PT   BE   GR   NL   AT   FR   IT  
    Global end of trial date
    09 Jun 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2026
    First version publication date
    01 Apr 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1141-CA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03112174
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    AbbVie, Global Medical Services, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    AbbVie, Global Medical Services, 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
    09 Jun 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study to evaluate the efficacy and safety of ibrutinib in combination with rituximab versus placebo in combination with rituximab in treatment naïve participants with follicular lymphoma (FL)
    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
    23 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Czechia: 17
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Spain: 65
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    Türkiye: 23
    Country: Number of subjects enrolled
    United States: 93
    Country: Number of subjects enrolled
    United Kingdom: 10
    Worldwide total number of subjects
    445
    EEA total number of subjects
    230
    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)
    44
    From 65 to 84 years
    383
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total, 445 participants were enrolled at 128 sites in 19 countries.

    Pre-assignment
    Screening details
    		 Participants were randomly assigned in a 3:1 ratio to the Ibrutinib + Rituximab arm (Arm A; n=334) or the Placebo + Rituximab arm (Arm B; n=111). Randomization was stratified based on: (a) age (60-69 vs. ≥70 yrs), (b) Follicular Lymphoma-specific International Prognostic Index (FLIPI)-1 score (low vs. intermediate/high) and (c) ECOG PS (0/1 vs. 2).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The interactive voice or web response system (IXRS) assigned a unique treatment code, which dictated the treatment assignment and matching study treatment kit for the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Ibrutinib + Rituximab
    Arm description
    		 Subjects were randomized to receive ibrutinib 560mg orally (PO) once daily (QD) until disease progression or unacceptable toxicity and rituximab 375mg/m^2 weekly (QW) for the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22). Beginning with Cycle 3, Day 1, rituximab maintenance therapy was administered as a single dose of 375 mg/m^2 IV every 8 weeks for up to 12 additional doses (approximately 2 years) or until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Imbruvica
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib 560mg administered orally daily

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Rituxan
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 375mg/m^2 intravenously (IV) weekly

    Arm title
    		 Arm B: Placebo + Rituximab
    Arm description
    		 Subjects were randomized to receive placebo PO (4 capsules) daily until disease progression or unacceptable toxicity and rituximab 375mg/m^2 weekly for the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22). Beginning with Cycle 3, Day 1, rituximab maintenance therapy was administered as a single dose of 375 mg/m^2 IV every 8 weeks for up to 12 additional doses (approximately 2 years) or until disease progression, unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Rituxan
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab 375mg/m^2 intravenously (IV) weekly

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules to match ibrutinib administered orally daily

    Number of subjects in period 1
    		Arm A: Ibrutinib + Rituximab Arm B: Placebo + Rituximab
    Started
    334
    111
    Completed
    158
    55
    Not completed
    176
    56
         Withdrawal of Consent
    50
    14
         Death
    109
    35
         Not Specified
    10
    3
         Lost to follow-up
    7
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Ibrutinib + Rituximab
    Reporting group description
    		 Subjects were randomized to receive ibrutinib 560mg orally (PO) once daily (QD) until disease progression or unacceptable toxicity and rituximab 375mg/m^2 weekly (QW) for the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22). Beginning with Cycle 3, Day 1, rituximab maintenance therapy was administered as a single dose of 375 mg/m^2 IV every 8 weeks for up to 12 additional doses (approximately 2 years) or until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Arm B: Placebo + Rituximab
    Reporting group description
    		 Subjects were randomized to receive placebo PO (4 capsules) daily until disease progression or unacceptable toxicity and rituximab 375mg/m^2 weekly for the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22). Beginning with Cycle 3, Day 1, rituximab maintenance therapy was administered as a single dose of 375 mg/m^2 IV every 8 weeks for up to 12 additional doses (approximately 2 years) or until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group values
    		 Arm A: Ibrutinib + Rituximab Arm B: Placebo + Rituximab Total
    Number of subjects
    		 334 111 445
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.7 ( 6.38 ) 74.2 ( 5.96 ) -
    Gender categorical
    Units: Subjects
        Female
    		 183 53 236
        Male
    		 151 58 209

