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    Clinical Trial Results:
    A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab

    Summary
    EudraCT number
    2013-002110-12
    Trial protocol
    CZ   SE   BE   GB   AT   IT   FR   NL   HU   DK   DE   ES   PL  
    Global end of trial date
    03 Aug 2022

    Results information
    Results version number
    v3(current)
    This version publication date
    28 Oct 2023
    First version publication date
    19 May 2018
    Other versions
    v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    GO28667
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02005471
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.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
    03 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of venetoclax (V) and rituximab (R) compared with bendamustine (B) and rituximab in participants with relapsed or refractory chronic lymphocytic leukemia (CLL) as measured by investigator-assessed progression-free survival (PFS)
    Protection of trial subjects
    This study was conducted in full conformance with the International Council on Harmonization (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). The study complied with U.S. FDA regulations and applicable local, state, and federal laws. In the EU/EEA the study complied with the EU Clinical Trial Directive (2001/20/EC).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Mar 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Australia: 73
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    Czechia: 44
    Country: Number of subjects enrolled
    Hungary: 26
    Country: Number of subjects enrolled
    Poland: 46
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Sweden: 3
    Worldwide total number of subjects
    389
    EEA total number of subjects
    237
    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)
    186
    From 65 to 84 years
    201
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    A total 389 participants took part in the study across 109 investigative sites in 20 countries from 17 March 2014 to 03 August 2022. The trial consisted of a main study and an optional Retreatment/Crossover (R/C) sub study.

    Pre-assignment
    Screening details
    Of the 389 participants enrolled 7 participants in the bendamustine + rituximab (BR) arm did not receive a valid dose of study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bendamustine + Rituximab
    Arm description
    Participants received bendamustine at a dose of 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine was administered at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles.

    Arm title
    Venetoclax + Rituximab
    Arm description
    Participants were initially placed on a venetoclax ramp-up period of 5 weeks and received an initial dose of 20 mg via tablet orally once daily (QD) for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg, orally, QD. Participants continued receiving venetoclax at a dose of 400 mg, orally, QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    GDC-0199, ABT-199
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Venetoclax was administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during 4-5 weeks ramp-up period. Venetoclax was continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first.

    Number of subjects in period 1
    Bendamustine + Rituximab Venetoclax + Rituximab
    Started
    195
    194
    Safety evaluable (SE) population
    188
    194
    Completed
    71
    118
    Not completed
    124
    76
         Physician decision
    3
    1
         Consent withdrawn by subject
    26
    11
         Adverse Event
    -
    1
         Death
    83
    52
         Randomized but not Dosed
    8
    -
         Lost to follow-up
    4
    5
         Reason not Specified
    -
    6
    Period 2
    Period 2 title
    Re-treatment/Crossover (R/C) Substudy
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bendamustine + Rituximab Crossover Substudy
    Arm description
    Participants who entered the crossover substudy had a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, participants received 6 cycles of rituximab, 375 mg/m^2, as IV infusion on the Day 1 of each 28-day cycle. Participants who did not progress following the completion of the 6 cycles continued to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 crossover Day 1 of the substudy.
    Arm type
    Experimental

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    GDC-0199, ABT-199
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Venetoclax was administered at an initial dose of 20 mg via tablet orally QD, incremented weekly to reach the target dose of 400 mg during 5 weeks ramp-up period. Venetoclax was continued at 400 mg QD Day 1 of Cycle 1 of substudy up to PD or 2 years, whichever occurred first.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered at a dose of 375 mg/m^2, single IV infusion for 6 cycles on the first day of each 28-day cycle.

    Arm title
    Venetoclax + Rituximab Re-Treatment Substudy
    Arm description
    Participants who entered the re-treatment substudy had a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, participants received 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants who did not progress following the completion of the 6 cycles continued to receive venetoclax monotherapy until disease progression or for a maximum of 2 year from Cycle 1 re-treatment Day 1 of the substudy.
    Arm type
    Experimental

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    GDC-0199, ABT-199
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Venetoclax was administered at an initial dose of 20 mg via tablet orally QD, incremented weekly to reach the target dose of 400 mg during 5 weeks ramp-up period. Venetoclax was continued at 400 mg QD Day 1 of Cycle 1 of substudy up to PD or 2 years, whichever occurred first.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was administered at a dose of 375 mg/m^2, single IV infusion for 6 cycles on the first day of each 28-day cycle.

    Number of subjects in period 2 [1]
    Bendamustine + Rituximab Crossover Substudy Venetoclax + Rituximab Re-Treatment Substudy
    Started
    9
    25
    Completed
    7
    15
    Not completed
    2
    10
         Consent withdrawn by subject
    -
    1
         Death
    1
    8
         Lost to follow-up
    1
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 9 participants from BR arm and 25 participants from VR arm entered R/C substudy.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bendamustine + Rituximab
    Reporting group description
    Participants received bendamustine at a dose of 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

    Reporting group title
    Venetoclax + Rituximab
    Reporting group description
    Participants were initially placed on a venetoclax ramp-up period of 5 weeks and received an initial dose of 20 mg via tablet orally once daily (QD) for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg, orally, QD. Participants continued receiving venetoclax at a dose of 400 mg, orally, QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

    Reporting group values
    Bendamustine + Rituximab Venetoclax + Rituximab Total
    Number of subjects
    195 194 389
    Age Categorical
    Units: Subjects
    Age Continuous
    Intent-to-treat (ITT) population, included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    Units: years
        arithmetic mean (standard deviation)
    64.4 ± 9.6 63.9 ± 10.5 -
    Gender Categorical
    Units: Subjects
        Female
    44 58 102
        Male
    151 136 287

    End points

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    End points reporting groups
    Reporting group title
    Bendamustine + Rituximab
    Reporting group description
    Participants received bendamustine at a dose of 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

    Reporting group title
    Venetoclax + Rituximab
    Reporting group description
    Participants were initially placed on a venetoclax ramp-up period of 5 weeks and received an initial dose of 20 mg via tablet orally once daily (QD) for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg, orally, QD. Participants continued receiving venetoclax at a dose of 400 mg, orally, QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.
    Reporting group title
    Bendamustine + Rituximab Crossover Substudy
    Reporting group description
    Participants who entered the crossover substudy had a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, participants received 6 cycles of rituximab, 375 mg/m^2, as IV infusion on the Day 1 of each 28-day cycle. Participants who did not progress following the completion of the 6 cycles continued to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 crossover Day 1 of the substudy.

    Reporting group title
    Venetoclax + Rituximab Re-Treatment Substudy
    Reporting group description
    Participants who entered the re-treatment substudy had a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, participants received 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants who did not progress following the completion of the 6 cycles continued to receive venetoclax monotherapy until disease progression or for a maximum of 2 year from Cycle 1 re-treatment Day 1 of the substudy.

    Subject analysis set title
    Bendamustine + Rituximab 17p Del. Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by Fluorescence in-situ Hybridization (FISH) test were included.

    Subject analysis set title
    Venetoclax + Rituximab 17p Del. Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6. Only participants with 17p deletion as identified by FISH test were included.

    Primary: Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

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    End point title
    Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death [1]
    End point description
    Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (greater than [>] 1.5 centimeters [cm]); unequivocal progression of non-target lesion; an increase of greater than or equal to (>/=) 50 percent (%) compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000 per microliter (mcL), or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 gram per deciliter (g/dL) or to less than [<] 10 g/dL. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Primary
    End point timeframe
    Baseline up to PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be analyzed for this endpoint.
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: percentage of participants
        number (not applicable)
    88.7
    70.1
    No statistical analyses for this end point

    Primary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines

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    End point title
    PFS as Assessed by the Investigator Using Standard iwCLL Guidelines
    End point description
    PFS= time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet/neutrophil count, hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Primary
    End point timeframe
    Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195 [2]
    194
    Units: months
        median (confidence interval 95%)
    17.0 (15.5 to 21.7)
    54.7 (52.3 to 59.9)
    Notes
    [2] - Analysis was performed on ITT population.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    0.31
    Notes
    [3] - Hazard ratio was estimated by Cox regression model.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    0.29
    Notes
    [4] - Hazard ratio was estimated by Cox regression model.

