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    Clinical Trial Results:
    A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib in Combination with Obinutuzumab versus Chlorambucil in Combination with Obinutuzumab in Subjects with Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Summary
    EudraCT number
    		 2014-002069-31
    Trial protocol
    		 SE   IT   CZ   AT   BE   ES   PL  
    Global end of trial date
    03 Sep 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 Aug 2020
    First version publication date
    12 Apr 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    In the current CSR addendum for Study 1130, data are summarized for subjects through the clinical data cut-off date for the final analysis (17 October 2019, with last subject last visit on 03 September 2019), covering approximately 19 months of additional follow-up. At study closure, sites with active subjects without progressive disease who were still receiving ibrutinib treatment were given an option to enroll in an extension study to continue ibrutinib treatment. Information on the subject di

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1130-CA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02264574
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharmacyclics LLC
    Sponsor organisation address
    995 East Arques Avenue, Sunnyvale, United States, 94085-4521
    Public contact
    Clinical Trial information, Pharmacyclics LLC, +1 4087740330, info@pcyc.com
    Scientific contact
    Clinical Trial information, Pharmacyclics LLC, +1 4087740330, info@pcyc.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of ibrutinib in combination with obinutuzumab compared to chlorambucil in combination with obinutuzumab based on the Independent Review Committee (IRC) assessment of progression-free survival (PFS) in subjects with treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 The anti-CD20 antibody obinutuzumab was chosen as the appropriate anti-CD20 antibody partner to ibrutinib in Study 1130 based on results from the Phase 3 CLL11 study demonstrating superior efficacy. In the CLL11 study, obinutuzumab was used with chlorambucil (Clb+Ob; N = 333) in the first-line setting in patients with CLL with comorbidities in a comparison to either chlorambucil alone or to the combination of chlorambucil and rituximab.
    Actual start date of recruitment
    06 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Turkey: 28
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 24
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    New Zealand: 9
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Russian Federation: 20
    Worldwide total number of subjects
    229
    EEA total number of subjects
    110
    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)
    46
    From 65 to 84 years
    177
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 71 sites: 8 in the US, 36 in the EU, and 27 sites in 6 additional countries (Canada, Australia, New Zealand, Russia, Israel, Turkey). The first subject consented 06 Oct 2014 and the data base lock for the last visit of the last subjects was 17 Oct 2019.

    Pre-assignment
    Screening details
    		 Eligible subjects required to have had a diagnosis of active CLL/SLL conformant to IWCLL 2008 criteria. All subjects were required to have measurable nodal disease. Key exclusion criteria included any previous CLL/SLL treatment; known lymphoma or leukemia of the central nervous system, history/ current evidence of Richter’s transformation.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IBR + OB
    Arm description
    		 Ibrutinib given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib given orally at a dose of 420 mg/day (3 capsules of 140 mg each) until progressive disease or unacceptable toxicity.

    Investigational medicinal product name
    obinutuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.

    Arm title
    		 CLB + OB
    Arm description
    		 Chlorambucil given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    chlorambucil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet and powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Chlorambucil given orally at a dose of 0.5 mg/kg body weight on Days 1 and 15 of each cycle plus intravenous obinutuzumab per instructions shown for Arm A up to a total of 6 cycles.

    Investigational medicinal product name
    obinutuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.

    Number of subjects in period 1
    		IBR + OB CLB + OB
    Started
    113
    116
    Completed
    107
    108
    Not completed
    6
    8
         Consent withdrawn by subject
    6
    5
         various other reasons
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IBR + OB
    Reporting group description
    		 Ibrutinib given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.

    Reporting group title
    CLB + OB
    Reporting group description
    		 Chlorambucil given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.

