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    Clinical Trial Results:
    A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions

    Summary
    EudraCT number
    2014-001810-24
    Trial protocol
    DE   DK   GB   EE   AT   BG   ES   HR   IT   FR   PL  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Sep 2019
    First version publication date
    01 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BO25323
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02242942
    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
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, 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
    Interim
    Date of interim/final analysis
    17 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Aug 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This study compared the efficacy and safety of a combined regimen of obinutuzumab and venetoclax versus obinutuzumab + chlorambucil in subjects with previously untreated chronic lymphocytic leukemia (CLL) and coexisting medical conditions. The study had a safety run-in phase and a main randomized phase with two treatment arms.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Dec 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 47
    Country: Number of subjects enrolled
    New Zealand: 20
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Croatia: 12
    Country: Number of subjects enrolled
    Estonia: 5
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 41
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Brazil: 22
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    United States: 30
    Country: Number of subjects enrolled
    Denmark: 21
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Germany: 58
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    United Kingdom: 8
    Worldwide total number of subjects
    445
    EEA total number of subjects
    262
    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)
    74
    From 65 to 84 years
    356
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 445 subjects were enrolled in the study in 130 centers in 21 countries. The safety run-in cohort enrolled 13 subjects and the main randomized main part of the trial enrolled 432 subjects.

    Pre-assignment
    Screening details
    Subjects with previously untreated CLL and coexisting medical conditions were enrolled in the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Obinutuzumab + Chlorambucil
    Arm description
    Subjects received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised of 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Chlorambucil
    Investigational medicinal product code
    RO0059978
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Chlorambucil was administered orally at a dose of 0.5 mg/kg on Day 1 and Day 15 of each 28-day cycle for 12 cycles.

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    RO5072759
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received obinutuzumab 1000 mg on Days 1, 8 and 15 of Cycle 1 and 1000 mg on Day 1 through Cycles 2-6.

    Arm title
    Obinutuzumab + Venetoclax
    Arm description
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    RO5072759
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received obinutuzumab 1000 mg on Days 1, 8 and 15 of Cycle 1 and 1000 mg on Day 1 through Cycles 2-6.

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    RO553-7382
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received venetoclax 400 mg daily orally for twelve 28-day cycles.

    Arm title
    Safety Run-in Obinutuzumab + Venetoclax
    Arm description
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    RO5072759
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received obinutuzumab intravenously for six 28-day cycles.

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    RO553-7382
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received venetoclax 400 mg orally daily for twelve 28-day cycles.

    Number of subjects in period 1
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Safety Run-in Obinutuzumab + Venetoclax
    Started
    216
    216
    13
    Treated
    214
    212
    13
    Completed
    0
    0
    0
    Not completed
    216
    216
    13
         On-going in Study
    190
    186
    11
         Physician decision
    1
    -
    -
         Adverse event, serious fatal
    17
    20
    2
         Consent withdrawn by subject
    8
    10
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Obinutuzumab + Chlorambucil
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised of 28 days.

    Reporting group title
    Obinutuzumab + Venetoclax
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

    Reporting group title
    Safety Run-in Obinutuzumab + Venetoclax
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

    Reporting group values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Safety Run-in Obinutuzumab + Venetoclax Total
    Number of subjects
    216 216 13 445
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    37 36 1 74
        Elderly (From 65-84 years)
    174 172 10 356
        Elderly 85 years and over
    5 8 2 15
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    71.1 ± 8.0 71.1 ± 8.2 75.4 ± 7.8 -
    Sex: Female, Male
    Units: Subjects
        Female
    73 70 5 148
        Male
    143 146 8 297

    End points

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    End points reporting groups
    Reporting group title
    Obinutuzumab + Chlorambucil
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised of 28 days.

    Reporting group title
    Obinutuzumab + Venetoclax
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

    Reporting group title
    Safety Run-in Obinutuzumab + Venetoclax
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

    Primary: Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria

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    End point title
    Progression Free Survival (PFS) Based on Investigator Assessment According to IWCLL Criteria [1]
    End point description
    PFS was determined according to IWCLL 2008 criteria and defined as the time from randomisation to the first occurrence of PD or death from any cause. Disease progression was characterized by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology. Intent to treat (ITT) population was defined as all randomised subjects. Here, 9999 indicates that the data for the specific time point were not evaluable due to insufficient number of subjects with events.
    End point type
    Primary
    End point timeframe
    Baseline until disease progression or death up to approximately 3.75 years
    Notes
    [1] - 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: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: months
        median (confidence interval 95%)
    9999 (31.1 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    Main study analysis
    Comparison groups
    Obinutuzumab + Venetoclax v Obinutuzumab + Chlorambucil
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.53