    Secondary: Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

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    End point title
    Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines
    End point description
    Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death, whichever occurred first (up to approximately 3 years)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: percentage of participants
        number (not applicable)
    54.4
    18.0
    No statistical analyses for this end point

    Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines

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    End point title
    PFS as Assessed by the IRC Using Standard iwCLL Guidelines
    End point description
    PFS= time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet/neutrophil count, hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death, whichever occurred first (up to approximately 3 years)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195 [5]
    194 [6]
    Units: months
        median (confidence interval 95%)
    18.1 (15.8 to 22.3)
    99999 (99999 to 99999)
    Notes
    [5] - Analysis was performed on ITT population.
    [6] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.13
         upper limit
    0.28
    Notes
    [7] - Hazard ratio was estimated by Cox regression model.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.14
         upper limit
    0.3
    Notes
    [8] - Hazard ratio was estimated by Cox regression model.

    Secondary: Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence in-situ Hybridization (FISH) Test

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    End point title
    Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence in-situ Hybridization (FISH) Test
    End point description
    Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab 17p Del. Population Venetoclax + Rituximab 17p Del. Population
    Number of subjects analysed
    46
    46
    Units: percentage of participants
        number (not applicable)
    80.4
    80.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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    End point title
    Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test
    End point description
    Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death, whichever occurred first (up to approximately 3 years)
    End point values
    Bendamustine + Rituximab 17p Del. Population Venetoclax + Rituximab 17p Del. Population
    Number of subjects analysed
    46
    46
    Units: percentage of participants
        number (not applicable)
    47.8
    19.6
    No statistical analyses for this end point

    Secondary: PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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    End point title
    PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test
    End point description
    PFS = time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab 17p Del. Population Venetoclax + Rituximab 17p Del. Population
    Number of subjects analysed
    46 [9]
    46
    Units: months
        median (confidence interval 95%)
    15.4 (10.0 to 21.0)
    47.9 (37.4 to 59.9)
    Notes
    [9] - Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.22
         upper limit
    0.56
    Notes
    [10] - Hazard ratio was estimated by Cox regression model.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis; Stratification factor: geographic region.
    Comparison groups
    Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    0.57
    Notes
    [11] - Hazard ratio was estimated by Cox regression model.

    Secondary: PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

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    End point title
    PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test
    End point description
    PFS = time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD or death, whichever occurred first (up to approximately 3 years)
    End point values
    Bendamustine + Rituximab 17p Del. Population Venetoclax + Rituximab 17p Del. Population
    Number of subjects analysed
    46 [12]
    46 [13]
    Units: months
        median (confidence interval 95%)
    16.1 (13.6 to 22.3)
    99999 (27.6 to 99999)
    Notes
    [12] - Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    [13] - ‘99999’ signifies that data could not be estimated due to low number of participants with an event.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis; Stratification factor: geographic region.
    Comparison groups
    Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.49
    Notes
    [14] - Hazard ratio was estimated by Cox regression model.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Bendamustine + Rituximab 17p Del. Population v Venetoclax + Rituximab 17p Del. Population
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.46
    Notes
    [15] - Hazard ratio was estimated by Cox regression model.

    Secondary: Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

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    End point title
    Percentage of Participants With Best Overall Response of Complete Response (CR), CR with Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines
    End point description
    Response per investigator per iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. ITT population = all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 8 years 5 months
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195 [16]
    194 [17]
    Units: percentage of participants
    number (confidence interval 95%)
        CR
    8.2 (4.76 to 12.98)
    26.3 (20.24 to 33.07)
        CRi
    0.5 (0.01 to 2.82)
    1.5 (0.32 to 4.45)
        nPR
    6.2 (3.22 to 10.50)
    3.6 (1.46 to 7.29)
        PR
    52.8 (45.56 to 59.99)
    61.9 (54.62 to 68.72)
    Notes
    [16] - Analysis was performed on ITT population.
    [17] - Participants without post-baseline response assessment were considered as non-responders.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    7.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.97
         upper limit
    15.37
    Notes
    [18] - Odds Ratio (OR) was estimated using logistic regression model. The 95% CI was computed using Wald test.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    25.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.88
         upper limit
    33.33
    Notes
    [19] - 95% CI for rates were constructed using Pearson- Clopper method. 95% CI for difference in rates were constructed using Anderson-Hauck method.

    Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

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    End point title
    Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines
    End point description
    Response per investigator according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. ITT population = all randomized participants.
    End point type
    Secondary
    End point timeframe
    End of combination treatment response (EoCTR) visit (8 to 12 weeks after Cycle [C] 6 Day [1]); Cycle length = 28 days
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195 [20]
    194 [21]
    Units: percentage of participants
        number (confidence interval 95%)
    63.1 (55.89 to 69.86)
    88.1 (82.74 to 92.33)
    Notes
    [20] - Analysis was performed on ITT population.
    [21] - Participants without post-baseline response assessment were considered as non-responders.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    25.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.63
         upper limit
    33.51
    Notes
    [22] - The 95% CI was computed using Anderson-Hauck method.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.68
         upper limit
    7.88
    Notes
    [23] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.

    Secondary: Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

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    End point title
    Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines
    End point description
    Response per IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. ITT population = all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to last FUV (up to approximately 3 years)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195 [24]
    194 [25]
    Units: percentage of participants
        number (confidence interval 95%)
    67.7 (60.64 to 74.20)
    93.3 (88.81 to 96.38)
    Notes
    [24] - Analysis was performed on ITT population.
    [25] - Participants without post-baseline response assessment were considered as non-responders.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    7.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.97
         upper limit
    15.37
    Notes
    [26] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    25.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.88
         upper limit
    33.33
    Notes
    [27] - 95% CI for rates were constructed using Pearson- Clopper method. 95% CI for difference in rates were constructed using Anderson-Hauck method.

    Secondary: Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

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    End point title
    Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at end of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines
    End point description
    Response per IRC according to the iwCLL guidelines and was confirmed by repeat assessment >/=4 weeks after initial documentation. CR: peripheral blood lymphocytes <4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with <30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: >/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils >1500/mcL, platelets >100000/mcL, hemoglobin >11.0 g/dL or >/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. ITT population = all randomized participants.
    End point type
    Secondary
    End point timeframe
    EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195 [28]
    194 [29]
    Units: percentage of participants
        number (confidence interval 95%)
    62.6 (55.37 to 69.37)
    87.1 (81.57 to 91.48)
    Notes
    [28] - Analysis was performed on ITT population.
    [29] - Participants without post-baseline response assessment were considered as non-responders.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.68
         upper limit
    7.85
    Notes
    [30] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference in Response Rates
    Point estimate
    24.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16
         upper limit
    33.1
    Notes
    [31] - The 95% CI was computed using Anderson-Hauck method.

    Secondary: Percentage of Participants Who Died

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    End point title
    Percentage of Participants Who Died
    End point description
    Percentage of participants who died from any cause, during the study, was reported. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 8 years 5 months
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: percentage of participants
        number (not applicable)
    43.1
    30.9
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. The median OS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. Analysis was performed on ITT population. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received. '9999' = upper limit was not estimable due to low number of participants with event. '99999' = median, lower limit and upper limit were not estimable due to low number of participants with event.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 8 years 5 months
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: months
        median (confidence interval 95%)
    87.8 (70.1 to 9999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [32]
    P-value
    = 0.0003
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    0.76
    Notes
    [32] - Hazard ratio was estimated by Cox regression model.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    = 0.0002
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    0.74
    Notes
    [33] - Hazard ratio was estimated by Cox regression model.