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Ibrutinib + Rituximab
    Reporting group description
    		 Subjects were randomized to receive ibrutinib 560mg orally (PO) once daily (QD) until disease progression or unacceptable toxicity and rituximab 375mg/m^2 weekly (QW) for the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22). Beginning with Cycle 3, Day 1, rituximab maintenance therapy was administered as a single dose of 375 mg/m^2 IV every 8 weeks for up to 12 additional doses (approximately 2 years) or until disease progression, unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Arm B: Placebo + Rituximab
    Reporting group description
    		 Subjects were randomized to receive placebo PO (4 capsules) daily until disease progression or unacceptable toxicity and rituximab 375mg/m^2 weekly for the first 4 weeks of study treatment (Cycle 1: Days 1, 8, 15, and 22). Beginning with Cycle 3, Day 1, rituximab maintenance therapy was administered as a single dose of 375 mg/m^2 IV every 8 weeks for up to 12 additional doses (approximately 2 years) or until disease progression, unacceptable toxicity, or withdrawal of consent.

    Primary: Progression-Free Survival (PFS) as Assessed by Investigator

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    End point title
    		 Progression-Free Survival (PFS) as Assessed by Investigator
    End point description
    PFS is the time from the date of randomization to the date of the first documented evidence of disease progression (based on the Revised Response Criteria for Malignant Lymphoma [Cheson 2014, Lugano Classification]) or death from any cause, whichever occurs first. Subjects who initiated subsequent anticancer therapy or missed two or more consecutive overall disease assessments were censored as described in the SAP. Estimated by Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    Primary Analysis cut-off; median overall follow-up of 53.75 months
    End point values
    		 Arm A: Ibrutinib + Rituximab Arm B: Placebo + Rituximab
    Number of subjects analysed
    334 [1]
    111 [2]
    Units: months
        median (confidence interval 95%)
    42.02 (33.31 to 50.83)
    32.76 (22.05 to 38.67)
    Notes
    [1] - ITT Population.
    [2] - ITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ibrutinib + Rituximab v Arm B: Placebo + Rituximab
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0231 [4]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.713
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.532
         upper limit
    		 0.955
    Notes
    [3] - A stratified log-rank test was used to compare PFS between the two arms.
    [4] - Stratification was based on FLIPI-1 and ECOG reported at randomization combined into a 3 strata variable: FLIPI-1 score=low; FLIPI-1 score=intermediate/high and ECOG PS score =0/1; FLIPI-1 score=intermediate/high and ECOG PS score=2.

    Secondary: Overall Response Rate (ORR) as Assessed by Investigator

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    End point title
    		 Overall Response Rate (ORR) as Assessed by Investigator
    End point description
    ORR is the proportion of subjects who achieved a best overall response of complete response (CR) or partial response (PR) as determined by the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014, Lugano Classification). ORR was assessed from the date of randomization through the date of first documented disease progression or initiation of subsequent anti-cancer therapy, whichever occurred first. Subjects who did not have any post-baseline disease assessments or who initiated subsequent anti-cancer therapy prior to a documented response are considered non-responders.
    End point type
    Secondary
    End point timeframe
    Primary Analysis; median overall follow-up of 53.75 months
    End point values
    		 Arm A: Ibrutinib + Rituximab Arm B: Placebo + Rituximab
    Number of subjects analysed
    334
    111
    Units: Percentage of subjects
        number (confidence interval 95%)
    81.4 (76.8 to 85.5)
    68.5 (59.0 to 77.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ibrutinib + Rituximab v Arm B: Placebo + Rituximab
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response Rate Ratio
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.039
         upper limit
    		 1.364
    Notes
    [5] - Adjustment based on FLIPI-1 and ECOG at randomization combined into a 3 strata variable: FLIPI-1 score=low; FLIPI-1 score=intermediate/high and ECOG performance status score=0/1; FLIPI-1 score=intermediate/high and ECOG performance status score=2.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival is defined as the interval between the date of randomization and the date of the participant's death from any cause. If a participant is not known to have died (this includes participants with unknown death date), OS will be censored at the date the participant was last known to have been alive. Estimated by Kaplan-Meier method. 99999 Explanation: Not reached/ not estimable
    End point type
    Secondary
    End point timeframe
    Final Analysis; median overall follow-up of 58.97 months
    End point values
    		 Arm A: Ibrutinib + Rituximab Arm B: Placebo + Rituximab
    Number of subjects analysed
    334 [6]
    111 [7]
    Units: months
        median (confidence interval 95%)
    99999 (69.72 to 99999)
    78.98 (57.36 to 99999)
    Notes
    [6] - ITT Population
    [7] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm A: Ibrutinib + Rituximab v Arm B: Placebo + Rituximab
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.6608
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.758
         upper limit
    		 1.548
    Notes
    [8] - Hazard ratio is estimated using stratified Cox regression model.