    Secondary: Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria

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    End point title
    Progression Free Survival (PFS) Based on Institutional Review Committee (IRC)-Assessments According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria [2]
    End point description
    PFS was determined according to IWCLL 2008 criteria and defined as the time from randomisation to the first occurrence of progressive disease (PD) or death from any cause. Disease progression was characterised by at least one of the following: 1) >/= 50% increase in the absolute number of circulating lymphocytes to at least 5*10^9/L, 2) Appearance of new palpable lymph nodes (> 15 mm in longest diameter) or any new extra-nodal lesion; 3) >/= 50% increase in the longest diameter of any previous site of lymphadenopathy; 4) >/= 50% increase in the enlargement of the liver and/or spleen; 5) Transformation to a more aggressive histology. ITT population was defined as all randomised subjects. Here, 9999 indicates that the data for the specific time point were not evaluable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death up to approximately 3.75 years
    Notes
    [2] - 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: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: months
        median (confidence interval 95%)
    9999 (31.1 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria

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    End point title
    Percentage of Subjects With an Overall Response (OR) at Completion of Treatment, as Determined by the Investigator According to IWCLL Criteria [3]
    End point description
    OR: complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and computed tomography (CT) scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow normocellular for age without clonal infiltrate (except for Cri). PR: two of the following for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. ITT population: all randomised subjects. 9999: data not evaluable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    71.3 (64.77 to 77.23)
    84.7 (79.22 to 89.24)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria

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    End point title
    Percentage of Subjects With a Complete Response Rate (CRR) at the Completion of Treatment Assessment as Determined by the Investigator According to IWCLL Criteria [4]
    End point description
    CRR was defined as the rate of a clinical response of CR or CRi according to IWCLL 2008 criteria. CR requires all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow at least normocellular for age without clonal infiltrate (except for Cri). ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
    Notes
    [4] - 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: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    23.1 (17.70 to 29.35)
    49.5 (42.68 to 56.40)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment

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    End point title
    Percentage of Subjects With Minimal Residual Disease (MRD) Negativity in Peripheral Blood as Measured by Allele-Specific Oligonucleotide Polymerase Chain Reaction (ASO-PCR) at Completion of Treatment [5]
    End point description
    MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood. ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    35.2 (28.83 to 41.95)
    75.5 (69.17 to 81.05)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With MRD Negativity in Bone marrow as Measured by ASO-PCR at Completion of Treatment

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    End point title
    Percentage of Subjects With MRD Negativity in Bone marrow as Measured by ASO-PCR at Completion of Treatment [6]
    End point description
    MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow. ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    At the completion of treatment assessment 3 months after treatment completion (at approximately 15 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    17.1 (12.36 to 22.83)
    56.9 (50.05 to 63.64)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS) [7]
    End point description
    OS was defined as the time between the date of randomization and the date of death due to any cause. ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline until death, up to approximately 5.75 years
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [8] - Data to be reported upon study completion.
    [9] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment

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    End point title
    Percentage of Subjects With MRD Negativity in Peripheral Blood as Measured by ASO-PCR at Completion of Combination Treatment Assessment [10]
    End point description
    MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in peripheral blood. ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 9 or 3 months after last IV infusion, approximately 9 months
    Notes
    [10] - 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: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    38.4 (31.91 to 45.27)
    71.3 (64.77 to 77.23)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment

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    End point title
    Percentage of Subjects With MRD Negativity in Bone Marrow as Measured by ASO-PCR at Completion of Combination Treatment Assessment [11]
    End point description
    MRD negativity was defined as having < 1 CLL cell per 10,000 leucocytes in bone marrow. ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 9 or 3 months after last IV infusion at approximately 9 months
    Notes
    [11] - 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: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    13.0 (8.79 to 18.19)
    51.4 (44.51 to 58.23)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With OR at Completion of Combination Treatment Response Assessment

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    End point title
    Percentage of Subjects With OR at Completion of Combination Treatment Response Assessment [12]
    End point description
    OR was defined as CR, CRi or PR according to IWCLL 2008 criteria. CR required all of the following: peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination, no hepatomegaly or splenomegaly, Absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PR: two of the following features for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following blood counts: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 Cycle 7 or 28 days after last IV infusion, approximately 6 months
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: percentage of subjects
        number (confidence interval 95%)
    86.6 (81.29 to 90.82)
    88.4 (83.39 to 92.37)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response (DOR)