    Reporting group values
    		 IBR + OB CLB + OB Total
    Number of subjects
    		 113 116 229
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 22 24 46
        From 65-84 years
    		 88 89 177
        85 years and over
    		 3 3 6
    Age continuous
    Units: years
        median (full range (min-max))
    		 70.0 (47 to 87) 72.0 (40 to 86) -
    Gender categorical
    Units: Subjects
        Female
    		 46 37 83
        Male
    		 67 79 146

    End points

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    End points reporting groups
    Reporting group title
    IBR + OB
    Reporting group description
    		 Ibrutinib given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity.

    Reporting group title
    CLB + OB
    Reporting group description
    		 Chlorambucil given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity.

    Primary: Progression Free Survival (PFS) - Investigator asssessed

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    End point title
    		 Progression Free Survival (PFS) - Investigator asssessed
    End point description
    PFS in this final analysis is defined as time from the date of randomization to the date of first investigator-confirmed disease progression (PD) or date of death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. As the median PFS was not reached in the experimental (Ibr+Ob) arm at time of analysis, Kaplan Meier point estimates of the PFS rate at 48 months are presented. For the final analysis the primary efficacy endpoint was investigator-assessed PFS (primary analysis: IRC-assessed PFS).
    End point type
    Primary
    End point timeframe
    The final analysis was performed after a median follow-up time 44.6 months.
    End point values
    		 IBR + OB CLB + OB
    Number of subjects analysed
    113
    116
    Units: percent
        number (confidence interval 95%)
    74.0 (64.3 to 81.4)
    22.0 (11.0 to 35.4)
    Statistical analysis title
    		 Progression free survival (PFS)
    Statistical analysis description
    The treatment effect was tested with an unstratified log rank test. The hazard ratio and its 95% confidence interval were based on a Cox regression model with treatment as the only covariate.
    Comparison groups
    IBR + OB v CLB + OB
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.251
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.162
         upper limit
    		 0.389

    Secondary: PFS in high-risk subpopulation - Investigator assessed

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    End point title
    		 PFS in high-risk subpopulation - Investigator assessed
    End point description
    PFS per investigator assessment as defined in primary endpoint was analyzed within a high-risk subpopulation which defined as randomized subjects with del17p/TP53 mutation or del 11q or unmutated IGHV at baseline. As the upper 95% CI value was not estimable in the experimental (Ibr+Ob) arm at time of analysis, Kaplan Meier point estimates of the PFS rate at 48 months are presented. Median PFS was 49.0 months in the Ibr+Ob arm and 18.0 months in the Clb+Ob arm.
    End point type
    Secondary
    End point timeframe
    Results after an overall median follow-up time of 44.6 months.
    End point values
    		 IBR + OB CLB + OB
    Number of subjects analysed
    73
    75
    Units: percent
        number (confidence interval 95%)
    70.3 (57.6 to 79.8)
    8.0 (2.3 to 18.6)
    Statistical analysis title
    		 PFS in high risk group
    Statistical analysis description
    The treatment effect was tested with an unstratified log rank test. The hazard ratio and its 95% confidence interval were based on an unstratified Cox regression model with treatment as the only covariate.
    Comparison groups
    IBR + OB v CLB + OB
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.169
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.102
         upper limit
    		 0.282

    Secondary: Rate of Sustained Hemoglobin Improvement

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    End point title
    		 Rate of Sustained Hemoglobin Improvement
    End point description
    Proportion of subjects with hemoglobin increase ≥ 2 g/dL over baseline continuously for ≥ 56 days without blood transfusions or growth factors.
    End point type
    Secondary
    End point timeframe
    Results at an overall median follow-up time of 44.6 months.
    End point values
    		 IBR + OB CLB + OB
    Number of subjects analysed
    113
    116
    Units: percent
        number (not applicable)
    44.2
    44.0
    Statistical analysis title
    		 Proportion of Sustained Hemoglobin Improvement
    Comparison groups
    IBR + OB v CLB + OB
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9657
    Method
    		 Chi-squared
    Confidence interval

