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    Clinical Trial Results:
    A Phase 3, Randomized Study of Zanubrutinib (BGB-3111) Compared with Ibrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Summary
    EudraCT number
    		 2018-001366-42
    Trial protocol
    		 FR   ES   BE   CZ   GB   SE   NL   IT  
    Global end of trial date
    28 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2025
    First version publication date
    16 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BGB-3111-305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03734016
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ChinaDrugTrials.org: CTR20190098
    Sponsors
    Sponsor organisation name
    BeiGene, Ltd., c/o BeiGene USA, Inc.
    Sponsor organisation address
    1840 Gateway Drive, San Mateo, CA , United States, 94404
    Public contact
    BeiGene Clinical Support, BeiGene, Ltd., 1 877-828-5568, clinicaltrials@beigene.com
    Scientific contact
    BeiGene Clinical Support, BeiGene, Ltd., 1 877-828-5568, clinicaltrials@beigene.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
    28 Feb 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is designed to compare the overall response rate of zanubrutinib versus ibrutinib in participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
    Protection of trial subjects
    This study was conducted in accordance with sponsor procedures, which comply with the principles of Good Clinical Practice (GCP), International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guidelines, the Declaration of Helsinki, and applicable local regulatory requirements. The protocol, any amendments, and informed consent forms were reviewed and approved by the Independent Ethics Committee/Institutional Review Board in conformance with GCP and applicable regulatory requirements. Before a patient was enrolled in the study, he or she was provided with a written informed consent form that complied with GCP. The investigator (or designee) explained to each patient the nature of the study, its purpose, procedures, expected duration, and the benefits and risks involved with study participation. Patients were given the opportunity to ask questions and were informed of their right to withdraw from the study at any time without prejudice. After this explanation and before enrolling in the study, patients or their legal representatives signed 2 copies of the informed consent form (one copy for the patient and the other for filing with the patient’s study records). Informed consent was obtained before any screening or study-specific procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2018
    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: 16
    Country: Number of subjects enrolled
    China: 90
    Country: Number of subjects enrolled
    New Zealand: 42
    Country: Number of subjects enrolled
    Türkiye: 4
    Country: Number of subjects enrolled
    United States: 111
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Poland: 216
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czechia: 58
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 17
    Worldwide total number of subjects
    652
    EEA total number of subjects
    357
    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)
    251
    From 65 to 84 years
    387
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 113 study centers in 15 countries (Australia, Belgium, China, the Czech Republic, France, Germany, Italy, the Netherlands, New Zealand, Poland, Spain, Sweden, Turkey, the United Kingdom, and the United States).

    Pre-assignment
    Screening details
    		 Participants were randomly assigned to one of two treatment groups. Randomization was stratified according to age (< 65 versus ≥ 65 years), geographic region (China vs non-China), refractory status (yes or no), and chromosome 17p deletion or TP53 mutation status (present or absent).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zanubrutinib
    Arm description
    		 Participants received 160 mg zanubrutinib orally twice daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zanubrutinib
    Investigational medicinal product code
    BGB-3111
    Other name
    Brukinsa
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Arm title
    		 Ibrutinib
    Arm description
    		 Participants received ibrutinib 420 mg orally once daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Imbruvica
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day

    Number of subjects in period 1
    		Zanubrutinib Ibrutinib
    Started
    327
    325
    Received Study Drug
    324
    324
    Completed
    0
    0
    Not completed
    327
    325
         Consent withdrawn by subject
    21
    27
         Physician decision
    1
    12
         Sponsor Ended Study
    225
    200
         Death
    69
    83
         Miscellaneous
    5
    1
         Lost to follow-up
    6
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zanubrutinib
    Reporting group description
    		 Participants received 160 mg zanubrutinib orally twice daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.

    Reporting group title
    Ibrutinib
    Reporting group description
    		 Participants received ibrutinib 420 mg orally once daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.

    Reporting group values
    		 Zanubrutinib Ibrutinib Total
    Number of subjects
    		 327 325 652
    Age categorical
    Units: Subjects
        < 65 years
    		 126 125 251
        ≥ 65 years
    		 201 200 401
    Age continuous
    Units: years
        median (full range (min-max))
    		 67.0 (35 to 90) 68.0 (35 to 89) -
    Gender categorical
    Units: Subjects
        Female
    		 114 93 207
        Male
    		 213 232 445
    Race
    Units: Subjects
        Asian
    		 47 44 91
        Native Hawaiian or Other Pacific Islander
    		 3 0 3
        Black or African American
    		 4 2 6
        White
    		 261 265 526
        Other
    		 2 2 4
        Multiple
    		 1 0 1
        Unknown/Not Reported
    		 9 12 21
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 7 13 20
        Not Hispanic or Latino
    		 309 298 607
        Unknown or Not Reported
    		 11 14 25
    Geographic Region
    Units: Subjects
        Asia
    		 49 45 94
        Australia/New Zealand
    		 28 30 58
        Europe
    		 198 191 389
        North America
    		 52 59 111
    Chromosome 17p Deletion (del[17p]) and TP53 Mutation Status
    Deletion 17p is a chromosomal abnormality that occurs when part or all of the short arm of chromosome 17 is lost. The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53) which acts as a tumor suppressor.
    Units: Subjects
        Del(17p) and/or TP53 mutation
    		 75 75 150
        Neither Del(17p) nor TP53 mutation
    		 251 250 501
        Missing
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Zanubrutinib
    Reporting group description
    		 Participants received 160 mg zanubrutinib orally twice daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.

    Reporting group title
    Ibrutinib
    Reporting group description
    		 Participants received ibrutinib 420 mg orally once daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.