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    End point title
    Duration of Objective Response (DOR) [13]
    End point description
    PD was defined as lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Time from the first occurrence of a documented objective response to the time of PD as determined by the investigator or death from any cause, up to approximately 5.75 years
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data will be analysed only for the randomised arms in the main study once data collection is complete.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [14] - Data to be reported upon study completion.
    [15] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD)

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    End point title
    Percentage of Subjects By Best Response Achieved (CR, CRi, PR, Stable Disease (SD), or PD) [16]
    End point description
    CR: Peripheral blood lymphocytes below 4x10^9/L, absence of lymphadenopathy by physical examination and CT scan, no hepatomegaly or splenomegaly, absence of disease or constitutional symptoms, blood counts of neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L, bone marrow normocellular for age without clonal infiltrate (except for Cri). PR: any 2 for at least 2 months: >/= 50% decrease in peripheral blood lymphocyte count from the pretreatment value, >/=50% reduction in lymphadenopathy, >/=50% reduction of liver and/or spleen enlargement, and at least one of the following: neutrophils >1.5*10^9/L, platelets >100*10^9/L and hemoglobin >110 g/L. PD: lymphadenopathy, >=50% increase in liver or spleen size, >=50% increase in lymphocyte count, transformation to a more aggressive histology or occurrence of cytopenia. SD: non-response used to characterize subjects who did not achieve a CR or a PR, and who have not exhibited PD. ITT population: all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to the completion of treatment assessment 3 months after treatment completion (up to approximately 15 months)
    Notes
    [16] - 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: Efficacy data were analysed only for the randomised arms in the main study.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    216
    216
    Units: percentage of subjects
    number (not applicable)
        CR
    56.0
    70.4
        CRi
    5.6
    7.9
        PR
    29.2
    13.4
        SD
    1.9
    0.5
        PD
    0.5
    0.5
    No statistical analyses for this end point

    Secondary: Event-Free Survival

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    End point title
    Event-Free Survival [17]
    End point description
    ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Time between date of randomisation and the date of disease progression/relapse on the basis of investigator-assessment, death, or start of a new anti-leukemic therapy, up to 5.75 years
    Notes
    [17] - 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: Data will be analysed only for the randomised arms in the main study once data collection is complete.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [18] - Data to be reported upon study completion.
    [19] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Time to Next Anti-Leukemic Treatment

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    End point title
    Time to Next Anti-Leukemic Treatment [20]
    End point description
    ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Time between the date of randomization and the date of first intake of new anti-leukemic therapy, up to 5.75 years
    Notes
    [20] - 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: Data will be analysed only for the randomised arms in the main study once data collection is complete.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [21]
    0 [22]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [21] - Data to be reported upon study completion.
    [22] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs)

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    End point title
    Number of Subjects With Adverse Events (AEs) [23]
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs. Safety population was defined as all subjects who received at least one dose of any study medication (i.e., obinutuzumab, venetoclax, or chlorambucil).
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.75 years
    Notes
    [23] - 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: Data will be analysed only for the randomised arms in the main study once data collection is complete.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: subjects
    Notes
    [24] - Data to be reported upon study completion.
    [25] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With CD19 + /CD5+ B Cells or CD14+ monocytes

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    End point title
    Percentage of Subjects With CD19 + /CD5+ B Cells or CD14+ monocytes
    End point description
    ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5.75 years
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Safety Run-in Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [26]
    0 [27]
    0 [28]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [26] - Data to be reported upon study completion.
    [27] - Data to be reported upon study completion.
    [28] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Human-Anti-Human Antibodies

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    End point title
    Percentage of Subjects With Human-Anti-Human Antibodies
    End point description
    ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5.75 years
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Safety Run-in Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [29]
    0 [30]
    0 [31]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [29] - Data to be reported upon study completion.
    [30] - Data to be reported upon study completion.
    [31] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Recorded as Premature Study Withdrawals

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    End point title
    Percentage of Subjects Recorded as Premature Study Withdrawals
    End point description
    ITT population was defined as all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to approximately 5.75 years
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Safety Run-in Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [32]
    0 [33]
    0 [34]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [32] - Data to be reported upon study completion.
    [33] - Data to be reported upon study completion.
    [34] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Venetoclax