    Secondary: MRD negative response rate

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    End point title
    		 MRD negative response rate
    End point description
    MRD-negative response in bone marrow and/or peripheral blood samples. MRD samples collected before initiation of subsequent antineoplastic treatment and the MRD status were reported by central lab within 5 days after sample taken are used in this summary. Subjects with missing MRD data are considered non-responders.
    End point type
    Secondary
    End point timeframe
    Results at an overall median follow-up time of 44.6 months.
    End point values
    		 IBR + OB CLB + OB
    Number of subjects analysed
    113
    116
    Units: percent
        number (not applicable)
    38.1
    25.0
    No statistical analyses for this end point

    Secondary: Overall Response Rate - Investigator assessed

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    End point title
    		 Overall Response Rate - Investigator assessed
    End point description
    ORR included subjects with complete response, complete response with incomplete blood count recovery, and partial response.
    End point type
    Secondary
    End point timeframe
    Results after a median follow-up time of 44.6 months.
    End point values
    		 IBR + OB CLB + OB
    Number of subjects analysed
    113
    116
    Units: percent
        number (not applicable)
    91.2
    81.0
    Statistical analysis title
    		 Overall response rate
    Comparison groups
    IBR + OB v CLB + OB
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0273
    Method
    		 Chi-squared
    Parameter type
    		 Rate ratio
    Point estimate
    1.125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.013
         upper limit
    		 1.25

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    As the median OS was not reached in either treatment arm at time of analysis, Kaplan Meier point estimates of the OS rate at 48 months are presented.
    End point type
    Secondary
    End point timeframe
    Results are presented after a median follow-up time of 44.6 months.
    End point values
    		 IBR + OB CLB + OB
    Number of subjects analysed
    113
    116
    Units: percent
        number (confidence interval 95%)
    80.5 (71.6 to 86.9)
    81.3 (72.8 to 87.4)
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    IBR + OB v CLB + OB
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7934
    Method
    		 unstratified logrank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.595
         upper limit
    		 1.973

    Secondary: Rate of sustained platelet improvement

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    End point title
    		 Rate of sustained platelet improvement
    End point description
    Sustained platelet improvement was defined as platelet counts increase ≥50% over baseline continuously for ≥56 days without blood transfusion or growth factors.
    End point type
    Secondary
    End point timeframe
    Results are presented after a median follow-up time of 44.6 months.
    End point values
    		 IBR + OB CLB + OB
    Number of subjects analysed
    113
    116
    Units: percent
        number (not applicable)
    30.1
    14.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after the last dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Arm IBR + OB
    Reporting group description
    		 -