    Primary: Overall Response Rate (ORR) Assessed by the Investigator

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    End point title
    		 Overall Response Rate (ORR) Assessed by the Investigator
    End point description
    ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) per investigator assessment. Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL. ORR was analyzed in the Intent to Treat (ITT) Analysis Set which includes all randomized participants.
    End point type
    Primary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    327
    325
    Units: percentage of participants
        number (confidence interval 95%)
    83.5 (79.0 to 87.3)
    74.2 (69.0 to 78.8)
    Statistical analysis title
    		 Non-inferiority Analysis of ORR
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 Stratified Wald test
    Parameter type
    		 Response ratio
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 1.22
    Notes
    [1] - Non-inferiority testing for ORR was performed using a stratified Wald test based on the stratified Mantel-Haenszel response ratio estimate against the non-inferiority margin of 0.8558 on the log scale. Stratification was based on the randomization stratification factors (age, geographic region, refractory status, and 17p deletion and TP53 mutation status).
    Statistical analysis title
    		 Superiority Analysis of ORR
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0035
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - Superiority testing was performed using a 2-sided stratified Cochran-Mantel-Haenszel test stratified by the randomization stratification factors (age, geographic region, refractory status, and 17p deletion and TP53 mutation status).

    Secondary: ORR Assessed by the Independent Review Committee (IRC)

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    End point title
    		 ORR Assessed by the Independent Review Committee (IRC)
    End point description
    ORR is defined as the percentage of participants with a complete response (CR) / complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) assessed by a blinded independent review committee. Overall response was assessed by the IRC for the purpose of regulatory filing with the Food and Drug Administration (FDA). Disease response was assessed in accordance with the 2008 criteria of the International Workshop on CLL (IWCLL), with modification for treatment-related lymphocytosis in participants with CLL and in accordance with the Lugano classification in participants with SLL. ORR was analyzed using the ITT Analysis Set.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    327
    325
    Units: percentage of participants
        number (confidence interval 95%)
    86.2 (82.0 to 89.8)
    75.7 (70.7 to 80.3)
    Statistical analysis title
    		 Non-inferiority Analysis of ORR
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001
    Method
    		 Stratified Wald test
    Parameter type
    		 Response ratio
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 1.22
    Notes
    [3] - Non-inferiority testing for ORR was performed using a stratified Wald test based on the stratified Mantel-Haenszel response ratio estimate against the non-inferiority margin of 0.8558 on the log scale. Stratification was based on the randomization stratification factors (age, geographic region, refractory status, and 17p deletion and TP53 mutation status).
    Statistical analysis title
    		 Superiority Analysis of ORR
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0007
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Superiority testing was performed using a 2-sided stratified Cochran-Mantel-Haenszel test stratified by the randomization stratification factors (age, geographic region, refractory status, and 17p deletion and TP53 mutation status).

    Secondary: Progression-free Survival (PFS) Assessed by the Investigator

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    End point title
    		 Progression-free Survival (PFS) Assessed by the Investigator
    End point description
    PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. PFS was analyzed using the ITT Analysis Set. "99999" indicates values that could not be estimated due to an insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    327
    325
    Units: months
        median (confidence interval 95%)
    99999 (34.3 to 99999)
    34.2 (33.3 to 99999)
    Statistical analysis title
    		 Non-inferiority Analysis of PFS
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.0001
    Method
    		 Stratified Wald test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.86
    Notes
    [5] - Non-inferiority was tested with a non-inferiority margin (hazard ratio) of 1.33 with the use of a stratified Wald test based on the four randomization stratification factors (age, geographic region, refractory status, and 17p deletion and TP53 mutation status).
    Statistical analysis title
    		 Superiority Analysis of PFS
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0024 [6]
    Method
    		 Stratified Log-rank test
    Confidence interval
    Notes
    [6] - Log-rank test stratified by the randomization stratification factors (age, geographic region, refractory status, and 17p deletion and TP53 mutation status)

    Secondary: Progression-free Survival Assessed by the Independent Review Committee

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    End point title
    		 Progression-free Survival Assessed by the Independent Review Committee
    End point description
    PFS is defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. PFS was analyzed using the ITT Analysis Set. "99999" indicates values that could not be estimated due to an insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    327
    325
    Units: months
        median (confidence interval 95%)
    99999 (34.3 to 99999)
    35.0 (33.2 to 44.3)
    Statistical analysis title
    		 Non-inferiority Analysis of PFS per IRC
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [7]
    P-value
    		 < 0.0001
    Method
    		 Stratified Wald test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.86
    Notes
    [7] - Non-inferiority was tested with a non-inferiority margin (hazard ratio) of 1.33 with the use of a stratified Wald test based on the four randomization stratification factors (age, geographic region, refractory status, and 17p deletion and TP53 mutation status).
    Statistical analysis title
    		 Superiority Analysis of PFS per IRC
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.0024
    Method
    		 Stratified Log-rank test
    Confidence interval
    Notes
    [8] - Log-rank test stratified by the randomization stratification factors (age, geographic region, refractory status, and 17p deletion and TP53 mutation status)

    Secondary: Percentage of Participants With Atrial Fibrillation or Atrial Flutter

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    End point title
    		 Percentage of Participants With Atrial Fibrillation or Atrial Flutter
    End point description
    Participants were considered as having an atrial fibrillation/flutter event if they had a treatment-emergent AE of either "atrial fibrillation" or "atrial flutter". The analysis was conducted using the Safety Analysis Set which includes all participants who received any dose of study drug.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    324
    324
    Units: percentage of participants
        number (confidence interval 95%)
    5.2 (3.1 to 8.3)
    13.3 (9.8 to 17.5)
    Statistical analysis title
    		 Analysis of Atrial Fibrillation/Flutter
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    648
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Chi-squared
    Parameter type
    		 Rate Difference
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.4
         upper limit
    		 -3.6