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    End point title
    Plasma Concentrations of Venetoclax [35]
    End point description
    Analysis population consisted of those subjects from whom one or more plasma samples were collected and who had received at least one dose of venetoclax treatment.
    End point type
    Secondary
    End point timeframe
    Pre-venetoclax dose (0 hour) and 4 hours post- venetoclax dose on Day 1 Cycle 4
    Notes
    [35] - 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: Samples were only collected for the obinutuzumab + venetoclax arm in the study.
    End point values
    Obinutuzumab + Venetoclax
    Number of subjects analysed
    201
    Units: μg/mL
    arithmetic mean (standard deviation)
        Pre-Dose (n=129)
    0.578 ± 0.533
        4 hours Post-Dose (n=142)
    1.21 ± 0.765
    No statistical analyses for this end point

    Secondary: Serum Concentrations of Obinutuzumab

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    End point title
    Serum Concentrations of Obinutuzumab [36]
    End point description
    Analysis population consisted of subjects from whom one or more serum samples were collected and who had received at least one dose of obinutuzumab treatment.
    End point type
    Secondary
    End point timeframe
    Pre-obinutuzumab infusion (0 hour) and end of obinutuzumab infusion on Day 1 Cycle 4
    Notes
    [36] - 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: Samples were only collected for the obinutuzumab + venetoclax arm in the study.
    End point values
    Obinutuzumab + Venetoclax
    Number of subjects analysed
    201
    Units: μg/mL
    arithmetic mean (standard deviation)
        Pre-Dose (n=133)
    258 ± 140
        4 hours Post-Dose (n=133)
    568 ± 187
    No statistical analyses for this end point

    Secondary: Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) score

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    End point title
    Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) score [37]
    End point description
    MDASI-CLL: questionnaire of 25 items related to CLL specific symptoms that a subject may have experienced in the past 24 hours. Subjects were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is “not present”/“did not interfere” with the subject’s activities and 10 indicating “as bad as you can imagine”/“interfered completely”. Scores were averaged (range 0 to 10) for each part.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5.75 years
    Notes
    [37] - 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: Data will be analysed only for the randomised arms in the main study once data collection is complete.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [38]
    0 [39]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [38] - Data to be reported upon study completion.
    [39] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)

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    End point title
    Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQC30)
    End point description
    The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality−of−life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from “not at all” to “very much,” and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from “very poor” to “excellent.” Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5.75 years
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Safety Run-in Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [40]
    0 [41]
    0 [42]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Notes
    [40] - Data to be reported upon study completion.
    [41] - Data to be reported upon study completion.
    [42] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Secondary: Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L)

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    End point title
    Change From Baseline in EuroQol 5 Dimension Questionnaire (EQ-5D-3L) [43]
    End point description
    The EQ-5D-3L questionnaire is a generic, preference based health utility measure that assesses 5 health states (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and is used to build a composite of the patient’s health status. The EQ-5D-3L was employed in this study to calculate health utilities for economic modeling, which ranged 0-1. The EQ-5D-3L also contained a visual analog scale (VAS) to assess the participant’s overall health, which ranged from 0-100 with a higher score indicating a worse health status.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 5.75 years
    Notes
    [43] - 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: Data will be analysed only for the randomised arms in the main study once data collection is complete.
    End point values
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax
    Number of subjects analysed
    0 [44]
    0 [45]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [44] - Data to be reported upon study completion.
    [45] - Data to be reported upon study completion.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs: up to 1 year, Grade 3-4 AEs: up to 1.5 years, Grade 3-4 major infections: up to 3 years (causality only if subject received leukemic treatment). SAEs: before PD up to 3.75 years, after PD only related SAEs and second primary malignancies.
    Adverse event reporting additional description
    Safety population was defined as all subjects who received at least one dose of any study medication (i.e., obinutuzumab, venetoclax, or chlorambucil).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Obinutuzumab + Chlorambucil
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and chlorambucil for 12 cycles. Cycles comprised of 28 days.

    Reporting group title
    Obinutuzumab + Venetoclax
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

    Reporting group title
    Safety Run-in Obinutuzumab + Venetoclax
    Reporting group description
    Subjects received obinutuzumab for 6 cycles and venetoclax for 12 cycles. Cycles comprised of 28 days.