    Secondary: Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

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    End point title
    Percentage of Participants With PD/Relapse, Start of a new Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines
    End point description
    Percentage of participants with PD/relapse, death from any cause, or start of a new non-protocol-specified anti-CLL therapy as assessed by the investigator, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: percentage of participants
        number (not applicable)
    89.2
    71.1
    No statistical analyses for this end point

    Secondary: Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

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    End point title
    Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines
    End point description
    DOR was defined as the time from first occurrence of a documented response of CR, CRi, nPR, or PR until PD/relapse, as assessed by the investigator according to the iwCLL guidelines, or death from any cause. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without PD or death after response were censored at the last date of adequate response assessment. Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR.
    End point type
    Secondary
    End point timeframe
    From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    132
    181
    Units: months
        median (confidence interval 95%)
    19.1 (16.1 to 23.6)
    53.6 (49.1 to 57.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

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    End point title
    Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines
    End point description
    Percentage of participants with PD as assessed by the investigator according to the iwCLL guidelines, or death from any cause, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; an increase of >/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count >/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of >/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by >2 g/dL or to <10 g/dL. Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR.
    End point type
    Secondary
    End point timeframe
    From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    132
    181
    Units: percentage of participants
        number (not applicable)
    95.5
    68.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

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    End point title
    Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator
    End point description
    Percentage of participants with start of new non-protocol-specified anti-CLL therapy, as assessed by the investigator, or death from any cause, during the study, was reported. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: percentage of participants
        number (not applicable)
    81.5
    62.4
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

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    End point title
    Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines
    End point description
    EFS was defined as the time from date of randomization until the date of PD/relapse, start of a new non-protocol-specified anti-CLL therapy, or death from any cause, whichever occurred first, as assessed by the investigator. PD: occurrence of one of the following: new lesion; new palpable lymph node (>1.5 cm); unequivocal progression of non-target lesion; increase of >/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count >/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of >/=50% in platelet or neutrophil count, or hemoglobin level by >2 g/dL or to <10 g/dL. Participants without any of the specified event at the time of analysis were censored at the date of last adequate response assessment. In case of no post-baseline response assessment, participants were censored at the randomization date. ITT population = all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195 [34]
    194
    Units: months
        median (confidence interval 95%)
    16.4 (14.2 to 21.0)
    53.7 (48.5 to 59.3)
    Notes
    [34] - Analysis was performed on ITT population.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    0.31
    Notes
    [35] - Hazard ratio was estimated by Cox regression model.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.29
    Notes
    [36] - Hazard ratio was estimated by Cox regression model.

    Secondary: Percentage of Participants With MRD Negativity in Bone Marrow

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    End point title
    Percentage of Participants With MRD Negativity in Bone Marrow
    End point description
    MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed flow cytometry technique. Percentage of participants with MRD-negativity was reported. The 95% CI was computed using Pearson-Clopper method. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: participants
        number (confidence interval 95%)
    1.0 (0.12 to 3.66)
    14.4 (9.81 to 20.18)
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    OR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    16.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.82
         upper limit
    69.35
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [37]
    P-value
    < 0.0001
    Method
    Chi-squared
    Parameter type
    Difference in MRD negative rates
    Point estimate
    16.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.99
         upper limit
    18.82
    Notes
    [37] - The 95% CI was computed using Anderson-Hauck method.

    Secondary: Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

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    End point title
    Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator
    End point description
    TTNT was defined as the time from randomization until start of new non-protocol-specified anti-CLL treatment or death from any cause. Participants without the event at the time of analysis were censored at the last visit date for this outcome measure analysis. The median TTNT was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months)
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: months
        median (confidence interval 95%)
    24.0 (20.7 to 29.5)
    63.0 (56.1 to 73.6)
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [38]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.25
         upper limit
    0.41
    Notes
    [38] - Hazard ratio was estimated by Cox regression model.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.39
    Notes
    [39] - Hazard ratio was estimated by Cox regression model.

    Secondary: Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood

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    End point title
    Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood
    End point description
    MRD-negativity was defined as the presence of <1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed by the allele specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry technique. Percentage of participants with MRD-negativity at the EoCTR visit was reported. The 95% CI was computed using Pearson-Clopper method. ITT population included all randomized participants, with participants grouped according to randomized treatment group, regardless of the actual treatment received.
    End point type
    Secondary
    End point timeframe
    EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    195
    194
    Units: percentage of participants
        number (confidence interval 95%)
    13.3 (8.90 to 18.92)
    62.4 (55.15 to 69.21)
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [40]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    10.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.5
         upper limit
    17.85
    Notes
    [40] - OR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Bendamustine + Rituximab v Venetoclax + Rituximab
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    superiority [41]
    P-value
    < 0.0001
    Method
    Chi-squared
    Parameter type
    Difference in MRD Negativity Rates
    Point estimate
    49.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    40.44
         upper limit
    57.64
    Notes
    [41] - The 95% CI was computed using Anderson-Hauck method.

    Secondary: Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

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    End point title
    Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores
    End point description
    MDASI is a 25-item validated questionnaire consisting of 2 parts. Part 1: 19-items divided into 2 scales, Core Symptom Severity (average of Questions 1 to 13) and Module Symptom Severity (average of Questions 14 to 19). Part 2: 6-items to assess Interference (symptom distress) (average of Questions 20 to 25). Each item was rated from 0 to 10, with lower scores indicating better outcome. Total score for Core Symptom Severity, Module Symptom Severity, and Interference are reported which range from 0 to 10, with lower scores indicating better health-related quality of life (HRQoL). Patient reported outcome (PRO) evaluable population, included all participants with baseline and at least one post-baseline PRO assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    117 [42]
    42 [43]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; Core symptom severity (n=116,42)
    1.76 ± 1.55
    1.55 ± 1.31
        Change at C1D1; Core symptom severity (n=116,36)
    0.0 ± 0.0
    -0.08 ± 0.98
        Change at C1D8; Core symptom severity (n=107,36)
    0.26 ± 1.34
    -0.30 ± 0.84
        Change at C1D15; Core symptom severity (n=104,33)
    0.00 ± 1.31
    -0.27 ± 0.93
        Change at C2D1; Core symptom severity (n=101,35)
    -0.23 ± 1.30
    -0.33 ± 0.91
        Change at C2D8; Core symptom severity (n=91,36)
    0.17 ± 1.59
    -0.45 ± 0.91
        Change at C2D15; Core symptom severity (n=90,37)
    -0.13 ± 1.53
    -0.53 ± 0.90
        Change at C3D1; Core symptom severity (n=89,36)
    -0.26 ± 1.60
    -0.40 ± 1.13
        Change at C3D8; Core symptom severity (n=72,30)
    -0.13 ± 1.63
    -0.66 ± 1.20
        Change at C3D15; Core symptom severity (n=73,32)
    -0.42 ± 1.52
    -0.53 ± 1.05
        Baseline; Module symptom severity (n=116,42)
    1.60 ± 1.46
    1.57 ± 1.11
        Change at C1D1; Module symptom severity (n=116,36)
    0.00 ± 0.00
    -0.19 ± 0.96
        Change at C1D8;Module symptom severity(n=107,36)
    -0.22 ± 1.40
    -0.53 ± 0.96
        Change atC1D15;Module symptom severity(n=104,33)
    -0.43 ± 1.51
    -0.73 ± 1.13
        Change at C2D1; Module symptom severity (n=101,34)
    -0.49 ± 1.46
    -0.65 ± 0.92
        Change at C2D8; Module symptom severity (n=91,35)
    -0.46 ± 1.63
    -0.77 ± 0.87
        Change at C2D15; Module symptom severity (n=90,36)
    -0.69 ± 1.47
    -0.94 ± 0.93
        Change at C3D1; Module symptom severity (n=86,35)
    -0.65 ± 1.48
    -0.81 ± 0.97
        Change at C3D8; Module symptom severity (n=72,30)
    -0.51 ± 1.58
    -0.83 ± 0.97
        Change at C3D15; Module symptom severity (n=73,32)
    -0.83 ± 1.51
    -0.92 ± 0.97
        Baseline; Interference (n=116,41)
    1.81 ± 2.05
    1.90 ± 2.25
        Change at C1D1; Interference (n=116,35)
    0.00 ± 0.00
    -0.13 ± 1.49
        Change at C1D8; Interference (n=107,33)
    0.45 ± 1.78
    -0.29 ± 2.14
        Change at C1D15; Interference (n=104,32)
    0.36 ± 1.85
    0.01 ± 2.04
        Change at C2D1; Interference (n=101,33)
    0.01 ± 1.73
    -0.34 ± 1.78
        Change at C2D8; Interference (n=91,34)
    0.58 ± 2.20
    -0.58 ± 1.81
        Change at C2D15; Interference (n=89,35)
    0.06 ± 1.84
    -0.64 ± 1.59
        Change at C3D1; Interference (n=86,34)
    -0.02 ± 2.02
    -0.73 ± 2.06
        Change at C3D8; Interference (n=72,29)
    0.15 ± 1.91
    -0.82 ± 2.09
        Change at C3D15; Interference (n=72,30)
    -0.07 ± 2.01
    -0.55 ± 2.18
    Notes
    [42] - 'Number of Subject Analysed' = participants evaluable for this outcome measure
    [43] - 'n' = participants evaluable at specified time point, for each arm respectively
    No statistical analyses for this end point