    Secondary: Duration of Response Assessed by the Independent Review Committee

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    End point title
    		 Duration of Response Assessed by the Independent Review Committee
    End point description
    DOR is defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurred first, determined by independent central review. Median DOR was estimated using the Kaplan-Meier method. The analysis was conducted in participants in the ITT Analysis Set with an objective response per the IRC. "99999" indicates values that could not be estimated due to an insufficient number of participants with an event.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    282 [9]
    246 [10]
    Units: months
        median (confidence interval 95%)
    99999 (31.3 to 99999)
    33.9 (32.2 to 41.4)
    Notes
    [9] - Participants with an objective response per IRC
    [10] - Participants with an objective response per IRC
    No statistical analyses for this end point

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

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    End point title
    		 Duration of Response (DOR) Assessed by the Investigator
    End point description
    DOR is defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurred first, determined by investigator assessment. Median DOR was estimated using the Kaplan-Meier method. The analysis was conducted in participants in the ITT Analysis Set with an objective response per the Investigator. "99999" indicates values that could not be estimated due to an insufficient number of participants with an event.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    273 [11]
    241 [12]
    Units: months
        median (confidence interval 95%)
    99999 (31.3 to 99999)
    33.9 (33.9 to 99999)
    Notes
    [11] - Participants with an objective response per the investigator
    [12] - Participants with an objective response per the investigator
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure

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    End point title
    		 Time to Treatment Failure
    End point description
    Time to treatment failure is defined as the time from randomization to discontinuation of study drug due to any reason. Median time to treatment failure was estimated by the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    327
    325
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (34.4 to 99999)
    Statistical analysis title
    		 Analysis of Time to Treatment Failure
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.72

    Secondary: Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee

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    End point title
    		 Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Independent Review Committee
    End point description
    The rate of partial response with lymphocytosis or better is defined as the percentage of participants who achieved a complete response or a complete response with incomplete bone marrow recovery (CR/CRi), nodular partial response, partial response, or partial response with lymphocytosis assessed by the blinded IRC. Disease response was assessed per iwCLL 2008 criteria, with modification for treatment-related lymphocytosis for participants with CLL and per Lugano classification for participants with SLL.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    327
    325
    Units: percentage of participants
        number (confidence interval 95%)
    91.7 (88.2 to 94.5)
    83.1 (78.5 to 87.0)
    No statistical analyses for this end point

    Secondary: Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator

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    End point title
    		 Rate of Partial Response With Lymphocytosis (PR-L) or Higher Assessed by the Investigator
    End point description
    The rate of partial response with lymphocytosis or better is defined as the percentage of participants who achieved a complete response or complete response with incomplete bone marrow recovery (CR/CRi), nodular partial response, partial response, or partial response with lymphocytosis as assessed by the investigator. Disease response was assessed according to the iwCLL 2008 criteria, with modification for treatment-related lymphocytosis for participants with CLL and in accordance with Lugano classification for participants with SLL. Partial response with lymphocytosis: blood lymphocytes decreased < 50% or increased from baseline, and otherwise meeting criteria for PR.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    327
    325
    Units: percentage of participants
        number (confidence interval 95%)
    89.9 (86.1 to 93.0)
    82.5 (77.9 to 86.4)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival is defined as the time from randomization to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. The analysis was conducted in the ITT Analysis Set. "99999" indicates values that could not be estimated due to an insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From randomization to the final efficacy analysis cutoff date of 08 August 2022, median time on follow-up was 29.6 months (maximum of 45.2 months).
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    327
    325
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Analysis of OS
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.11

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL), Physical Functioning and Role Functioning Scores
    End point description
    The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Higher scores in GHS and functional scales indicate better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 24 and 48
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    315 [13]
    313 [14]
    Units: score on a scale
    least squares mean (confidence interval 95%)
        GHS/QoL Scale at Week 24
    8.18 (6.25 to 10.12)
    5.18 (3.20 to 7.17)
        GHS/QoL Scale at Week 48
    7.28 (5.41 to 9.15)
    5.93 (3.97 to 7.89)
        Physical Functioning Scale at Week 24
    6.55 (4.96 to 8.15)
    4.73 (3.08 to 6.38)
        Physical Functioning Scale at Week 48
    5.46 (3.87 to 7.04)
    4.31 (2.65 to 5.97)
        Role Functioning Scale at Week 24
    6.95 (4.85 to 9.06)
    6.32 (4.14 to 8.50)
        Role Functioning Scale at Week 48
    6.81 (4.61 to 9.02)
    5.01 (2.69 to 7.33)
    Notes
    [13] - Participants in the ITT Analysis Set who completed the EORTC QLQ-C30 at Baseline
    [14] - Participants in the ITT Analysis Set who completed the EORTC QLQ-C30 at Baseline
    Statistical analysis title
    		 Analysis of Change in GHS/QOL at Week 24
    Statistical analysis description
    A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0338
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 5.77
    Statistical analysis title
    		 Analysis of Change in GHS/QOL at Week 48
    Statistical analysis description
    A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3304
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.37
         upper limit
    		 4.06
    Statistical analysis title
    		 Analysis of Physical Functioning at Week 24
    Statistical analysis description
    A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1189
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 4.12
    Statistical analysis title
    		 Analysis of Physical Functioning at Week 48
    Statistical analysis description
    A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3274
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 3.44
    Statistical analysis title
    		 Analysis of Role Functioning at Week 24
    Statistical analysis description
    A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6821
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 3.66
    Statistical analysis title
    		 Analysis of Role Functioning at Week 48
    Statistical analysis description
    A linear mixed model for repeated measures (MMRM) includes the repeated measurement of the change from baseline as the dependent variable, and the treatment arm by assessment timepoint interaction, and baseline score as a covariate with an unstructured covariance matrix.
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2701
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 5