    Reporting group title
    Arm CLB +OB
    Reporting group description
    		 -

    Serious adverse events
    		 Arm IBR + OB Arm CLB +OB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    69 / 113 (61.06%)
    41 / 115 (35.65%)
         number of deaths (all causes)
    22
    21
         number of deaths resulting from adverse events
    14
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    3 / 113 (2.65%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign renal neoplasm
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Essential thrombocythaemia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Prostate cancer
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 113 (3.54%)
    4 / 115 (3.48%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site haematoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Multi-organ disorder
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 113 (1.77%)
    8 / 115 (6.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    6 / 113 (5.31%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    3 / 113 (2.65%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    5 / 113 (4.42%)
    7 / 115 (6.09%)
         occurrences causally related to treatment / all
    4 / 5
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 113 (2.65%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    4 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 113 (0.88%)
    2 / 115 (1.74%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal rupture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 115 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 113 (1.77%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inclusion body myositis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    8 / 113 (7.08%)
    5 / 115 (4.35%)
         occurrences causally related to treatment / all
    8 / 14
    2 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    3 / 113 (2.65%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 113 (2.65%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective staphylococcal
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective aneurysm
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 113 (1.77%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 115 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular device infection
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate infection
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 113 (0.00%)
    5 / 115 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm IBR + OB Arm CLB +OB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 113 (99.12%)
    112 / 115 (97.39%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 113 (19.47%)
    5 / 115 (4.35%)
         occurrences all number
    24
    10
    Hypotension
         subjects affected / exposed
    1 / 113 (0.88%)
    6 / 115 (5.22%)
         occurrences all number
    1
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    22 / 113 (19.47%)
    19 / 115 (16.52%)
         occurrences all number
    27
    24
    Pyrexia
         subjects affected / exposed
    19 / 113 (16.81%)
    28 / 115 (24.35%)
         occurrences all number
    29
    37
    Oedema peripheral
         subjects affected / exposed
    14 / 113 (12.39%)
    8 / 115 (6.96%)
         occurrences all number
    18
    9
    Asthenia
         subjects affected / exposed
    12 / 113 (10.62%)
    17 / 115 (14.78%)
         occurrences all number
    14
    18
    Chills
         subjects affected / exposed
    7 / 113 (6.19%)
    10 / 115 (8.70%)
         occurrences all number
    7
    11
    Peripheral swelling
         subjects affected / exposed
    7 / 113 (6.19%)
    2 / 115 (1.74%)
         occurrences all number
    8
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    33 / 113 (29.20%)
    14 / 115 (12.17%)
         occurrences all number
    48
    19
    Dyspnoea
         subjects affected / exposed
    12 / 113 (10.62%)
    15 / 115 (13.04%)
         occurrences all number
    20
    20
    Oropharyngeal pain
         subjects affected / exposed
    8 / 113 (7.08%)
    4 / 115 (3.48%)
         occurrences all number
    11
    4
    Productive cough
         subjects affected / exposed
    8 / 113 (7.08%)
    2 / 115 (1.74%)
         occurrences all number
    9
    2
    Epistaxis
         subjects affected / exposed
    7 / 113 (6.19%)
    9 / 115 (7.83%)
         occurrences all number
    11
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 113 (11.50%)
    5 / 115 (4.35%)
         occurrences all number
    14
    5
    Anxiety
         subjects affected / exposed
    10 / 113 (8.85%)
    8 / 115 (6.96%)
         occurrences all number
    12
    8
    Depression
         subjects affected / exposed
    7 / 113 (6.19%)
    1 / 115 (0.87%)
         occurrences all number
    10
    1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    8 / 113 (7.08%)
    1 / 115 (0.87%)