    Secondary: Infusion-related Reaction Rate Assessed by Investigator

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    End point title
    		 Infusion-related Reaction Rate Assessed by Investigator
    End point description
    The infusion-related reactions (IRR) rate is the proportion of subjects experiencing infusion related reactions that start on the day of a rituximab infusion and are assessed as related or possibly related to rituximab.
    End point type
    Secondary
    End point timeframe
    Primary Analysis; median overall follow-up of 53.75 months
    End point values
    		 Arm A: Ibrutinib + Rituximab Arm B: Placebo + Rituximab
    Number of subjects analysed
    334 [9]
    111 [10]
    Units: percentage of subjects
        number (confidence interval 95%)
    21.3 (17.0 to 26.0)
    27.0 (19.0 to 36.3)
    Notes
    [9] - ITT Population
    [10] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Arm B: Placebo + Rituximab v Arm A: Ibrutinib + Rituximab
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2087 [11]
    Method
    		 Chi-squared
    Parameter type
    		 Rate Ratio
    Point estimate
    0.787
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.544
         upper limit
    		 1.137
    Notes
    [11] - P-value for rate ratio is based on Chi-Square test.

    Secondary: Duration of Response (DOR) as Assessed by Investigator

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    End point title
    		 Duration of Response (DOR) as Assessed by Investigator
    End point description
    DOR is defined as the time from initial complete response (CR) or partial response (PR) to progressive disease (PD) or death due to any cause, whichever is first reported, regardless of discontinuation of study treatment. If such event did not occur, then participants were to be censored at the last adequate disease assessment as required for PFS censoring. Estimated by Kaplan-Meier method. 99999 Explanation: Not reached/ not estimable
    End point type
    Secondary
    End point timeframe
    Primary Analysis; median overall follow-up of 53.75 months
    End point values
    		 Arm A: Ibrutinib + Rituximab Arm B: Placebo + Rituximab
    Number of subjects analysed
    272 [12]
    76 [13]
    Units: months
        median (confidence interval 95%)
    44.25 (36.63 to 99999)
    34.56 (29.21 to 47.31)
    Notes
    [12] - ITT Population. Subjects achieving a response (partial response or better) are included in analysis.
    [13] - ITT Population. Subjects achieving a response (partial response or better) are included in analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The treatment-emergent period is defined as the period from the date of the first dose of study treatment up to 30 days after the date of the last dose of study treatment or the day before initiation of subsequent anti-cancer therapy, whichever comes first. The treatment-emergent adverse events (TEAEs) are those events that occur or worsen during the treatment-emergent period or that are related to the study treatment.
    End point type
    Secondary
    End point timeframe
    Overall median treatment duration of 22.11 months
    End point values
    		 Arm A: Ibrutinib + Rituximab Arm B: Placebo + Rituximab
    Number of subjects analysed
    330 [14]
    111 [15]
    Units: count of subjects
    number (not applicable)
        Any Treatment-Emergent Adverse Event (TEAE)
    324
    106
        Grade ≥3 TEAEs
    259
    63
        Serious Adverse Events (SAEs)
    204
    45
        Fatal TEAEs
    48
    6
        Discontinued study drug due to AE
    144
    16
        Most frequent Grade ≥3 TEAE (neutropenia)
    52
    8
    Notes
    [14] - Safety Population
    [15] - Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality and adverse event tables include events reported from the time of informed consent/enrollment to end of study. Median time on follow-up was 58.2 months for Arm A (Ibrutinib + Rituximab) and 60.0 months for Arm B (Placebo + Rituximab).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Placebo_Rituximab
    Reporting group description
    		 -