    Serious adverse events
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Safety Run-in Obinutuzumab + Venetoclax
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 214 (42.06%)
    104 / 212 (49.06%)
    10 / 13 (76.92%)
         number of deaths (all causes)
    9
    16
    2
         number of deaths resulting from adverse events
    1
    5
    0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Aortic valve replacement
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device removal
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Anal squamous cell carcinoma
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bladder cancer recurrent
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Penile cancer
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland adenoma
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sarcoma of skin
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Skin squamous cell carcinoma metastatic
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    3 / 214 (1.40%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    T-cell lymphoma
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    7 / 214 (3.27%)
    8 / 212 (3.77%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    5 / 8
    3 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chillblains
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    13 / 214 (6.07%)
    9 / 212 (4.25%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    12 / 13
    9 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasoplegia syndrome
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound evisceration
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 214 (1.40%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 214 (1.87%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 214 (1.40%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 214 (0.47%)
    3 / 212 (1.42%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 214 (1.40%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Gilbert's syndrome
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 214 (0.93%)
    3 / 212 (1.42%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 214 (0.93%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 214 (0.47%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coombs negative haemolytic anaemia
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    8 / 214 (3.74%)
    11 / 212 (5.19%)
    3 / 13 (23.08%)
         occurrences causally related to treatment / all
    9 / 10
    11 / 12
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 214 (0.47%)
    3 / 212 (1.42%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenomegaly
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    5 / 214 (2.34%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 214 (0.93%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye inflammation
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 214 (0.47%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 214 (0.93%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    4 / 214 (1.87%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 214 (0.93%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 214 (0.00%)
    3 / 212 (1.42%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eczema infected
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 214 (0.93%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 214 (0.93%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 214 (4.21%)
    10 / 212 (4.72%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    6 / 11
    3 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 214 (0.47%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 214 (0.93%)
    6 / 212 (2.83%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    2 / 5
    0 / 1
    Septic shock
         subjects affected / exposed
    2 / 214 (0.93%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Sinusitis aspergillus
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 214 (0.47%)
    2 / 212 (0.94%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection fungal
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Obinutuzumab + Chlorambucil Obinutuzumab + Venetoclax Safety Run-in Obinutuzumab + Venetoclax
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    205 / 214 (95.79%)
    193 / 212 (91.04%)
    12 / 13 (92.31%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 214 (1.40%)
    2 / 212 (0.94%)
    2 / 13 (15.38%)
         occurrences all number
    3
    2
    2
    Hypertension
         subjects affected / exposed
    11 / 214 (5.14%)
    12 / 212 (5.66%)
    0 / 13 (0.00%)
         occurrences all number
    12
    17
    0
    Hypotension
         subjects affected / exposed
    8 / 214 (3.74%)
    11 / 212 (5.19%)
    2 / 13 (15.38%)
         occurrences all number
    10
    15
    2
    Thrombophlebitis
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    5 / 214 (2.34%)
    6 / 212 (2.83%)
    1 / 13 (7.69%)
         occurrences all number
    6
    6
    1
    Benign breast neoplasm
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    Skin papilloma
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Asthenia
         subjects affected / exposed
    17 / 214 (7.94%)
    14 / 212 (6.60%)
    0 / 13 (0.00%)