    Secondary: Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea

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    End point title
    		 Change From Baseline in EORTC QLQ-C30 Symptom Scales of Fatigue, Nausea and Vomiting, Pain, and Diarrhoea
    End point description
    The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 = Not at all (best) and 4 = Very Much (worst) and 2 global health quality of life (QOL) questions answered on a 7-point scale where 1 = Very poor and 7 = Excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. Lower scores in symptom scales indicate better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 24 and 48
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    315 [15]
    313 [16]
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Fatigue Symptom Scale at Week 24
    -12.54 (-14.47 to -10.60)
    -10.63 (-12.63 to -8.62)
        Fatigue Symptom Scale at Week 48
    -11.13 (-13.19 to -9.08)
    -10.78 (-12.93 to -8.63)
        Nausea and Vomiting Symptom Scale at Week 24
    -1.21 (-2.03 to -0.38)
    -0.92 (-1.77 to -0.07)
        Nausea and Vomiting Symptom Scale at Week 48
    -0.92 (-1.94 to 0.10)
    -0.40 (-1.47 to 0.66)
        Pain Symptom Scale at Week 24
    -5.06 (-7.21 to -2.91)
    -3.63 (-5.85 to -1.42)
        Pain Symptom Scale at Week 48
    -5.18 (-7.38 to -2.97)
    -2.75 (-5.06 to -0.44)
        Diarrhoea Symptom Scale at Week 24
    -2.11 (-3.80 to -0.42)
    -0.52 (-2.27 to 1.22)
        Diarrhoea Symptom Scale at Week 48
    -3.23 (-4.79 to -1.66)
    -1.38 (-3.03 to 0.27)
    Notes
    [15] - Participants in the ITT Analysis Set who completed the EORTC QLQ-C30 at Baseline
    [16] - Participants in the ITT Analysis Set who completed the EORTC QLQ-C30 at Baseline
    Statistical analysis title
    		 Analysis of Change in Fatigue Symptoms at Week 24
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1778
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 0.87
    Statistical analysis title
    		 Analysis of Change in Fatigue Symptoms at Week 48
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8174
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.32
         upper limit
    		 2.62
    Statistical analysis title
    		 Analysis of Nausea and Vomiting Symptom at Week 24
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6294
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.48
         upper limit
    		 0.89
    Statistical analysis title
    		 Analysis of Nausea and Vomiting Symptom at Week 48
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4933
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 0.96
    Statistical analysis title
    		 Analysis of Pain Symptoms at Week 24
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3643
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.51
         upper limit
    		 1.66
    Statistical analysis title
    		 Analysis of Pain Symptoms at Week 48
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1363
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.62
         upper limit
    		 0.77
    Statistical analysis title
    		 Analysis of Diarrhoea Symptoms at Week 24
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2001
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.01
         upper limit
    		 0.84
    Statistical analysis title
    		 Analysis of Diarrhoea Symptoms at Week 48
    Comparison groups
    Zanubrutinib v Ibrutinib
    Number of subjects included in analysis
    628
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1121
    Method
    		 Mixed model for repeated measures (MMRM)
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.12
         upper limit
    		 0.43

    Secondary: Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS)

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    End point title
    		 Change From Baseline in European Quality of Life 5-dimensions 5-levels Health Questionnaire (EQ-5D-5L) Visual Analog Scale (VAS)
    End point description
    The EQ-5D-5L VAS measures a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 24 and 48
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    315 [17]
    315 [18]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 24
    7.92 ( 18.245 )
    3.44 ( 16.972 )
        Week 48
    7.75 ( 18.806 )
    3.92 ( 16.778 )
    Notes
    [17] - Participants with available data at Baseline and each time point. Week 24: N=278; Week 48: N=276
    [18] - Participants with available data at Baseline and each time point. Week 24: N=260; Week 48: N=254
    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 adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose: -Resulted in death. -Was life-threatening. -Required hospitalization or prolongation of existing hospitalization. -Resulted in disability/incapacity. -Resulted in a congenital anomaly/birth defect. -Was considered a significant medical AE by the investigator based on medical judgment. The Safety Analysis Set includes all participants who received any dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days after last dose, up to the end of study data cutoff (28 February 2024); median (range) time on treatment was 41.2 (0.4-59.1) months in the zanubrutinib arm and 37.8 (0.1-60.4) months in the ibrutinib arm.
    End point values
    		 Zanubrutinib Ibrutinib
    Number of subjects analysed
    324
    324
    Units: participants
        Any TEAE
    322
    323
        Serious adverse events
    172
    196
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after last dose, up to the end of study data cutoff (28 February 2024); median (range) time on treatment was 41.2 (0.4-59.1) months in the zanubrutinib arm and 37.8 (0.1-60.4) months in the ibrutinib arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Zanubrutinib
    Reporting group description
    		 Participants received 160 mg zanubrutinib orally twice daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.

    Reporting group title
    Ibrutinib
    Reporting group description
    		 Participants received ibrutinib 420 mg orally once daily until disease progression, intolerable toxicity, initiation of alternative anticancer therapy, investigator/Sponsor decision, need for prohibited medication, study withdrawal, or pregnancy.