    Reporting group title
    Ibrutinib_Rituximab
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo_Rituximab Ibrutinib_Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 111 (43.24%)
    214 / 334 (64.07%)
         number of deaths (all causes)
    40
    123
         number of deaths resulting from adverse events
    9
    53
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BREAST CANCER RECURRENT
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BOWEN'S DISEASE
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADENOCARCINOMA OF COLON
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADENOCARCINOMA GASTRIC
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CANCER FATIGUE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    OROPHARYNGEAL NEOPLASM BENIGN
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NASAL CAVITY CANCER
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTATIC RENAL CELL CARCINOMA
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTASES TO PERITONEUM
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    LUNG CARCINOMA CELL TYPE UNSPECIFIED STAGE IV
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    LUNG CANCER METASTATIC
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INVASIVE LOBULAR BREAST CARCINOMA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INVASIVE DUCTAL BREAST CARCINOMA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FOLLICULAR LYMPHOMA
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    CANCER PAIN
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROSTATE CANCER RECURRENT
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SIGNET-RING CELL CARCINOMA
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSITIONAL CELL CANCER OF THE RENAL PELVIS AND URETER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR NECROSIS
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL CELL CARCINOMA RECURRENT
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLISM
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTERIOSCLEROSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AORTIC ANEURYSM
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL VENOUS DISEASE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL VASCULAR DISORDER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUROGENIC SHOCK
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHILLS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    2 / 111 (1.80%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 111 (0.00%)
    6 / 334 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    PROSTATITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UTERINE MASS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    RHINORRHOEA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 334 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    RESPIRATORY ACIDOSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    3 / 111 (2.70%)
    5 / 334 (1.50%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORGANISING PNEUMONIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFILTRATION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HAEMOTHORAX
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 334 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHYLOTHORAX
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    2 / 111 (1.80%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIAL OBSTRUCTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DELIRIUM
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PSYCHOTIC DISORDER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    OCCULT BLOOD POSITIVE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CRANIOFACIAL FRACTURE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EXTRA-AXIAL HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 334 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FRACTURE DISPLACEMENT
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    1 / 111 (0.90%)
    4 / 334 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    2 / 111 (1.80%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETERIC INJURY
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRAUMATIC HAEMATOMA
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIOVENTRICULAR BLOCK SECOND DEGREE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    2 / 111 (1.80%)
    21 / 334 (6.29%)
         occurrences causally related to treatment / all
    0 / 2
    17 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    1 / 111 (0.90%)
    4 / 334 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    CARDIAC ASTHMA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 111 (0.90%)
    5 / 334 (1.50%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC CORONARY SYNDROME
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY OCCLUSION
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY STENOSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYCARDIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    STIFF PERSON SYNDROME
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASAL GANGLIA HAEMORRHAGE
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN OEDEMA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCIATICA
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 111 (0.90%)
    6 / 334 (1.80%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRACRANIAL HAEMATOMA
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HAEMORRHAGIC TRANSFORMATION STROKE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGIC STROKE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COGNITIVE DISORDER
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL HAEMATOMA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    2 / 111 (1.80%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBARACHNOID HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 334 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    LABYRINTHINE FISTULA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VERTIGO
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    EPIRETINAL MEMBRANE
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RETINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VITREOUS HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OBSTRUCTIVE PANCREATITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL POLYP HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHOIDAL HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS PARALYTIC
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INCARCERATED INGUINAL HERNIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL PERFORATION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE POLYP
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALLORY-WEISS SYNDROME
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MOUTH ULCERATION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 111 (0.90%)
    6 / 334 (1.80%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMATOSIS INTESTINALIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    0 / 111 (0.00%)
    5 / 334 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATOLITHIASIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILIARY COLIC
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BILIARY OBSTRUCTION