    Secondary: Plasma Venetoclax Concentrations

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    End point title
    Plasma Venetoclax Concentrations [44]
    End point description
    Pharmacokinetic (PK) evaluable population, included all participants in the ‘Venetoclax + Rituximab’ arm who received at least one dose of venetoclax with at least one post-dose PK concentration result available. Here, 'Number of Subject Analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour, anytime before venetoclax administration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma venetoclax concentrations was only analyzed for VR arm of the study.
    End point values
    Venetoclax + Rituximab
    Number of subjects analysed
    184
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        C1D1, Pre-dose (n=151)
    0.626 ± 0.540
        C1D1, 4 hours Post-Dose (n=159)
    1.34 ± 0.881
        C4D1, Pre-dose (n=112)
    0.681 ± 0.745
        C4D1, 4 hours Post-Dose (n=121)
    1.34 ± 0.905
    No statistical analyses for this end point

    Secondary: Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

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    End point title
    Change from Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score
    End point description
    EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into 5 functional scales (Physical, Role, Cognitive, Emotional, and Social), 3 symptom scales (fatigue, pain, nausea, and vomiting), a global health status/global QoL scale, and single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Scores were averaged, transformed to 0-100 scale; where higher score for functional scales=poor level of functioning; higher score for global health status/global QoL=better HRQoL. PRO evaluable population = all participants with baseline and at least one post-baseline PRO assessment. ‘99999’=either data were not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time point.
    End point type
    Secondary
    End point timeframe
    Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    177 [45]
    69 [46]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; Physical functioning (n=177,69)
    82.59 ± 17.46
    83.77 ± 15.27
        Change at C1D1; Physical functioning (n=177,67)
    0.0 ± 0.0
    1.39 ± 12.90
        Change at C2D1; Physical functioning (n=172,67)
    0.31 ± 15.81
    2.99 ± 12.83
        Change at C3D1; Physical functioning (n=160,64)
    0.22 ± 16.43
    1.46 ± 14.76
        Change at C4D1; Physical functioning (n=154,65)
    2.11 ± 14.95
    5.54 ± 14.17
        Change at C5D1; Physical functioning (n=149,65)
    2.44 ± 18.19
    4.62 ± 15.27
        Change at C6D1; Physical functioning (n=143,65)
    2.25 ± 16.82
    4.51 ± 16.59
        Change at STC/EW; Physical functioning (n=162,64)
    1.68 ± 18.76
    4.53 ± 16.04
        Change at EoCTR; Physical functioning (n=142,63)
    2.92 ± 18.03
    4.34 ± 16.12
        Change at FUV1; Physical functioning (n=124,63)
    2.27 ± 18.86
    3.81 ± 16.27
        Change at FUV2; Physical functioning (n=114,63)
    2.40 ± 19.21
    2.75 ± 17.17
        Change at FUV3; Physical functioning (n=95,62)
    2.54 ± 17.83
    3.44 ± 17.31
        Change at FUV4; Physical functioning (n=77,47)
    4.74 ± 20.14
    0.85 ± 21.06
        Change at FUV5; Physical functioning (n=57,19)
    1.90 ± 17.68
    -1.75 ± 19.35
        Change at FUV6; Physical functioning (n=33,5)
    -1.41 ± 15.34
    1.33 ± 5.58
        Change at FUV7; Physical functioning (n=13,1)
    -3.08 ± 11.74
    0.00 ± 99999
        Change at FUV8; Physical functioning (n=5,1)
    -9.33 ± 23.38
    0.00 ± 99999
        Change at FUV9; Physical functioning (n=2,0)
    -10.00 ± 33.0
    99999 ± 99999
        Baseline; Role functioning (n=177,69)
    78.25 ± 25.67
    83.82 ± 21.00
        Change at C1D1; Role functioning (n=177,67)
    0.0 ± 0.0
    -1.74 ± 23.23
        Change at C2D1; Role functioning (n=172,67)
    -1.26 ± 27.45
    2.49 ± 23.07
        Change at C3D1; Role functioning (n=160,64)
    -0.10 ± 29.64
    1.82 ± 26.08
        Change at C4D1; Role functioning (n=154,65)
    0.87 ± 29.01
    5.13 ± 22.03
        Change at C5D1; Role functioning (n=149,65)
    0.45 ± 30.75
    4.36 ± 23.44
        Change at C6D1; Role functioning (n=143,65)
    0.70 ± 29.92
    1.79 ± 25.71
        Change at STC/EW; Role functioning (n=162,64)
    -0.41 ± 32.91
    2.60 ± 25.58
        Change at EoCTR; Role functioning (n=143,63)
    3.26 ± 29.95
    2.12 ± 26.69
        Change at FUV1; Role functioning (n=125,63)
    2.93 ± 32.31
    2.65 ± 27.47
        Change at FUV2; Role functioning (n=114,63)
    3.07 ± 32.63
    -1.85 ± 31.84
        Change at FUV3; Role functioning (n=95,62)
    5.26 ± 31.16
    1.88 ± 28.17
        Change at FUV4; Role functioning (n=77,47)
    5.41 ± 33.16
    -0.35 ± 30.39
        Change at FUV5; Role functioning (n=57,19)
    2.34 ± 29.79
    1.75 ± 34.20
        Change at FUV6; Role functioning (n=33,5)
    -4.04 ± 27.01
    -13.33 ± 32.06
        Change at FUV7; Role functioning (n=13,1)
    2.56 ± 29.54
    -16.67 ± 99999
        Change at FUV8; Role functioning (n=5,1)
    0.00 ± 23.57
    16.67 ± 99999
        Change at FUV9; Role functioning (n=2,0)
    -16.67 ± 23.57
    99999 ± 99999
        Baseline; Emotional functioning (n=176,69)
    78.98 ± 22.47
    82.13 ± 15.80
        Change at C1D1; Emotional functioning (n=176,67)
    0.0 ± 0.0
    4.35 ± 15.17
        Change at C2D1; Emotional functioning (n=171,67)
    2.24 ± 20.07
    5.60 ± 14.68
        Change at C3D1; Emotional functioning (n=158,64)
    2.99 ± 20.06
    5.34 ± 19.09
        Change at C4D1; Emotional functioning (n=151,65)
    2.61 ± 18.35
    4.19 ± 15.45
        Change at C5D1; Emotional functioning (n=146,65)
    1.14 ± 18.79
    3.97 ± 17.37
        Change at C6D1; Emotional functioning (n=143,65)
    2.06 ± 18.74
    3.08 ± 17.96
        Change at STC/EW; Emotional functioning (n=160,64)
    2.43 ± 20.61
    5.34 ± 18.69