         occurrences all number
    20
    20
    0
    Chills
         subjects affected / exposed
    10 / 214 (4.67%)
    12 / 212 (5.66%)
    1 / 13 (7.69%)
         occurrences all number
    13
    14
    1
    Extravasation
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    1
    Fatigue
         subjects affected / exposed
    29 / 214 (13.55%)
    32 / 212 (15.09%)
    3 / 13 (23.08%)
         occurrences all number
    36
    40
    6
    Influenza like illness
         subjects affected / exposed
    3 / 214 (1.40%)
    4 / 212 (1.89%)
    1 / 13 (7.69%)
         occurrences all number
    3
    4
    1
    Oedema
         subjects affected / exposed
    7 / 214 (3.27%)
    3 / 212 (1.42%)
    1 / 13 (7.69%)
         occurrences all number
    7
    3
    1
    Oedema peripheral
         subjects affected / exposed
    16 / 214 (7.48%)
    17 / 212 (8.02%)
    1 / 13 (7.69%)
         occurrences all number
    18
    20
    2
    Pyrexia
         subjects affected / exposed
    26 / 214 (12.15%)
    40 / 212 (18.87%)
    3 / 13 (23.08%)
         occurrences all number
    28
    53
    4
    Sensation of foreign body
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 214 (0.47%)
    8 / 212 (3.77%)
    1 / 13 (7.69%)
         occurrences all number
    1
    8
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Eye contusion
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Fall
         subjects affected / exposed
    8 / 214 (3.74%)
    5 / 212 (2.36%)
    1 / 13 (7.69%)
         occurrences all number
    11
    7
    1
    Head injury
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Infusion related reaction
         subjects affected / exposed
    103 / 214 (48.13%)
    89 / 212 (41.98%)
    9 / 13 (69.23%)
         occurrences all number
    131
    122
    10
    Limb injury
         subjects affected / exposed
    4 / 214 (1.87%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    4
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 214 (6.07%)
    11 / 212 (5.19%)
    0 / 13 (0.00%)
         occurrences all number
    15
    15
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 214 (7.94%)
    12 / 212 (5.66%)
    0 / 13 (0.00%)
         occurrences all number
    20
    14
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    6 / 214 (2.80%)
    7 / 212 (3.30%)
    1 / 13 (7.69%)
         occurrences all number
    6
    9
    2
    Blood glucose increased
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 214 (0.93%)
    2 / 212 (0.94%)
    2 / 13 (15.38%)
         occurrences all number
    2
    2
    2
    Blood magnesium decreased
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Blood phosphorus increased
         subjects affected / exposed
    1 / 214 (0.47%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    1
    C-reactive protein increased
         subjects affected / exposed
    2 / 214 (0.93%)
    4 / 212 (1.89%)
    1 / 13 (7.69%)
         occurrences all number
    2
    4
    1
    Neutrophil count decreased
         subjects affected / exposed
    11 / 214 (5.14%)
    10 / 212 (4.72%)
    0 / 13 (0.00%)
         occurrences all number
    32
    27
    0
    Procalcitonin increased
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Protein total decreased
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Transaminases increased
         subjects affected / exposed
    2 / 214 (0.93%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    1
    Weight decreased
         subjects affected / exposed
    5 / 214 (2.34%)
    5 / 212 (2.36%)
    1 / 13 (7.69%)
         occurrences all number
    5
    5
    1
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 214 (0.47%)
    5 / 212 (2.36%)
    1 / 13 (7.69%)
         occurrences all number
    1
    5
    1
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 214 (11.21%)
    33 / 212 (15.57%)
    6 / 13 (46.15%)
         occurrences all number
    27
    37
    6
    Dyspnoea
         subjects affected / exposed
    11 / 214 (5.14%)
    11 / 212 (5.19%)
    1 / 13 (7.69%)
         occurrences all number
    12
    12
    2
    Epistaxis
         subjects affected / exposed
    4 / 214 (1.87%)
    3 / 212 (1.42%)
    1 / 13 (7.69%)
         occurrences all number
    5
    3
    1
    Pharyngeal paraesthesia
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Productive cough
         subjects affected / exposed
    3 / 214 (1.40%)
    6 / 212 (2.83%)
    1 / 13 (7.69%)
         occurrences all number
    3
    6
    2
    Rhinorrhoea
         subjects affected / exposed
    3 / 214 (1.40%)
    3 / 212 (1.42%)
    1 / 13 (7.69%)
         occurrences all number
    3
    3
    1
    Throat irritation
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    39 / 214 (18.22%)
    33 / 212 (15.57%)
    2 / 13 (15.38%)
         occurrences all number
    55
    53
    2
    Leukopenia
         subjects affected / exposed
    13 / 214 (6.07%)
    12 / 212 (5.66%)
    1 / 13 (7.69%)
         occurrences all number
    19
    23
    1
    Neutropenia
         subjects affected / exposed
    122 / 214 (57.01%)
    121 / 212 (57.08%)
    8 / 13 (61.54%)
         occurrences all number
    294
    370
    12
    Thrombocytopenia
         subjects affected / exposed