    Serious adverse events
    		 Zanubrutinib Ibrutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    172 / 324 (53.09%)
    196 / 324 (60.49%)
         number of deaths (all causes)
    69
    83
         number of deaths resulting from adverse events
    43
    41
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer metastatic
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    2 / 324 (0.62%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atypical fibroxanthoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 324 (0.93%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign lung neoplasm
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm malignant
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Breast cancer
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choroid melanoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chromophobe renal cell carcinoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer recurrent
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucoepidermoid carcinoma of salivary gland
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neuroendocrine carcinoma of the cervix
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oral haemangioma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    4 / 324 (1.23%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (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
    3 / 324 (0.93%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superficial spreading melanoma stage II
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thymoma malignant recurrent
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell cancer of the renal pelvis and ureter
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Varicose vein
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site haematoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 324 (1.23%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 324 (0.62%)
    5 / 324 (1.54%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic organ prolapse
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulva cyst
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    3 / 324 (0.93%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 324 (0.62%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (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 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal obstruction
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary necrosis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         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
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 324 (0.31%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    False positive investigation result
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Traumatic haematoma
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fall
         subjects affected / exposed
    2 / 324 (0.62%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (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
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Traumatic liver injury
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic ulcer
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Bronchogenic cyst
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 324 (0.62%)
    11 / 324 (3.40%)
         occurrences causally related to treatment / all
    1 / 3
    8 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 324 (0.00%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiac failure
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dilated cardiomyopathy
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 324 (0.62%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    2 / 324 (0.62%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 324 (0.31%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cerebrovascular accident
         subjects affected / exposed
    3 / 324 (0.93%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dysarthria
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 324 (1.54%)
    4 / 324 (1.23%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglobulinaemia
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytosis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic haemorrhage
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract nuclear
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryostenosis acquired
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital oedema
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 324 (0.00%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated umbilical hernia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 324 (0.31%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric panniculitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Noninfective sialoadenitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal food impaction
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (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
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 324 (0.31%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bladder dysplasia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         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
    Chondrocalcinosis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc compression
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acinetobacter bacteraemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 324 (0.31%)
    3 / 324 (0.93%)
         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 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    COVID-19
         subjects affected / exposed
    28 / 324 (8.64%)
    20 / 324 (6.17%)
         occurrences causally related to treatment / all
    5 / 35
    1 / 27
         deaths causally related to treatment / all
    0 / 7
    0 / 7
    COVID-19 pneumonia
         subjects affected / exposed
    33 / 324 (10.19%)
    22 / 324 (6.79%)
         occurrences causally related to treatment / all
    7 / 44
    11 / 35
         deaths causally related to treatment / all
    2 / 8
    3 / 8
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 324 (0.93%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dacryocystitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalomyelitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis viral
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal abscess central nervous system
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis fungal
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis bacterial
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infective tenosynovitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 324 (0.31%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis bacterial
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 324 (0.93%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia cryptococcal
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 324 (0.62%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    24 / 324 (7.41%)
    33 / 324 (10.19%)
         occurrences causally related to treatment / all
    12 / 39
    28 / 47
         deaths causally related to treatment / all
    2 / 5
    2 / 4