        Change at EoCTR; Emotional functioning (n=142,62)
    2.58 ± 19.45
    3.49 ± 17.83
        Change at FUV1; Emotional functioning (n=124,63)
    3.49 ± 20.91
    4.37 ± 18.50
        Change at FUV2; Emotional functioning (n=114,63)
    4.39 ± 20.33
    0.66 ± 21.02
        Change at FUV3; Emotional functioning (n=92,62)
    0.63 ± 19.97
    2.82 ± 17.66
        Change at FUV4; Emotional functioning (n=76,47)
    4.82 ± 19.73
    1.95 ± 18.41
        Change at FUV5; Emotional functioning (n=56,19)
    3.13 ± 17.95
    2.63 ± 20.61
        Change at FUV6; Emotional functioning (n=33,5)
    2.27 ± 21.78
    5.00 ± 17.28
        Change at FUV7; Emotional functioning (n=13,1)
    5.77 ± 17.48
    -8.33 ± 99999
        Change at FUV8; Emotional functioning (n=5,1)
    3.33 ± 28.01
    0.00 ± 99999
        Change at FUV9; Emotional functioning (n=2,0)
    -16.67 ± 11.79
    99999 ± 99999
        Baseline; Cognitive functioning (n=176,69)
    86.55 ± 16.78
    89.86 ± 14.91
        Change at C1D1; Cognitive functioning (n=176,67)
    0.0 ± 0.0
    -1.24 ± 14.01
        Change at C2D1; Cognitive functioning (n=171,67)
    -0.19 ± 15.34
    0.25 ± 14.06
        Change at C3D1; Cognitive functioning (n=158,64)
    -0.32 ± 16.34
    -1.56 ± 17.50
        Change at C4D1; Cognitive functioning (n=152,65)
    -1.54 ± 17.41
    -0.26 ± 17.05
        Change at C5D1; Cognitive functioning (n=146,65)
    -1.94 ± 18.10
    -0.26 ± 14.28
        Change at C6D1; Cognitive functioning (n=143,65)
    -2.68 ± 16.97
    -0.77 ± 15.98
        Change at STC/EW; Cognitive functioning (n=160,64)
    -2.19 ± 17.65
    1.04 ± 18.28
        Change at EoCTR; Cognitive functioning (n=142,62)
    -2.23 ± 18.11
    -0.27 ± 16.94
        Change at FUV1; Cognitive functioning (n=124,63)
    -2.02 ± 17.21
    -0.26 ± 15.98
        Change at FUV2; Cognitive functioning (n=114,63)
    1.32 ± 16.16
    -2.38 ± 18.17
        Change at FUV3; Cognitive functioning (n=92,62)
    -1.63 ± 14.84
    -2.96 ± 18.24
        Change at FUV4; Cognitive functioning (n=76,47)
    0.44 ± 17.63
    -1.77 ± 19.11
        Change at FUV5; Cognitive functioning (n=56,19)
    -1.49 ± 15.66
    -6.14 ± 21.67
        Change at FUV6; Cognitive functioning (n=33,5)
    -0.51 ± 14.72
    0.00 ± 0.00
        Change at FUV7; Cognitive functioning (n=13,1)
    -1.28 ± 14.37
    0.00 ± 99999
        Change at FUV8; Cognitive functioning (n=5,1)
    0.00 ± 23.57
    0.00 ± 99999
        Change at FUV9; Cognitive functioning (n=2,0)
    16.67 ± 23.57
    99999 ± 99999
        Baseline; Social functioning (n=176,69)
    82.48 ± 22.06
    85.51 ± 21.18
        Change at C1D1; Social functioning (n=176,67)
    0.0 ± 0.0
    -1.74 ± 19.92
        Change at C2D1; Social functioning (n=171,67)
    -2.44 ± 21.44
    0.25 ± 18.46
        Change at C3D1; Social functioning (n=158,64)
    -2.32 ± 22.61
    3.65 ± 25.45
        Change at C4D1; Social functioning (n=151,65)
    -0.55 ± 22.15
    4.62 ± 20.09
        Change at C5D1; Social functioning (n=146,65)
    -5.48 ± 26.49
    2.56 ± 20.46
        Change at C6D1; Social functioning (n=143,65)
    -5.13 ± 24.80
    3.85 ± 24.61
        Change at STC/EW; Social functioning (n=160,64)
    -4.06 ± 27.71
    1.04 ± 19.22
        Change at EoCTR; Social functioning (n=142,62)
    -0.47 ± 24.95
    1.88 ± 20.49
        Change at FUV1; Social functioning (n=124,63)
    -1.08 ± 26.09
    1.59 ± 24.27
        Change at FUV2; Social functioning (n=114,63)
    0.58 ± 24.68
    1.32 ± 27.97
        Change at FUV3; Social functioning (n=92,62)
    -0.91 ± 24.00
    1.88 ± 25.98
        Change at FUV4; Social functioning (n=76,47)
    1.97 ± 27.35
    1.06 ± 32.12
        Change at FUV5; Social functioning (n=56,19)
    1.79 ± 26.72
    0.00 ± 33.79
        Change at FUV6; Social functioning (n=33,5)
    1.52 ± 29.27
    10.00 ± 14.91
        Change at FUV7; Social functioning (n=13,1)
    -2.56 ± 23.42
    33.33 ± 99999
        Change at FUV8; Social functioning (n=5,1)
    -10.00 ± 22.36
    33.33 ± 99999
        Change at FUV9; Social functioning (n=2,0)
    -25.00 ± 35.36
    99999 ± 99999
        Baseline; Global health status/QoL (n=176,69)
    63.02 ± 21.45
    67.39 ± 22.17
        Change at C1D1;Global health status/QoL(n=176,67)
    0.0 ± 0.0
    6.34 ± 18.41
        Change at C2D1;Global health status/QoL (n=171,67)
    2.73 ± 21.69
    5.35 ± 20.14
        Change at C3D1;Global health status/QoL (n=157,64)
    2.34 ± 24.66
    2.21 ± 23.58
        Change at C4D1;Global health status/QoL (n=152,65)
    3.84 ± 22.26
    7.05 ± 21.05
        Change at C5D1;Global health status/QoL (n=146,65)
    7.36 ± 24.20
    7.18 ± 21.94
        Change at C6D1;Global health status/QoL (n=143,65)
    4.25 ± 25.00
    5.90 ± 25.16
        Change at STC/EW;Global health status/QoL;n=160,64
    4.32 ± 26.20
    6.51 ± 23.22
        Change at EoCTR;Global health status/QoL(n=142,62)
    6.10 ± 23.65
    7.66 ± 24.11
        Change at FUV1;Global health status/QoL (n=124,63)
    5.91 ± 24.57
    7.01 ± 25.01
        Change at FUV2;Global health status/QoL (n=114,63)
    6.94 ± 24.81
    4.50 ± 26.51
        Change at FUV3; Global health status/QoL (n=92,62)
    4.80 ± 25.30
    6.32 ± 27.36
        Change at FUV4; Global health status/QoL (n=76,47)
    7.35 ± 26.77
    6.38 ± 27.60
        Change at FUV5; Global health status/QoL (n=56,19)
    4.46 ± 23.89
    4.39 ± 18.08
        Change at FUV6; Global health status/QoL (n=33,5)
    1.01 ± 24.00
    5.00 ± 7.45
        Change at FUV7; Global health status/QoL (n=13,1)
    8.33 ± 25.69
    16.67 ± 99999
        Change at FUV8; Global health status/QoL (n=5,1)
    6.67 ± 16.03
    8.33 ± 99999
        Change at FUV9; Global health status/QoL (n=2,0)
    0.00 ± 0.00
    99999 ± 99999
    Notes
    [45] - 'Number of Subject Analysed' = participants evaluable for this outcome measure
    [46] - 'n' = participants evaluable at specified time point, for each arm respectively
    No statistical analyses for this end point