         occurrences all number
    14
    1
    Weight decreased
         subjects affected / exposed
    3 / 113 (2.65%)
    6 / 115 (5.22%)
         occurrences all number
    3
    6
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    26 / 113 (23.01%)
    61 / 115 (53.04%)
         occurrences all number
    30
    70
    Fall
         subjects affected / exposed
    10 / 113 (8.85%)
    3 / 115 (2.61%)
         occurrences all number
    10
    4
    Contusion
         subjects affected / exposed
    6 / 113 (5.31%)
    1 / 115 (0.87%)
         occurrences all number
    6
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    16 / 113 (14.16%)
    0 / 115 (0.00%)
         occurrences all number
    20
    0
    Palpitations
         subjects affected / exposed
    7 / 113 (6.19%)
    3 / 115 (2.61%)
         occurrences all number
    7
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 113 (10.62%)
    7 / 115 (6.09%)
         occurrences all number
    15
    9
    Headache
         subjects affected / exposed
    9 / 113 (7.96%)
    13 / 115 (11.30%)
         occurrences all number
    16
    17
    Tremor
         subjects affected / exposed
    4 / 113 (3.54%)
    7 / 115 (6.09%)
         occurrences all number
    4
    7
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    50 / 113 (44.25%)
    73 / 115 (63.48%)
         occurrences all number
    153
    216
    Thrombocytopenia
         subjects affected / exposed
    39 / 113 (34.51%)
    29 / 115 (25.22%)
         occurrences all number
    97
    58
    Anaemia
         subjects affected / exposed
    19 / 113 (16.81%)
    29 / 115 (25.22%)
         occurrences all number
    31
    47
    Spontaneous haematoma
         subjects affected / exposed
    10 / 113 (8.85%)
    1 / 115 (0.87%)
         occurrences all number
    12
    1
    Increased tendency to bruise
         subjects affected / exposed
    6 / 113 (5.31%)
    0 / 115 (0.00%)
         occurrences all number
    7
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    11 / 113 (9.73%)
    1 / 115 (0.87%)
         occurrences all number
    13
    1
    Vision blurred
         subjects affected / exposed
    9 / 113 (7.96%)
    7 / 115 (6.09%)
         occurrences all number
    11
    8
    Lacrimation increased
         subjects affected / exposed
    8 / 113 (7.08%)
    5 / 115 (4.35%)
         occurrences all number
    8
    7
    Dry eye
         subjects affected / exposed
    7 / 113 (6.19%)
    3 / 115 (2.61%)
         occurrences all number
    7
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    39 / 113 (34.51%)
    12 / 115 (10.43%)
         occurrences all number
    61
    13
    Constipation
         subjects affected / exposed
    19 / 113 (16.81%)
    14 / 115 (12.17%)
         occurrences all number
    24
    17
    Nausea
         subjects affected / exposed
    15 / 113 (13.27%)
    34 / 115 (29.57%)
         occurrences all number
    18
    44
    Vomiting
         subjects affected / exposed
    12 / 113 (10.62%)
    14 / 115 (12.17%)
         occurrences all number
    18
    17
    Dyspepsia
         subjects affected / exposed
    9 / 113 (7.96%)
    2 / 115 (1.74%)
         occurrences all number
    10
    2
    Abdominal pain
         subjects affected / exposed
    9 / 113 (7.96%)
    6 / 115 (5.22%)
         occurrences all number
    12
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 113 (7.08%)
    3 / 115 (2.61%)
         occurrences all number
    9
    3
    Stomatitis
         subjects affected / exposed
    7 / 113 (6.19%)
    1 / 115 (0.87%)
         occurrences all number
    12
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    17 / 113 (15.04%)
    2 / 115 (1.74%)
         occurrences all number
    27
    2
    Rash
         subjects affected / exposed
    10 / 113 (8.85%)
    1 / 115 (0.87%)
         occurrences all number
    15
    1
    Pruritus
         subjects affected / exposed
    9 / 113 (7.96%)
    4 / 115 (3.48%)
         occurrences all number
    13
    4
    Dry skin
         subjects affected / exposed
    7 / 113 (6.19%)
    0 / 115 (0.00%)
         occurrences all number
    7
    0
    Ecchymosis
         subjects affected / exposed
    7 / 113 (6.19%)
    0 / 115 (0.00%)
         occurrences all number
    8
    0
    Onychoclasis
         subjects affected / exposed
    7 / 113 (6.19%)
    0 / 115 (0.00%)
         occurrences all number
    7
    0
    Petechiae
         subjects affected / exposed
    6 / 113 (5.31%)
    0 / 115 (0.00%)
         occurrences all number
    8
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    6 / 113 (5.31%)
    0 / 115 (0.00%)
         occurrences all number
    7
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    27 / 113 (23.89%)
    12 / 115 (10.43%)
         occurrences all number
    33
    12
    Back pain
         subjects affected / exposed
    21 / 113 (18.58%)
    12 / 115 (10.43%)