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 324 (0.31%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 324 (1.23%)
    3 / 324 (0.93%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Sinusitis
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    2 / 324 (0.62%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sporotrichosis
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 324 (0.31%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tick-borne viral encephalitis
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         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
    2 / 324 (0.62%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 324 (2.16%)
    10 / 324 (3.09%)
         occurrences causally related to treatment / all
    5 / 8
    2 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 324 (0.62%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (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 / 324 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 324 (0.00%)
    2 / 324 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Water intoxication
         subjects affected / exposed
    1 / 324 (0.31%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Zanubrutinib Ibrutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    310 / 324 (95.68%)
    314 / 324 (96.91%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    14 / 324 (4.32%)
    15 / 324 (4.63%)
         occurrences all number
    21
    23
    Basal cell carcinoma
         subjects affected / exposed
    11 / 324 (3.40%)
    17 / 324 (5.25%)
         occurrences all number
    18
    40
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 324 (0.93%)
    11 / 324 (3.40%)
         occurrences all number
    3
    11
    Hypertension
         subjects affected / exposed
    82 / 324 (25.31%)
    74 / 324 (22.84%)
         occurrences all number
    154
    155
    Haematoma
         subjects affected / exposed
    17 / 324 (5.25%)
    14 / 324 (4.32%)
         occurrences all number
    23
    17
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    21 / 324 (6.48%)
    13 / 324 (4.01%)
         occurrences all number
    30
    16
    Chest pain
         subjects affected / exposed
    2 / 324 (0.62%)
    10 / 324 (3.09%)
         occurrences all number
    2
    10
    Fatigue
         subjects affected / exposed
    36 / 324 (11.11%)
    49 / 324 (15.12%)
         occurrences all number
    43
    57
    Influenza like illness
         subjects affected / exposed
    10 / 324 (3.09%)
    7 / 324 (2.16%)
         occurrences all number
    28
    10
    Oedema peripheral
         subjects affected / exposed
    24 / 324 (7.41%)
    24 / 324 (7.41%)
         occurrences all number
    27
    31
    Peripheral swelling
         subjects affected / exposed
    14 / 324 (4.32%)
    26 / 324 (8.02%)
         occurrences all number
    15
    30
    Pyrexia
         subjects affected / exposed
    35 / 324 (10.80%)
    37 / 324 (11.42%)
         occurrences all number
    44
    50
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    12 / 324 (3.70%)
    12 / 324 (3.70%)
         occurrences all number
    13
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    46 / 324 (14.20%)
    43 / 324 (13.27%)
         occurrences all number
    59
    55
    Oropharyngeal pain
         subjects affected / exposed
    12 / 324 (3.70%)
    10 / 324 (3.09%)
         occurrences all number
    14
    10
    Dyspnoea
         subjects affected / exposed
    16 / 324 (4.94%)
    13 / 324 (4.01%)
         occurrences all number
    19
    16
    Productive cough
         subjects affected / exposed
    17 / 324 (5.25%)
    11 / 324 (3.40%)
         occurrences all number
    18
    12
    Epistaxis
         subjects affected / exposed
    27 / 324 (8.33%)
    24 / 324 (7.41%)
         occurrences all number
    46
    45
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    25 / 324 (7.72%)
    26 / 324 (8.02%)
         occurrences all number
    27
    28
    Anxiety
         subjects affected / exposed
    11 / 324 (3.40%)
    14 / 324 (4.32%)
         occurrences all number
    11
    22
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 324 (3.70%)
    20 / 324 (6.17%)
         occurrences all number
    20
    29
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 324 (2.16%)
    16 / 324 (4.94%)
         occurrences all number
    12
    23
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 324 (1.54%)
    10 / 324 (3.09%)
         occurrences all number
    8
    15
    Blood bilirubin increased
         subjects affected / exposed
    8 / 324 (2.47%)
    11 / 324 (3.40%)
         occurrences all number
    14
    20
    Blood creatinine increased
         subjects affected / exposed
    18 / 324 (5.56%)
    12 / 324 (3.70%)
         occurrences all number
    36
    21
    Blood pressure increased
         subjects affected / exposed
    6 / 324 (1.85%)
    12 / 324 (3.70%)
         occurrences all number
    19
    27
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    10 / 324 (3.09%)
    11 / 324 (3.40%)
         occurrences all number
    14
    16
    Neutrophil count decreased
         subjects affected / exposed
    26 / 324 (8.02%)
    24 / 324 (7.41%)
         occurrences all number
    75
    69
    Platelet count decreased
         subjects affected / exposed
    11 / 324 (3.40%)
    20 / 324 (6.17%)
         occurrences all number
    40
    47
    Weight decreased
         subjects affected / exposed
    22 / 324 (6.79%)
    14 / 324 (4.32%)
         occurrences all number
    27
    20
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    49 / 324 (15.12%)
    38 / 324 (11.73%)
         occurrences all number
    62
    44
    Fall
         subjects affected / exposed
    16 / 324 (4.94%)
    23 / 324 (7.10%)
         occurrences all number
    19
    27
    Skin laceration
         subjects affected / exposed
    12 / 324 (3.70%)
    6 / 324 (1.85%)
         occurrences all number
    12
    6
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    22 / 324 (6.79%)
    45 / 324 (13.89%)
         occurrences all number
    27
    69
    Sinus bradycardia
         subjects affected / exposed
    8 / 324 (2.47%)
    12 / 324 (3.70%)
         occurrences all number
    10
    15
    Palpitations
         subjects affected / exposed
    13 / 324 (4.01%)
    14 / 324 (4.32%)
         occurrences all number
    19
    16
    Cardiac failure
         subjects affected / exposed
    6 / 324 (1.85%)
    10 / 324 (3.09%)
         occurrences all number
    7
    10
    Nervous system disorders
    Syncope
         subjects affected / exposed
    11 / 324 (3.40%)
    8 / 324 (2.47%)
         occurrences all number
    14
    9
    Paraesthesia
         subjects affected / exposed
    3 / 324 (0.93%)
    10 / 324 (3.09%)
         occurrences all number
    3
    12
    Headache
         subjects affected / exposed
    29 / 324 (8.95%)
    35 / 324 (10.80%)
         occurrences all number
    36
    46
    Dizziness
         subjects affected / exposed
    32 / 324 (9.88%)
    26 / 324 (8.02%)
         occurrences all number
    39
    28
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    53 / 324 (16.36%)
    56 / 324 (17.28%)