    Secondary: Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

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    End point title
    Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score
    End point description
    The EORTC QLQ-CLL16 module is designed for participants with Stage 0 to Stage 4 CLL. It is composed of 16 questions and there are four multi-item scales on Fatigue (2 items), Treatment-related side effects (TRSE, 4 items), Disease-related symptoms (DRS, 4 items), and Infection (4 items); and two single-item scales on social activities and future health worries. Multi-item scales score are reported and the total score for each multi-item scale was transformed to result in a total score range of 0 to 100, where higher score = poor HRQoL. PRO evaluable population, included all participants with baseline and at least one post-baseline PRO assessment. 'Number of Subject Analysed' = participants evaluable for this outcome measure; 'n' = participants evaluable at specified time point; ‘99999’ = either mean was not available because no participant was evaluable or SD was not available because only 1 participant was evaluable at indicated time points.
    End point type
    Secondary
    End point timeframe
    Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    175
    69
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline; TRSE (n=175,69)
    14.29 ± 13.95
    9.42 ± 8.80
        Change at C1D1; TRSE (n=175,67)
    0.0 ± 0.0
    0.12 ± 10.10
        Change at C2D1; TRSE (n=170,67)
    1.62 ± 13.82
    0.62 ± 12.76
        Change at C3D1; TRSE (n=159,63)
    -0.26 ± 13.76
    1.98 ± 14.72
        Change at C4D1; TRSE (n=152,64)
    -0.49 ± 13.97
    0.52 ± 11.87
        Change at C5D1; TRSE (n=147,65)
    -0.51 ± 14.57
    0.64 ± 10.02
        Change at C6D1; TRSE (n=144,65)
    0.46 ± 15.51
    -0.13 ± 10.04
        Change at STC/EW; TRSE (n=161,64)
    0.81 ± 18.11
    0.13 ± 10.76
        Change at EoCTR; TRSE (n=142,63)
    -0.88 ± 16.06
    0.26 ± 12.61
        Change at FUV1; TRSE (n=123,63)
    -1.20 ± 14.87
    1.19 ± 12.24
        Change at FUV2; TRSE (n=113,63)
    -1.70 ± 15.28
    2.65 ± 14.03
        Change at FUV3; TRSE (n=95,62)
    -2.08 ± 12.64
    -0.13 ± 13.70
        Change at FUV4; TRSE (n=76,47)
    -1.97 ± 12.76
    2.84 ± 15.18
        Change at FUV5; TRSE (n=56,19)
    -2.68 ± 11.02
    1.32 ± 10.49
        Change at FUV6; TRSE (n=33,5)
    -1.01 ± 12.10
    -1.67 ± 3.73
        Change at FUV7; TRSE (n=13,1)
    2.56 ± 22.67
    -8.33 ± 99999
        Change at FUV8; TRSE (n=5,1)
    1.67 ± 13.69
    0.00 ± 99999
        Change at FUV9; TRSE (n=2,0)
    8.33 ± 11.79
    99999 ± 99999
        Baseline; DRS (n=175,69)
    19.57 ± 16.81
    16.95 ± 17.37
        Change at C1D1; DRS (n=175,67)
    0.0 ± 0.0
    -2.74 ± 16.18
        Change at C2D1; DRS (n=170,67)
    -3.33 ± 16.05
    -4.77 ± 16.84
        Change at C3D1; DRS (n=159,63)
    -4.77 ± 16.49
    -3.35 ± 17.48
        Change at C4D1; DRS (n=152,64)
    -6.03 ± 16.51
    -5.12 ± 17.72
        Change at C5D1; DRS (n=147,65)
    -5.90 ± 16.73
    -4.79 ± 17.50
        Change at C6D1; DRS (n=144,65)
    -6.40 ± 17.26
    -5.30 ± 16.72
        Change at STC/EW; DRS (n=161,64)
    -5.80 ± 18.52
    -6.51 ± 18.45
        Change at EoCTR; DRS (n=142,63)
    -6.57 ± 17.21
    -5.86 ± 20.38
        Change at FUV1; DRS (n=123,63)
    -6.55 ± 15.73
    -5.82 ± 19.20
        Change at FUV2; DRS (n=113,63)
    -8.63 ± 14.39
    -3.57 ± 18.31
        Change at FUV3; DRS (n=95,62)
    -7.37 ± 14.88
    -3.76 ± 19.25
        Change at FUV4; DRS (n=76,47)
    -8.55 ± 18.56
    -2.66 ± 20.49
        Change at FUV5; DRS (n=56,19)
    -8.33 ± 16.13
    -2.19 ± 19.41
        Change at FUV6; DRS (n=33,5)
    -6.31 ± 16.01
    -3.33 ± 13.94
        Change at FUV7; DRS (n=13,1)
    -15.38 ± 20.08
    -8.33 ± 99999
        Change at FUV8; DRS (n=5,1)
    -10.00 ± 16.03
    -8.33 ± 99999
        Change at FUV9; DRS (n=2,0)
    -4.17 ± 5.89
    99999 ± 99999
        Baseline; Fatigue (n=175,69)
    28.76 ± 24.66
    21.74 ± 20.67
        Change at C1D1; Fatigue (n=175,67)
    0.0 ± 0.0
    -2.24 ± 20.29
        Change at C2D1; Fatigue (n=170,67)
    -2.55 ± 22.86
    -5.47 ± 21.40
        Change at C3D1; Fatigue (n=159,63)
    -2.83 ± 25.17
    -3.17 ± 23.73
        Change at C4D1; Fatigue (n=152,64)
    -3.18 ± 23.23
    -4.17 ± 22.02
        Change at C5D1; Fatigue (n=147,65)
    -2.38 ± 27.52
    -4.36 ± 20.89
        Change at C6D1; Fatigue (n=144,65)
    -2.66 ± 26.35
    -2.31 ± 21.42
        Change at STC/EW; Fatigue (n=161,64)
    -3.11 ± 28.64
    -4.69 ± 21.30
        Change at EoCTR; Fatigue (n=142,63)
    -6.69 ± 26.78
    -3.97 ± 24.27
        Change at FUV1; Fatigue (n=123,63)
    -6.37 ± 26.61
    -4.23 ± 22.99
        Change at FUV2; Fatigue (n=113,63)
    -6.64 ± 24.55
    -1.85 ± 24.70
        Change at FUV3; Fatigue (n=95,62)
    -5.79 ± 23.29
    -2.42 ± 23.73
        Change at FUV4; Fatigue (n=76,47)
    -9.65 ± 26.84
    -0.35 ± 25.18
        Change at FUV5; Fatigue (n=56,19)
    -6.55 ± 25.56
    3.51 ± 23.95
        Change at FUV6; Fatigue (n=33,5)
    -5.05 ± 24.82
    3.33 ± 24.72
        Change at FUV7; Fatigue (n=13,1)
    -10.26 ± 30.08
    -33.33 ± 99999
        Change at FUV8; Fatigue (n=5,1)
    -6.67 ± 19.00
    0.00 ± 99999
        Change at FUV9; Fatigue (n=2,0)
    -8.33 ± 11.79
    99999 ± 99999
        Baseline; Infection (n=175,69)
    15.92 ± 17.63
    14.01 ± 18.99
        Change at C1D1; Infection (n=175,67)
    0.0 ± 0.0
    -2.24 ± 20.03
        Change at C2D1; Infection (n=170,67)
    -0.02 ± 19.98
    -3.61 ± 21.72
        Change at C3D1; Infection (n=159,63)
    -1.66 ± 19.21
    -1.32 ± 20.48
        Change at C4D1; Infection (n=152,64)
    -1.44 ± 22.07
    -3.13 ± 21.28
        Change at C5D1; Infection (n=147,65)
    -1.91 ± 24.00
    -2.56 ± 23.47
        Change at C6D1; Infection (n=143,65)
    -1.09 ± 20.66
    -2.95 ± 20.54
        Change at STC/EW; Infection (n=161,64)
    -0.12 ± 23.28
    -1.69 ± 23.34
        Change at EoCTR; Infection (n=142,63)
    -0.55 ± 21.73
    -3.44 ± 25.78
        Change at FUV1; Infection (n=121,63)
    1.08 ± 18.77
    -2.65 ± 26.51
        Change at FUV2; Infection (n=113,63)
    0.05 ± 23.29
    -0.53 ± 25.74
        Change at FUV3; Infection (n=95,62)
    -1.90 ± 16.97
    -0.54 ± 26.48
        Change at FUV4; Infection (n=76,47)
    -4.24 ± 16.71
    0.53 ± 25.56
        Change at FUV5; Infection (n=56,19)
    -4.51 ± 22.66
    7.46 ± 27.20
        Change at FUV6; Infection (n=33,5)
    -1.60 ± 18.90
    8.33 ± 15.59
        Change at FUV7; Infection (n=13,1)
    -0.43 ± 21.84
    -16.67 ± 99999
        Change at FUV8; Infection (n=5,1)
    8.89 ± 23.36
    -25.00 ± 99999
        Change at FUV9; Infection (n=2,0)
    -2.78 ± 3.93
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Number of Participants with Grade 3 or higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)

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    End point title
    Number of Participants with Grade 3 or higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A SAE is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. TLS and IRRs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant; Grade 4 = Life-threatening; Grade 5 = Death. A higher grade indicates a worse outcome. SE population.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent form up to approximately 8 years 5 months
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    188
    194
    Units: participants
        TLS
    2
    6
        IRRs
    10
    4
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A Serious Adverse Event (SAE) is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0). SE population included all randomized participants who received at least one dose of study treatment with participants grouped according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent form up to approximately 8 years 5 months
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    188
    194
    Units: participants
        AEs
    185
    194
        SAEs
    84
    101
    No statistical analyses for this end point

    Post-hoc: Euro QoL 5 Dimension (EQ-5D) Questionnaire Score

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    End point title
    Euro QoL 5 Dimension (EQ-5D) Questionnaire Score
    End point description
    PRO evaluable population included all participants with baseline and at least one post-baseline PRO assessment. Here, 'Overall Number of Participants Analyzed’ = participants evaluable for this outcome measure and 'Number Analyzed' = participants evaluable at specified time point.
    End point type
    Post-hoc
    End point timeframe
    Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days
    End point values
    Bendamustine + Rituximab Venetoclax + Rituximab
    Number of subjects analysed
    0 [47]
    0 [48]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [47] - Data were not presented as this is not an primary or secondary endpoint.
    [48] - Data were not presented as this is not an primary or secondary endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent form up to approximately 8 years 5 months
    Adverse event reporting additional description
    SE population included all randomized participants who received at least one dose of study treatment with participants grouped according to the actual treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Bendamustine + Rituximab Main Study
    Reporting group description
    Participants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

    Reporting group title
    Venetoclax + Rituximab Re-Treatment Substudy
    Reporting group description
    Participants who entered the re-treatment substudy had a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, participants received 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants who did not progress following the completion of the 6 cycles continued to receive venetoclax monotherapy until disease progression or for a maximum of 2 year from Cycle 1 re-treatment Day 1 of the substudy.