    49 / 214 (22.90%)
    49 / 212 (23.11%)
    2 / 13 (15.38%)
         occurrences all number
    76
    86
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    17 / 214 (7.94%)
    16 / 212 (7.55%)
    4 / 13 (30.77%)
         occurrences all number
    20
    18
    5
    Headache
         subjects affected / exposed
    21 / 214 (9.81%)
    23 / 212 (10.85%)
    3 / 13 (23.08%)
         occurrences all number
    24
    29
    3
    Paraesthesia
         subjects affected / exposed
    1 / 214 (0.47%)
    4 / 212 (1.89%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    1
    Presyncope
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    2 / 13 (15.38%)
         occurrences all number
    1
    1
    3
    Somnolence
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Syncope
         subjects affected / exposed
    4 / 214 (1.87%)
    5 / 212 (2.36%)
    2 / 13 (15.38%)
         occurrences all number
    4
    5
    2
    Tremor
         subjects affected / exposed
    3 / 214 (1.40%)
    6 / 212 (2.83%)
    1 / 13 (7.69%)
         occurrences all number
    4
    6
    1
    Ear and labyrinth disorders
    Excessive cerumen production
         subjects affected / exposed
    0 / 214 (0.00%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 214 (4.67%)
    11 / 212 (5.19%)
    2 / 13 (15.38%)
         occurrences all number
    11
    15
    2
    Abdominal pain upper
         subjects affected / exposed
    4 / 214 (1.87%)
    7 / 212 (3.30%)
    1 / 13 (7.69%)
         occurrences all number
    4
    7
    1
    Constipation
         subjects affected / exposed
    19 / 214 (8.88%)
    28 / 212 (13.21%)
    5 / 13 (38.46%)
         occurrences all number
    23
    32
    6
    Diarrhoea
         subjects affected / exposed
    32 / 214 (14.95%)
    59 / 212 (27.83%)
    5 / 13 (38.46%)
         occurrences all number
    42
    99
    8
    Dry mouth
         subjects affected / exposed
    4 / 214 (1.87%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    4
    0
    1
    Dyspepsia
         subjects affected / exposed
    3 / 214 (1.40%)
    7 / 212 (3.30%)
    1 / 13 (7.69%)
         occurrences all number
    3
    7
    1
    Epigastric discomfort
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    Nausea
         subjects affected / exposed
    46 / 214 (21.50%)
    40 / 212 (18.87%)
    4 / 13 (30.77%)
         occurrences all number
    62
    61
    7
    Stomatitis
         subjects affected / exposed
    2 / 214 (0.93%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    2
    Vomiting
         subjects affected / exposed
    18 / 214 (8.41%)
    21 / 212 (9.91%)
    3 / 13 (23.08%)
         occurrences all number
    22
    27
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 214 (0.93%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    1
    Renal failure
         subjects affected / exposed
    1 / 214 (0.47%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    3
    Renal impairment
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    6 / 214 (2.80%)
    4 / 212 (1.89%)
    2 / 13 (15.38%)
         occurrences all number
    7
    4
    2
    Erythema
         subjects affected / exposed
    4 / 214 (1.87%)
    2 / 212 (0.94%)
    2 / 13 (15.38%)
         occurrences all number
    4
    2
    2
    Pruritus
         subjects affected / exposed
    9 / 214 (4.21%)
    18 / 212 (8.49%)
    6 / 13 (46.15%)
         occurrences all number
    9
    20
    6
    Rash
         subjects affected / exposed
    12 / 214 (5.61%)
    12 / 212 (5.66%)
    2 / 13 (15.38%)
         occurrences all number
    13
    12
    3
    Urticaria
         subjects affected / exposed
    5 / 214 (2.34%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    5
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 214 (8.41%)
    16 / 212 (7.55%)
    1 / 13 (7.69%)
         occurrences all number
    23
    19
    1
    Back pain
         subjects affected / exposed
    20 / 214 (9.35%)
    21 / 212 (9.91%)
    2 / 13 (15.38%)
         occurrences all number
    21
    24
    2
    Groin pain
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    11 / 214 (5.14%)
    10 / 212 (4.72%)
    1 / 13 (7.69%)
         occurrences all number
    11
    11
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    2 / 13 (15.38%)
         occurrences all number
    0
    4
    2
    Musculoskeletal pain
         subjects affected / exposed
    4 / 214 (1.87%)
    7 / 212 (3.30%)
    1 / 13 (7.69%)
         occurrences all number
    4
    8
    2
    Pain in extremity
         subjects affected / exposed
    13 / 214 (6.07%)
    10 / 212 (4.72%)
    1 / 13 (7.69%)
         occurrences all number
    14
    11
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 214 (2.80%)
    10 / 212 (4.72%)
    1 / 13 (7.69%)
         occurrences all number
    8
    10
    1
    Gout
         subjects affected / exposed
    1 / 214 (0.47%)
    3 / 212 (1.42%)
    1 / 13 (7.69%)
         occurrences all number
    2
    4
    1
    Hyperglycaemia
         subjects affected / exposed
    7 / 214 (3.27%)
    14 / 212 (6.60%)
    2 / 13 (15.38%)
         occurrences all number
    7
    16
    4
    Hyperkalaemia
         subjects affected / exposed
    5 / 214 (2.34%)
    4 / 212 (1.89%)