         occurrences all number
    82
    122
    Thrombocytopenia
         subjects affected / exposed
    34 / 324 (10.49%)
    35 / 324 (10.80%)
         occurrences all number
    90
    92
    Neutropenia
         subjects affected / exposed
    81 / 324 (25.00%)
    73 / 324 (22.53%)
         occurrences all number
    195
    162
    Iron deficiency anaemia
         subjects affected / exposed
    6 / 324 (1.85%)
    11 / 324 (3.40%)
         occurrences all number
    10
    13
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    11 / 324 (3.40%)
    6 / 324 (1.85%)
         occurrences all number
    11
    6
    Eye disorders
    Cataract
         subjects affected / exposed
    18 / 324 (5.56%)
    10 / 324 (3.09%)
         occurrences all number
    22
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 324 (6.17%)
    21 / 324 (6.48%)
         occurrences all number
    32
    23
    Abdominal pain upper
         subjects affected / exposed
    14 / 324 (4.32%)
    7 / 324 (2.16%)
         occurrences all number
    18
    7
    Constipation
         subjects affected / exposed
    24 / 324 (7.41%)
    27 / 324 (8.33%)
         occurrences all number
    30
    31
    Diarrhoea
         subjects affected / exposed
    61 / 324 (18.83%)
    83 / 324 (25.62%)
         occurrences all number
    106
    158
    Dyspepsia
         subjects affected / exposed
    25 / 324 (7.72%)
    23 / 324 (7.10%)
         occurrences all number
    27
    32
    Gastrooesophageal reflux disease
         subjects affected / exposed
    15 / 324 (4.63%)
    17 / 324 (5.25%)
         occurrences all number
    22
    19
    Nausea
         subjects affected / exposed
    29 / 324 (8.95%)
    32 / 324 (9.88%)
         occurrences all number
    47
    38
    Stomatitis
         subjects affected / exposed
    11 / 324 (3.40%)
    11 / 324 (3.40%)
         occurrences all number
    17
    18
    Toothache
         subjects affected / exposed
    10 / 324 (3.09%)
    6 / 324 (1.85%)
         occurrences all number
    11
    9
    Vomiting
         subjects affected / exposed
    22 / 324 (6.79%)
    29 / 324 (8.95%)
         occurrences all number
    25
    35
    Mouth ulceration
         subjects affected / exposed
    5 / 324 (1.54%)
    10 / 324 (3.09%)
         occurrences all number
    6
    11
    Skin and subcutaneous tissue disorders
    Skin haemorrhage
         subjects affected / exposed
    8 / 324 (2.47%)
    12 / 324 (3.70%)
         occurrences all number
    12
    13
    Rash maculo-papular
         subjects affected / exposed
    12 / 324 (3.70%)
    7 / 324 (2.16%)
         occurrences all number
    15
    10
    Rash
         subjects affected / exposed
    38 / 324 (11.73%)
    44 / 324 (13.58%)
         occurrences all number
    69
    58
    Pruritus
         subjects affected / exposed
    24 / 324 (7.41%)
    9 / 324 (2.78%)
         occurrences all number
    32
    10
    Petechiae
         subjects affected / exposed
    32 / 324 (9.88%)
    19 / 324 (5.86%)
         occurrences all number
    41
    19
    Erythema
         subjects affected / exposed
    11 / 324 (3.40%)
    9 / 324 (2.78%)
         occurrences all number
    11
    10
    Ecchymosis
         subjects affected / exposed
    5 / 324 (1.54%)
    11 / 324 (3.40%)
         occurrences all number
    5
    12
    Actinic keratosis
         subjects affected / exposed
    8 / 324 (2.47%)
    12 / 324 (3.70%)
         occurrences all number
    16
    15
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    18 / 324 (5.56%)
    13 / 324 (4.01%)
         occurrences all number
    23
    20
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    26 / 324 (8.02%)
    26 / 324 (8.02%)
         occurrences all number
    30
    30
    Osteoarthritis
         subjects affected / exposed
    4 / 324 (1.23%)
    12 / 324 (3.70%)
         occurrences all number
    5
    14
    Myalgia
         subjects affected / exposed
    11 / 324 (3.40%)
    14 / 324 (4.32%)
         occurrences all number
    13
    14
    Muscle spasms
         subjects affected / exposed
    13 / 324 (4.01%)
    42 / 324 (12.96%)
         occurrences all number
    18
    51
    Arthralgia
         subjects affected / exposed
    54 / 324 (16.67%)
    63 / 324 (19.44%)
         occurrences all number
    69
    85
    Back pain
         subjects affected / exposed
    26 / 324 (8.02%)
    26 / 324 (8.02%)
         occurrences all number
    26
    30
    Joint swelling
         subjects affected / exposed
    10 / 324 (3.09%)
    10 / 324 (3.09%)
         occurrences all number
    10
    12
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    13 / 324 (4.01%)
    15 / 324 (4.63%)
         occurrences all number
    18
    20
    Bronchitis
         subjects affected / exposed
    19 / 324 (5.86%)
    26 / 324 (8.02%)
         occurrences all number
    22
    34
    COVID-19
         subjects affected / exposed
    121 / 324 (37.35%)
    84 / 324 (25.93%)
         occurrences all number
    163
    105
    Cellulitis
         subjects affected / exposed
    12 / 324 (3.70%)
    13 / 324 (4.01%)
         occurrences all number
    15
    16
    Conjunctivitis
         subjects affected / exposed
    7 / 324 (2.16%)
    15 / 324 (4.63%)
         occurrences all number
    10
    20
    Ear infection
         subjects affected / exposed
    10 / 324 (3.09%)
    4 / 324 (1.23%)
         occurrences all number
    12
    5
    Gastroenteritis
         subjects affected / exposed
    10 / 324 (3.09%)
    6 / 324 (1.85%)
         occurrences all number
    10
    6
    Herpes zoster
         subjects affected / exposed
    11 / 324 (3.40%)
    10 / 324 (3.09%)
         occurrences all number
    12
    14
    Lower respiratory tract infection
         subjects affected / exposed
    12 / 324 (3.70%)
    12 / 324 (3.70%)
         occurrences all number
    16
    14
    Nasopharyngitis
         subjects affected / exposed
    20 / 324 (6.17%)
    16 / 324 (4.94%)
         occurrences all number
    26
    23
    Oral herpes
         subjects affected / exposed
    4 / 324 (1.23%)
    13 / 324 (4.01%)
         occurrences all number
    9
    17
    Paronychia
         subjects affected / exposed
    5 / 324 (1.54%)
    11 / 324 (3.40%)
         occurrences all number
    6
    11
    Pharyngitis
         subjects affected / exposed
    6 / 324 (1.85%)
    12 / 324 (3.70%)
         occurrences all number
    8
    18
    Pneumonia
         subjects affected / exposed
    33 / 324 (10.19%)
    37 / 324 (11.42%)
         occurrences all number
    47
    57
    Respiratory tract infection
         subjects affected / exposed
    16 / 324 (4.94%)
    7 / 324 (2.16%)
         occurrences all number
    20
    8
    Rhinitis
         subjects affected / exposed
    10 / 324 (3.09%)
    10 / 324 (3.09%)
         occurrences all number
    11
    11
    Sinusitis
         subjects affected / exposed
    20 / 324 (6.17%)
    16 / 324 (4.94%)
         occurrences all number
    26
    19
    Skin infection
         subjects affected / exposed
    7 / 324 (2.16%)
    13 / 324 (4.01%)
         occurrences all number
    8
    16
    Upper respiratory tract infection
         subjects affected / exposed