    Reporting group title
    Bendamustine + Rituximab Crossover Substudy
    Reporting group description
    Participants who entered the crossover substudy had a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, participants received 6 cycles of rituximab, 375 mg/m^2, as IV infusion on the Day 1 of each 28-day cycle. Participants who did not progress following the completion of the 6 cycles continued to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 crossover Day 1 of the substudy.

    Reporting group title
    Venetoclax + Rituximab Main Study
    Reporting group description
    Participants were initially placed on a venetoclax ramp-up period of 5 weeks and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg, orally, QD. Participants continued receiving venetoclax at a dose of 400 mg, orally, QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab at a dose of 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 on Day 1 of Cycles 2-6.

    Serious adverse events
    Bendamustine + Rituximab Main Study Venetoclax + Rituximab Re-Treatment Substudy Bendamustine + Rituximab Crossover Substudy Venetoclax + Rituximab Main Study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    84 / 188 (44.68%)
    13 / 25 (52.00%)
    5 / 9 (55.56%)
    101 / 194 (52.06%)
         number of deaths (all causes)
    84
    8
    1
    60
         number of deaths resulting from adverse events
    4
    0
    0
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    3 / 188 (1.60%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 188 (0.53%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Medullary thyroid cancer
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastasis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sebaceous adenoma
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin squamous cell carcinoma recurrent
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    5 / 188 (2.66%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    13 / 188 (6.91%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    5 / 194 (2.58%)
         occurrences causally related to treatment / all
    11 / 15
    0 / 0
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Bronchiectasis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medical observation
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    6 / 188 (3.19%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scar
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Ventricular tachycardia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 188 (2.66%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    4 / 6
    1 / 1
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 188 (1.60%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 188 (1.06%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    3 / 188 (1.60%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    16 / 188 (8.51%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    7 / 194 (3.61%)
         occurrences causally related to treatment / all
    14 / 16
    0 / 1
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    1 / 9 (11.11%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary obstruction
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Actinic keratosis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 188 (1.06%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess neck
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 188 (0.53%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex otitis externa
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 188 (1.06%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    3 / 194 (1.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal bacteraemia
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal tuberculosis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    2 / 188 (1.06%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Moraxella infection
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    15 / 188 (7.98%)
    3 / 25 (12.00%)
    1 / 9 (11.11%)
    19 / 194 (9.79%)
         occurrences causally related to treatment / all
    5 / 17
    0 / 4
    2 / 2
    7 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    Pneumonia influenzal
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scedosporium infection
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 188 (2.13%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 1
    Respiratory tract infection fungal
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 188 (1.06%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    4 / 194 (2.06%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    1 / 9 (11.11%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Atypical mycobacterial infection
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    0 / 194 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 188 (0.53%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    4 / 194 (2.06%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bendamustine + Rituximab Main Study Venetoclax + Rituximab Re-Treatment Substudy Bendamustine + Rituximab Crossover Substudy Venetoclax + Rituximab Main Study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 188 (94.15%)
    9 / 25 (36.00%)
    5 / 9 (55.56%)
    190 / 194 (97.94%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 188 (3.72%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    15 / 194 (7.73%)
         occurrences all number
    7
    0
    0
    15
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    33 / 188 (17.55%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    27 / 194 (13.92%)
         occurrences all number
    44
    0
    0
    41
    Oedema peripheral
         subjects affected / exposed
    7 / 188 (3.72%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    10 / 194 (5.15%)
         occurrences all number
    11
    0
    0
    14
    Fatigue
         subjects affected / exposed
    39 / 188 (20.74%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    35 / 194 (18.04%)
         occurrences all number
    44
    1
    0
    41
    Chills
         subjects affected / exposed
    16 / 188 (8.51%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    8 / 194 (4.12%)
         occurrences all number
    20
    1
    0
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 188 (16.49%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    36 / 194 (18.56%)
         occurrences all number
    37
    0
    0
    51
    Dyspnoea
         subjects affected / exposed
    14 / 188 (7.45%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    11 / 194 (5.67%)
         occurrences all number
    17
    0
    0
    14
    Oropharyngeal pain
         subjects affected / exposed
    7 / 188 (3.72%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    10 / 194 (5.15%)
         occurrences all number
    7
    0
    0
    12
    Productive cough
         subjects affected / exposed
    4 / 188 (2.13%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    12 / 194 (6.19%)
         occurrences all number
    5
    0
    0
    14
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    12 / 188 (6.38%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    21 / 194 (10.82%)
         occurrences all number
    13
    0
    0
    22
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 188 (5.32%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    10 / 194 (5.15%)
         occurrences all number
    11
    0
    0
    17
    Neutrophil count decreased
         subjects affected / exposed
    13 / 188 (6.91%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    11 / 194 (5.67%)
         occurrences all number
    27
    0
    1
    27
    Blood creatinine increased
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    5 / 194 (2.58%)
         occurrences all number
    1
    0
    2
    6
    White blood cell count decreased
         subjects affected / exposed
    3 / 188 (1.60%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    1 / 194 (0.52%)
         occurrences all number
    4
    0
    1
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    40 / 188 (21.28%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    16 / 194 (8.25%)
         occurrences all number
    54
    0
    0
    21
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    0 / 194 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 188 (5.85%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    12 / 194 (6.19%)
         occurrences all number
    14
    0
    0
    14
    Headache
         subjects affected / exposed
    19 / 188 (10.11%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    21 / 194 (10.82%)
         occurrences all number
    21
    0
    0
    21
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    42 / 188 (22.34%)
    2 / 25 (8.00%)
    0 / 9 (0.00%)
    23 / 194 (11.86%)
         occurrences all number
    57
    2
    0
    30
    Neutropenia
         subjects affected / exposed
    85 / 188 (45.21%)
    5 / 25 (20.00%)
    3 / 9 (33.33%)
    120 / 194 (61.86%)
         occurrences all number
    182
    13
    5
    290
    Anaemia
         subjects affected / exposed
    40 / 188 (21.28%)
    1 / 25 (4.00%)
    1 / 9 (11.11%)
    28 / 194 (14.43%)
         occurrences all number
    68
    1
    1
    48
    Febrile neutropenia
         subjects affected / exposed
    3 / 188 (1.60%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    0 / 194 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    31 / 188 (16.49%)
    3 / 25 (12.00%)
    0 / 9 (0.00%)
    78 / 194 (40.21%)
         occurrences all number
    43
    4
    0
    120
    Constipation
         subjects affected / exposed
    39 / 188 (20.74%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    27 / 194 (13.92%)
         occurrences all number
    47
    0
    0
    31
    Abdominal pain
         subjects affected / exposed
    6 / 188 (3.19%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    13 / 194 (6.70%)
         occurrences all number
    7
    0
    0
    14
    Vomiting
         subjects affected / exposed
    22 / 188 (11.70%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    15 / 194 (7.73%)
         occurrences all number
    29
    0
    0
    18
    Nausea
         subjects affected / exposed
    64 / 188 (34.04%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    42 / 194 (21.65%)
         occurrences all number
    82
    0
    0
    58
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    5 / 194 (2.58%)
         occurrences all number
    0
    0
    1
    5
    Rash
         subjects affected / exposed
    25 / 188 (13.30%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    15 / 194 (7.73%)
         occurrences all number
    29
    0
    0
    19
    Pruritus
         subjects affected / exposed
    9 / 188 (4.79%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    10 / 194 (5.15%)
         occurrences all number
    9
    1
    0
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 188 (5.85%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    17 / 194 (8.76%)
         occurrences all number
    15
    0
    0
    22
    Back pain
         subjects affected / exposed
    11 / 188 (5.85%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    14 / 194 (7.22%)
         occurrences all number
    11
    0
    0
    14
    Muscle spasms
         subjects affected / exposed
    11 / 188 (5.85%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    4 / 194 (2.06%)
         occurrences all number
    11
    0
    0
    4
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    12 / 188 (6.38%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    8 / 194 (4.12%)
         occurrences all number
    12
    0
    0
    11
    Pharyngitis
         subjects affected / exposed
    1 / 188 (0.53%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    14 / 194 (7.22%)
         occurrences all number
    1
    1
    0
    17
    Sinusitis
         subjects affected / exposed
    5 / 188 (2.66%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    19 / 194 (9.79%)
         occurrences all number
    5
    0
    0
    26
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 188 (14.89%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    45 / 194 (23.20%)
         occurrences all number
    42
    1
    0
    81
    Urinary tract infection
         subjects affected / exposed
    7 / 188 (3.72%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    12 / 194 (6.19%)
         occurrences all number
    9
    0
    0
    22
    Nasopharyngitis
         subjects affected / exposed
    11 / 188 (5.85%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    22 / 194 (11.34%)
         occurrences all number
    15
    0
    0
    29
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 188 (2.13%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    11 / 194 (5.67%)
         occurrences all number
    4
    0
    0
    15
    Conjunctivitis
         subjects affected / exposed
    5 / 188 (2.66%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    10 / 194 (5.15%)
         occurrences all number
    5
    0
    0
    11
    Bronchitis
         subjects affected / exposed
    13 / 188 (6.91%)
    1 / 25 (4.00%)
    0 / 9 (0.00%)
    20 / 194 (10.31%)
         occurrences all number
    14
    1
    0
    32
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 188 (9.04%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    8 / 194 (4.12%)
         occurrences all number
    18
    0
    0
    11
    Hyperkalaemia
         subjects affected / exposed
    0 / 188 (0.00%)
    0 / 25 (0.00%)
    0 / 9 (0.00%)
    11 / 194 (5.67%)
         occurrences all number
    0
    0
    0
    16
    Hypokalaemia
         subjects affected / exposed
    7 / 188 (3.72%)
    0 / 25 (0.00%)
    1 / 9 (11.11%)
    11 / 194 (5.67%)
         occurrences all number
    7
    0
    1
    12