         occurrences all number
    26
    14
    Muscle spasms
         subjects affected / exposed
    16 / 113 (14.16%)
    7 / 115 (6.09%)
         occurrences all number
    22
    8
    Pain in extremity
         subjects affected / exposed
    12 / 113 (10.62%)
    10 / 115 (8.70%)
         occurrences all number
    13
    10
    Myalgia
         subjects affected / exposed
    7 / 113 (6.19%)
    4 / 115 (3.48%)
         occurrences all number
    10
    4
    Musculoskeletal pain
         subjects affected / exposed
    6 / 113 (5.31%)
    3 / 115 (2.61%)
         occurrences all number
    7
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 113 (15.93%)
    7 / 115 (6.09%)
         occurrences all number
    22
    7
    Nasopharyngitis
         subjects affected / exposed
    15 / 113 (13.27%)
    4 / 115 (3.48%)
         occurrences all number
    29
    4
    Urinary tract infection
         subjects affected / exposed
    13 / 113 (11.50%)
    7 / 115 (6.09%)
         occurrences all number
    22
    7
    Conjunctivitis
         subjects affected / exposed
    12 / 113 (10.62%)
    2 / 115 (1.74%)
         occurrences all number
    20
    2
    Pneumonia
         subjects affected / exposed
    12 / 113 (10.62%)
    5 / 115 (4.35%)
         occurrences all number
    18
    5
    Respiratory tract infection
         subjects affected / exposed
    8 / 113 (7.08%)
    1 / 115 (0.87%)
         occurrences all number
    11
    1
    Oral herpes
         subjects affected / exposed
    1 / 113 (0.88%)
    6 / 115 (5.22%)
         occurrences all number
    1
    6
    Bronchitis
         subjects affected / exposed
    8 / 113 (7.08%)
    2 / 115 (1.74%)
         occurrences all number
    9
    2
    Cellulitis
         subjects affected / exposed
    6 / 113 (5.31%)
    3 / 115 (2.61%)
         occurrences all number
    7
    3
    Herpes zoster
         subjects affected / exposed
    6 / 113 (5.31%)
    3 / 115 (2.61%)
         occurrences all number
    7
    3
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    15 / 113 (13.27%)
    0 / 115 (0.00%)
         occurrences all number
    25
    0
    Decreased appetite
         subjects affected / exposed
    11 / 113 (9.73%)
    5 / 115 (4.35%)
         occurrences all number
    12
    5
    Hypokalaemia
         subjects affected / exposed
    7 / 113 (6.19%)
    2 / 115 (1.74%)
         occurrences all number
    10
    2
    Hyperglycaemia
         subjects affected / exposed
    6 / 113 (5.31%)
    7 / 115 (6.09%)
         occurrences all number
    9
    9
    Iron deficiency
         subjects affected / exposed
    9 / 113 (7.96%)
    0 / 115 (0.00%)
         occurrences all number
    10
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Aug 2014
    Updated safety information for ibrutinib. • Provided background and safety information for obinutuzumab including guidance for premedication for subjects at risk for tumor lysis syndrome, and dose modification upon development of thrombocytopenia. • Included interim analysis to be conducted at approximately 66 PFS events. • Clarified establishment of independent data monitoring committee to replace safety monitoring committee for monitoring of efficacy and safety data given the added interim efficacy analysis. • Clarified that progressive disease could be assessed based on ≥ 50% increase from nadir rather than baseline count if the ALC is ≥ 30,000/μL and lymphocyte doubling time is rapid
    10 May 2016
    • Aligned language with IB Version 9.0 and clarified certain aspects of the clinical study protocol • To include obinutuzumab-related infusion reactions by treatment arm under secondary safety objectives • Updated response evaluation schedule and number of subject visits. • Updated study evaluations information to expand biomarker analysis and include a peripheral blood and bone marrow aspirate for MRD assessment. • Removed the 36-month timepoint from interim analysis • Aligned pregnancy language with relevant study drug labels
    17 Feb 2017
    • Removed the planned interim analysis and updated plans for primary analysis to ensure maturity of PFS outcome data per FDA feedback. • Revised EQ-5D-5L endpoint in secondary efficacy analysis section to clarify that methods will be detailed in SAP. • Revised study design to include potential roll-over to long-term extension study for subjects who choose to continue ibrutinib on a clinical protocol when access to commercial ibrutinib is not feasible. • Updated safety language for alignment with latest version of ibrutinib IB. • Updated MRD information to clarify that peripheral blood or bone marrow would be used for the evaluation of MRD in all responders if available. • Updated criteria for CR to clarify that the confirmatory marrow aspirate and biopsy would be performed by local laboratory

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30522969
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