    95 / 324 (29.32%)
    64 / 324 (19.75%)
         occurrences all number
    155
    105
    Urinary tract infection
         subjects affected / exposed
    35 / 324 (10.80%)
    31 / 324 (9.57%)
         occurrences all number
    68
    58
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 324 (3.70%)
    22 / 324 (6.79%)
         occurrences all number
    12
    23
    Gout
         subjects affected / exposed
    4 / 324 (1.23%)
    10 / 324 (3.09%)
         occurrences all number
    10
    16
    Hyperglycaemia
         subjects affected / exposed
    13 / 324 (4.01%)
    8 / 324 (2.47%)
         occurrences all number
    21
    8
    Hyperuricaemia
         subjects affected / exposed
    16 / 324 (4.94%)
    22 / 324 (6.79%)
         occurrences all number
    37
    37
    Hypokalaemia
         subjects affected / exposed
    24 / 324 (7.41%)
    24 / 324 (7.41%)
         occurrences all number
    39
    39
    Hyponatraemia
         subjects affected / exposed
    10 / 324 (3.09%)
    8 / 324 (2.47%)
         occurrences all number
    18
    13
    Type 2 diabetes mellitus
         subjects affected / exposed
    14 / 324 (4.32%)
    3 / 324 (0.93%)
         occurrences all number
    15
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Aug 2018
    Key changes to the conduct of the study implemented with Amendment 1 were as follows: • Revised the inclusion criterion 9c: increased the upper limit of serum bilirubin to 3.0. • Revised exclusion criterion 11a of HBV reactivation monitoring. • Initial confirmation of progressive disease assessed by CT was sufficient for patients with SLL.
    29 Aug 2019
    Key changes to the conduct of the study implemented with Amendment 2 were as follows: • Updated background information of zanubrutinib, including nonclinical data, clinical pharmacology, preliminary efficacy and safety data. • Added “ORR determined by investigator assessment” as one of the secondary objectives and endpoints. • Revised exploratory objectives and endpoints: included MRD as one of the exploratory endpoints. • Updated study duration from 7 years to 60 months. • Updated study drug access at study closure to clarify patients who benefit from zanubrutinib or ibrutinib may enroll in Zanubrutinib Long-Term Extension Study. • Revision of inclusion criteria. • Revision of exclusion criteria. • Added that patients must sign an informed consent form before any screening procedures are conducted. • Revision of Safety Follow-up Visit to End-of-Treatment Visit. Clarified the separation of Long-term Follow-up and Survival follow-up throughout the document. • Revised efficacy assessments including primary endpoint. • Revised CT assessment. • Revised bone marrow examination. • Added new optional assessment of QoL, activity, and corresponding sections to protocol. • Added that laboratory assessments may be done with either central or local laboratory; same should be used throughout the study. The contents of applicable laboratory tests were revised accordingly. • Added HIV testing. • Added assessment of del(17p) and cytogenetics, MRD, TP53 mutations and other molecular analysis. • Added section of future research (optional). • Updated information of ibrutinib for administration, dose reduction/modification per local labeling. • Revised guidelines to follow for dose interruption or modification of zanubrutinib. • Added toxicity management recommendations. • Updated information for serious adverse events for reporting and record. • Deleted the appendix of medications known to prolong QT interval.
    31 Jan 2020
    Key changes to the conduct of the study implemented with Amendment 3 were as follows: • Increased the sample size from approximately 400 patients to approximately 600 patients. • Updated study duration to approximately 51 months. • Clarified that the CT or MRI would be performed as specified per the Schedule of Assessments, independent of possible study drug hold. • Clarified that samples taken at progression leading to permanent study drug discontinuation would be used for the assessment of relevant BTK pathway genes. • Added information on warnings and precautions for zanubrutinib. • Revised zanubrutinib dose reduction for nonhematologic toxicity. • Revised the summary of tumor lysis syndrome events in clinical studies for permitted medications. • Revised the summary for the primary endpoint (ORR) analysis to state that ORR was assessed by investigator, with assessment by independent central review performed to support the primary analysis and as the basis of regulatory decisions (in the United States). • Revised the summary for the key secondary endpoint (PFS) analyses to state that PFS was assessed by investigator, with assessment by independent central review performed to support the key secondary endpoint analysis and as the basis of regulatory decisions (in the United States). • Updated the noninferiority and superiority testing analysis summary for the primary endpoint (ORR). • Updated analysis summary for key secondary endpoint (PFS) to remove the interim analysis and state that a single analysis would be performed. • Deleted summary of planned sensitivity analyses for the primary efficacy endpoint (ORR) and the key secondary endpoint (PFS). • Added to the note of Appendix 2 and Appendix 3 that patient may continue study treatment post first assessed PD due to drug hold if it was perceived that the patient would benefit from continued treatment.
    03 Apr 2023
    Key changes to the conduct of the study implemented with Amendment 4 were as follows: • Added “Demographic factors such as age, gender, race, and ethnicity could influence the effects (safety and efficacy) of medicines and the risk/benefit assessment in different populations. Race and ethnicity data are collected in accordance with International Council for Harmonisation (ICH) guidance (ICH E5 1998, ICH E17 2017) adopted by the European Medicines Agency (EMA) and US FDA, to understand whether race/ethnicity could influence the PK, safety, and/or efficacy of the study drug. For example, population PK analysis is a well-established, quantitative method that can quantify and explain the variability in drug concentrations among patients. Such variability can be attributed to intrinsic factors (eg, body weight, age, gender, race/ethnicity), or to extrinsic factors (eg, concomitant medications), and can lead to clinically relevant changes in drug concentrations that require a change in the dose or dosing regimen. Results from race/ethnicity and other demographic analyses will be incorporated into drug product labeling to provide guidance on safety and efficacy variations (if any) linked to certain populations (eg, race or ethnic group) as well as any potential dose adjustment needed for those populations. Therefore, collecting race/ethnicity data in the study is essential to understand whether race/ethnicity could influence the PK, safety, and/or efficacy.” • Added Section 5.6.5 Survival Status language. • Added schedule and window for survival follow-up of every 24 weeks +/- 14 days.

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

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

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