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2013
    An exclusion of participants who had received potent cytochrome (CYP3A4) inhibitors was clarified to make consistent with the rest of the protocol; An exclusion criterion was added for participants with recent major surgery in line with the prescribing information for bendamustine; The pregnancy testing procedure was modified such that testing was required at each cycle of combination therapy and every 3 months thereafter until the end of treatment in order to obtain a more timely diagnosis of pregnancy.
    10 Jun 2014
    Modifications to the tumor lysis syndrome prophylaxis measures for participants with CLL were implemented following analysis of participants enrolled in different venetoclax trials: All participants randomized to the ‘Venetoclax + Rituximab’ arm were to initiate dosing with 20 mg venetoclax daily for at least 7 days; Outpatient dosing and monitoring for the first venetoclax dose at all dose levels (20 mg, 50 mg, 100 mg, 200 mg, 400 mg) was introduced for low- and medium-risk participants, if there was no indication to hospitalize; Outpatient IV hydration prior to the first venetoclax dose was introduced for medium-risk participants at 20 and 50 mg; Inpatient dosing and monitoring was introduced for high-risk participants prior to the first venetoclax dose only at the 20 mg and 50 mg dose levels; Outpatient dosing and IV hydration prior to the first venetoclax dose was introduced for high-risk participants at dose levels of 100 mg and above, if there was no indication to hospitalize; Reduced frequency of laboratory assessments after dosing; Prophylaxis with rasburicase had to be administered prior to the first dose of venetoclax only for high-risk participants with high uric acid levels and per regional standards/guidelines; Dose Modification for venetoclax + rituximab in case of non-hematologic toxicity was clarified globally.
    16 Oct 2014
    The recruitment of participants with occult or prior hepatitis B virus (HBV) infection if HBV deoxy-ribonucleic acid (DNA) was undetectable was allowed; In order to collect appropriate MRD information, bone marrow aspiration was added. This was previously only mandated in participants with CR. To synchronize with other venetoclax development studies MRD in peripheral blood was to be monitored for up to 1 year after completion of venetoclax single-agent therapy.
    22 Dec 2015
    The interim analysis was changed to be information-fraction-based as opposed to time-based (that is, percentage of total PFS) events; A secondary objective of best overall response rate as assessed by the investigator was added; Details regarding multiplicity adjustment and order for testing the key secondary endpoints were added; The secondary outcome measure of MRD response rate was clarified that this assessment was based on the EoCTR visit. MRD response rate at other disease response assessment timepoints were designated as exploratory outcome measures; Additional details were provided on the use of strong, moderate and weak CYP3A4 inhibitors and inducers as well as cautionary medications; Timings for the baseline QoL questionnaires for the ‘Venetoclax + Rituximab’ arm were incorporated; PK outcome measures were further defined to include concentrations of venetoclax.
    21 Nov 2016
    Allowed for a change in the clinical prioritization of the secondary efficacy endpoints to mirror the evolving relapsed/refractory CLL therapeutic and scientific landscape.
    03 Jun 2017
    The following updates in the protocol were made in Korea. - The description of the fixed sequence testing of the secondary efficacy endpoints in the statistical section of the protocol was streamlined and the details of the testing of secondary endpoints were set out in the statistical analysis plan, in accordance with the international guideline on Statistical Principles for Clinical Trials (ICH E9). This amendment is implemented to allow for a change in the clinical prioritization of the secondary efficacy endpoints to mirror the evolving R/R CLL therapeutic and scientific landscape. - The sample list of prohibited and cautionary medications was updated, incorporating the FDA’s updated guidelines.
    30 Mar 2018
    - An exploratory objective was added to evaluate best overall response rate (ORR) to next anti-chronic lymphocytic leukemia (CLL) treatment, as assessed by the investigator. - An optional R/C Substudy was added.At the interim analysis (now primary analysis), the study demonstrated that venetoclax and rituximab (venetoclax + R) is superior to bendamustine and rituximab (BR) in participants with relapsed/refractory CLL. The primary endpoint of investigator assessed progression-free survival (PFS) showed significant improvement with venetoclax. - Secondary endpoints, including overall survival (OS), ORR, and complete response rate, also showed consistent clinically meaningful improvements. The Sponsor included an optional R/C Substudy to allow: -- Eligible participants from Arm A (venetoclax + R) who had clinically progressed after finishing treatment, had not received new anti-CLL therapy, and were in need of treatment have the option to receive treatment with venetoclax + R again (re-treatment). This will allow the Sponsor to study the outcomes of participants who are re-treated with venetoclax + R following prior venetoclax + R treatment. -- Eligible participants from Arm B (BR) who had clinically progressed after finishing treatment, have not received new anti-CLL therapy, and are in need of treatment have the option to cross over and receive venetoclax + R given the results of the primary analysis demonstrating superior outcome for venetoclax + R treatment. - The study duration is extended for an additional 45 months to allow for the collection of long-term data including safety, PFS, and OS. At the primary read out, PFS and OS outcomes for participants in the venetoclax + R arm exceed original protocol expectations, thus requiring longer follow-up to enable estimation of a robust efficacy and median PFS.
    30 Mar 2018
    - The reporting of secondary malignancies has been extended after the reporting period to capture all events regardless of causality in order to satisfy health authority requirements. The rationale for biomarker assessments has been updated to include next-generation sequencing analysis. These analyses will provide a comprehensive characterization of genomics to enable the understanding of disease pathobiology. - Sample collection for peripheral blood minimal residual disease (MRD) samples has been extended until clinical progression because participants demonstrated persistent MRD negativity and there is a need to better understand the MRD kinetics over longer period of time.

    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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