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLESTASIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CYTOLYSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FAILURE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DECUBITUS ULCER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLISTER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXIC SKIN ERUPTION
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN DISCHARGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULAR
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH ERYTHEMATOUS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PETECHIAE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC SKIN ULCER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ECCHYMOSIS
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC FOOT
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 111 (0.00%)
    6 / 334 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CYSTITIS HAEMORRHAGIC
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSURIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL HAEMATOMA
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL HAEMORRHAGE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL TUBULAR NECROSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBULOINTERSTITIAL NEPHRITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT OBSTRUCTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRALGIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLANK PAIN
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JOINT EFFUSION
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCLE SPASMS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL OSTEOARTHRITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BRONCHITIS BACTERIAL
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL INFECTION
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABSCESS LIMB
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERIAL INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 111 (0.90%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHOPULMONARY ASPERGILLOSIS
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAMPYLOBACTER GASTROENTERITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAMPYLOBACTER INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CANDIDA SEPSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARBUNCLE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    6 / 334 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENDOCARDITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM COLITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 111 (0.90%)
    25 / 334 (7.49%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 31
         deaths causally related to treatment / all
    0 / 0
    1 / 6
    COVID-19 PNEUMONIA
         subjects affected / exposed
    5 / 111 (4.50%)
    21 / 334 (6.29%)
         occurrences causally related to treatment / all
    1 / 6
    9 / 35
         deaths causally related to treatment / all
    0 / 0
    3 / 12
    CYCLOSPORIDIUM INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC FOOT INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CENTRAL NERVOUS SYSTEM FUNGAL INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    ENTEROCOLITIS INFECTIOUS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ESCHERICHIA URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GANGRENE
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    2 / 111 (1.80%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS ROTAVIRUS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS B REACTIVATION
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTED SKIN ULCER
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    INFECTION
         subjects affected / exposed
    1 / 111 (0.90%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIOUS PLEURAL EFFUSION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    2 / 111 (1.80%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MENINGITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGEAL CANDIDIASIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    5 / 111 (4.50%)
    36 / 334 (10.78%)
         occurrences causally related to treatment / all
    1 / 5
    18 / 45
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    ERYSIPELAS
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    4 / 111 (3.60%)
    11 / 334 (3.29%)
         occurrences causally related to treatment / all
    1 / 4
    5 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROSTATITIS ESCHERICHIA COLI
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROTEUS INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    5 / 334 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    SEPSIS PASTEURELLA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 111 (0.00%)
    4 / 334 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    3 / 4
    SPLENIC ABSCESS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPONTANEOUS BACTERIAL PERITONITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    3 / 334 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STENOTROPHOMONAS INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STREPTOCOCCAL SEPSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    SUPERINFECTION BACTERIAL
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TONSILLITIS
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 111 (0.90%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT CANDIDIASIS
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA STREPTOCOCCAL
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION ENTEROCOCCAL
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION PSEUDOMONAL
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    0 / 111 (0.00%)
    2 / 334 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS INADEQUATE CONTROL
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR LYSIS SYNDROME
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 334 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERURICAEMIA
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 334 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo_Rituximab Ibrutinib_Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    101 / 111 (90.99%)
    310 / 334 (92.81%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    10 / 111 (9.01%)
    48 / 334 (14.37%)
         occurrences all number
    14
    76
    HYPOTENSION
         subjects affected / exposed
    6 / 111 (5.41%)
    9 / 334 (2.69%)
         occurrences all number
    7
    11
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    7 / 111 (6.31%)
    35 / 334 (10.48%)
         occurrences all number
    7
    44
    CHILLS
         subjects affected / exposed
    8 / 111 (7.21%)
    12 / 334 (3.59%)
         occurrences all number
    9
    15
    FATIGUE
         subjects affected / exposed
    16 / 111 (14.41%)
    72 / 334 (21.56%)
         occurrences all number
    25
    120
    OEDEMA PERIPHERAL
         subjects affected / exposed
    18 / 111 (16.22%)
    63 / 334 (18.86%)
         occurrences all number
    22
    95
    PYREXIA
         subjects affected / exposed
    15 / 111 (13.51%)
    35 / 334 (10.48%)
         occurrences all number
    21
    42
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    17 / 111 (15.32%)
    57 / 334 (17.07%)
         occurrences all number
    22
    72
    DYSPNOEA
         subjects affected / exposed
    20 / 111 (18.02%)
    38 / 334 (11.38%)
         occurrences all number
    29
    45
    EPISTAXIS