    5 / 13 (38.46%)
         occurrences all number
    6
    13
    7
    Hyperphosphataemia
         subjects affected / exposed
    3 / 214 (1.40%)
    4 / 212 (1.89%)
    1 / 13 (7.69%)
         occurrences all number
    3
    5
    1
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 214 (0.47%)
    2 / 212 (0.94%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 214 (2.34%)
    11 / 212 (5.19%)
    1 / 13 (7.69%)
         occurrences all number
    6
    14
    2
    Cystitis
         subjects affected / exposed
    2 / 214 (0.93%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    1
    Ear infection
         subjects affected / exposed
    0 / 214 (0.00%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    Eye infection
         subjects affected / exposed
    1 / 214 (0.47%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    3
    Herpes zoster
         subjects affected / exposed
    6 / 214 (2.80%)
    9 / 212 (4.25%)
    1 / 13 (7.69%)
         occurrences all number
    7
    9
    1
    Influenza
         subjects affected / exposed
    4 / 214 (1.87%)
    3 / 212 (1.42%)
    1 / 13 (7.69%)
         occurrences all number
    4
    3
    1
    Localised infection
         subjects affected / exposed
    3 / 214 (1.40%)
    1 / 212 (0.47%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    14 / 214 (6.54%)
    16 / 212 (7.55%)
    0 / 13 (0.00%)
         occurrences all number
    16
    16
    0
    Oral herpes
         subjects affected / exposed
    4 / 214 (1.87%)
    5 / 212 (2.36%)
    1 / 13 (7.69%)
         occurrences all number
    5
    7
    4
    Paronychia
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    3 / 214 (1.40%)
    6 / 212 (2.83%)
    1 / 13 (7.69%)
         occurrences all number
    3
    9
    1
    Respiratory tract infection
         subjects affected / exposed
    6 / 214 (2.80%)
    10 / 212 (4.72%)
    1 / 13 (7.69%)
         occurrences all number
    7
    14
    3
    Rhinitis
         subjects affected / exposed
    5 / 214 (2.34%)
    2 / 212 (0.94%)
    1 / 13 (7.69%)
         occurrences all number
    6
    3
    1
    Sinusitis
         subjects affected / exposed
    6 / 214 (2.80%)
    8 / 212 (3.77%)
    1 / 13 (7.69%)
         occurrences all number
    6
    8
    1
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 214 (7.01%)
    16 / 212 (7.55%)
    2 / 13 (15.38%)
         occurrences all number
    17
    19
    4
    Urinary tract infection
         subjects affected / exposed
    9 / 214 (4.21%)
    10 / 212 (4.72%)
    1 / 13 (7.69%)
         occurrences all number
    10
    13
    1
    Viral skin infection
         subjects affected / exposed
    0 / 214 (0.00%)
    0 / 212 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2014
    Correction of inclusion criterion and clarification of adverse event (AE) reporting.
    07 Nov 2014
    Alignment of contraceptive requirements with product information for obinutuzumab in the inclusion criteria.
    21 May 2015
    Modification/correction of tumor lysis syndrome (TLS) laboratory assessments. Correction/modification of inclusion and exclusion criteria regarding infection and timing of CYP3A inhibitors/inducers relative to venetoclax dosing. Reporting of AEs and serious adverse events (SAEs) during follow-up period was modified in accordance with German Ethics Committee Chairman recommendation. Contraception and pregnancy testing requirements were updated to comply with International Conference for Harmonization (ICH) and health authority guidance.
    02 Nov 2015
    Inclusion of new safety data for obinutuzumab relating to subjects with previous history of gastrointestinal bleeding. Cytogenetic sample moved to screening visit so that results are available prior to randomization of the subject into the trial, allowing investigators to decide whether alternative treatment should be considered, particularly for subjects with 17p deletion and/or TP53 mutation. Clarification of eligibility of subjects with previous infections and timing of CYP3A inhibitors/inducers relative to venetoclax dosing, and clarification that subjects with previous deep vein thrombosis or pulmonary embolism could continue treatment if they did not revert to > Grade 1.
    29 Mar 2017
    Modification of timing of the interim analysis for efficacy to introduce a date-based stopping rule for PFS. Amendment of PFS analysis assumptions. Clarification that all response assessments to be made according to iwCLL criteria. In addition, clarification of response criteria for stable disease. Removal of requirement for first meal of day to be a low-fat meal.
    12 Feb 2018
    Addition of the option to add an additional earlier interim efficacy analysis to mitigate the potential for an undue delay in delivery of the study read-out. Prolongation of blood sample collection to characterize MRD kinetics in subjects responding longer than originally expected. Addition of complete response as a stand-alone secondary endpoint. Clarification of time windows for assessment of blood sampling for B-cell recovery and removal of an inconsistency in reporting instructions for unrelated SAEs.

    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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