         subjects affected / exposed
    3 / 111 (2.70%)
    24 / 334 (7.19%)
         occurrences all number
    3
    31
    RHINORRHOEA
         subjects affected / exposed
    6 / 111 (5.41%)
    4 / 334 (1.20%)
         occurrences all number
    7
    4
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    12 / 111 (10.81%)
    27 / 334 (8.08%)
         occurrences all number
    13
    28
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    4 / 111 (3.60%)
    17 / 334 (5.09%)
         occurrences all number
    5
    21
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    16 / 111 (14.41%)
    27 / 334 (8.08%)
         occurrences all number
    18
    31
    FALL
         subjects affected / exposed
    11 / 111 (9.91%)
    33 / 334 (9.88%)
         occurrences all number
    12
    36
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 111 (0.90%)
    36 / 334 (10.78%)
         occurrences all number
    1
    39
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    5 / 111 (4.50%)
    32 / 334 (9.58%)
         occurrences all number
    5
    37
    HEADACHE
         subjects affected / exposed
    5 / 111 (4.50%)
    45 / 334 (13.47%)
         occurrences all number
    6
    71
    Blood and lymphatic system disorders
    INCREASED TENDENCY TO BRUISE
         subjects affected / exposed
    0 / 111 (0.00%)
    31 / 334 (9.28%)
         occurrences all number
    0
    40
    ANAEMIA
         subjects affected / exposed
    9 / 111 (8.11%)
    49 / 334 (14.67%)
         occurrences all number
    13
    83
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 111 (0.90%)
    31 / 334 (9.28%)
         occurrences all number
    1
    72
    NEUTROPENIA
         subjects affected / exposed
    12 / 111 (10.81%)
    67 / 334 (20.06%)
         occurrences all number
    15
    118
    Eye disorders
    DRY EYE
         subjects affected / exposed
    17 / 111 (15.32%)
    60 / 334 (17.96%)
         occurrences all number
    26
    84
    CATARACT
         subjects affected / exposed
    6 / 111 (5.41%)
    26 / 334 (7.78%)
         occurrences all number
    8
    30
    VITREOUS FLOATERS
         subjects affected / exposed
    12 / 111 (10.81%)
    26 / 334 (7.78%)
         occurrences all number
    17
    34
    VISUAL ACUITY REDUCED
         subjects affected / exposed
    17 / 111 (15.32%)
    39 / 334 (11.68%)
         occurrences all number
    27
    55
    VISION BLURRED
         subjects affected / exposed
    10 / 111 (9.01%)
    53 / 334 (15.87%)
         occurrences all number
    19
    74
    PHOTOPSIA
         subjects affected / exposed
    7 / 111 (6.31%)
    13 / 334 (3.89%)
         occurrences all number
    13
    18
    PHOTOPHOBIA
         subjects affected / exposed
    7 / 111 (6.31%)
    32 / 334 (9.58%)
         occurrences all number
    13
    41
    LACRIMATION INCREASED
         subjects affected / exposed
    13 / 111 (11.71%)
    40 / 334 (11.98%)
         occurrences all number
    22
    58
    EYE PAIN
         subjects affected / exposed
    7 / 111 (6.31%)
    23 / 334 (6.89%)
         occurrences all number
    11
    27
    EYE IRRITATION
         subjects affected / exposed
    18 / 111 (16.22%)
    41 / 334 (12.28%)
         occurrences all number
    26
    56
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    6 / 111 (5.41%)
    32 / 334 (9.58%)
         occurrences all number
    7
    42
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    9 / 111 (8.11%)
    27 / 334 (8.08%)
         occurrences all number
    9
    31
    CONSTIPATION
         subjects affected / exposed
    16 / 111 (14.41%)
    53 / 334 (15.87%)
         occurrences all number
    18
    65
    DIARRHOEA
         subjects affected / exposed
    15 / 111 (13.51%)
    116 / 334 (34.73%)
         occurrences all number
    19
    205
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    7 / 111 (6.31%)
    16 / 334 (4.79%)
         occurrences all number
    9
    19
    NAUSEA
         subjects affected / exposed
    12 / 111 (10.81%)
    69 / 334 (20.66%)
         occurrences all number
    18
    92
    STOMATITIS
         subjects affected / exposed
    2 / 111 (1.80%)
    26 / 334 (7.78%)
         occurrences all number
    2
    41
    VOMITING
         subjects affected / exposed
    5 / 111 (4.50%)
    41 / 334 (12.28%)
         occurrences all number
    5
    62
    Skin and subcutaneous tissue disorders
    ERYTHEMA
         subjects affected / exposed
    2 / 111 (1.80%)
    17 / 334 (5.09%)
         occurrences all number
    3
    18
    DRY SKIN
         subjects affected / exposed
    3 / 111 (2.70%)
    20 / 334 (5.99%)
         occurrences all number
    3
    20
    RASH MACULO-PAPULAR
         subjects affected / exposed
    4 / 111 (3.60%)
    31 / 334 (9.28%)
         occurrences all number
    5
    45
    RASH ERYTHEMATOUS
         subjects affected / exposed
    1 / 111 (0.90%)
    22 / 334 (6.59%)
         occurrences all number
    2
    31
    PRURITUS
         subjects affected / exposed
    13 / 111 (11.71%)
    26 / 334 (7.78%)
         occurrences all number
    14
    36
    ONYCHOCLASIS
         subjects affected / exposed
    0 / 111 (0.00%)
    17 / 334 (5.09%)
         occurrences all number
    0
    18
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    16 / 111 (14.41%)
    63 / 334 (18.86%)
         occurrences all number
    24
    83
    BACK PAIN
         subjects affected / exposed
    15 / 111 (13.51%)
    45 / 334 (13.47%)
         occurrences all number
    15
    54
    MUSCLE SPASMS
         subjects affected / exposed
    8 / 111 (7.21%)
    39 / 334 (11.68%)
         occurrences all number
    10
    52
    MYALGIA
         subjects affected / exposed
    6 / 111 (5.41%)
    22 / 334 (6.59%)
         occurrences all number
    7
    26
    PAIN IN EXTREMITY
         subjects affected / exposed
    6 / 111 (5.41%)
    30 / 334 (8.98%)
         occurrences all number
    9
    33
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    4 / 111 (3.60%)
    23 / 334 (6.89%)
         occurrences all number
    4
    27
    CONJUNCTIVITIS
         subjects affected / exposed
    5 / 111 (4.50%)
    21 / 334 (6.29%)
         occurrences all number
    5
    25
    COVID-19
         subjects affected / exposed
    22 / 111 (19.82%)
    62 / 334 (18.56%)
         occurrences all number
    26
    74
    URINARY TRACT INFECTION
         subjects affected / exposed
    10 / 111 (9.01%)
    60 / 334 (17.96%)
         occurrences all number
    13
    122
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    6 / 111 (5.41%)
    27 / 334 (8.08%)
         occurrences all number
    10
    41
    PNEUMONIA
         subjects affected / exposed
    4 / 111 (3.60%)
    20 / 334 (5.99%)
         occurrences all number
    5
    24
    NASOPHARYNGITIS
         subjects affected / exposed
    6 / 111 (5.41%)
    14 / 334 (4.19%)
         occurrences all number
    7
    18
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    4 / 111 (3.60%)
    34 / 334 (10.18%)
         occurrences all number
    4
    36
    HYPERURICAEMIA
         subjects affected / exposed
    6 / 111 (5.41%)
    27 / 334 (8.08%)
         occurrences all number
    6
    35
    HYPOKALAEMIA
         subjects affected / exposed
    3 / 111 (2.70%)
    35 / 334 (10.48%)
         occurrences all number
    5
    54

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2018
    Protocol Amendment 1 Key Changes: - Revised GELF criteria to avoid excluding potential eligible subjects. - Added infusion-related reactions (IRR) as a secondary objective. - Updated rituximab dosing instructions and directed sites to follow regional prescribing information. - Provided guidance on rituximab induction dosing during Cycle 1 if a scheduled dose is missed for reasons not related to rituximab tolerability.
    10 Mar 2021
    Protocol Amendment 2 Key Changes: - Responded to an extended enrollment delay by revising the analysis plan for Part 1 (PFS). - Increased the target event count for the final analysis to maintain robustness of the primary endpoint. - Introduced interim analyses, including a pre-specified futility assessment, to allow earlier evaluation and safeguard trial integrity.
    10 Oct 2022
    Protocol Amendment 3 Key Changes: -Updated the dose modification guidance for adverse reactions to align with the sponsor’s core product information for ibrutinib, aiming to reduce serious adverse events and improve tolerability for continued treatment.
    07 Feb 2023
    Protocol Amendment 4 Key Changes: - Removed Part 2 (Discontinuation Analysis Study) to enable extended overall survival (OS) follow-up. - Added an interim OS analysis timed with the Primary PFS Analysis. - Specified a final OS analysis to occur after accrual of additional OS events.
    10 May 2024
    Protocol Amendment 5 Key Changes: - Added definitions for serious adverse reactions (SAR) and suspected unexpected serious adverse reactions (SUSAR), including how the sponsor will report them. - Introduced/updated language on protection of subject-specific information (privacy/data protection). - Added or revised wording to ensure compliance with Good Clinical Practice (GCP), the EU Clinical Trials Regulation (EU‑CTR), and applicable local and global regulatory requirements.

    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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