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    Clinical Trial Results:
    A Study of Obinutuzumab in Combination With CHOP Chemotherapy Versus Rituximab With CHOP in Participants With CD20-Positive Diffuse Large B-Cell Lymphoma (GOYA)

    Summary
    EudraCT number
    		 2010-024194-39
    Trial protocol
    		 ES   GB   SK   CZ   HU   IT   DE   AT   DK   PL  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    23 Apr 2017
    First version publication date
    23 Apr 2017
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    BO21005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01287741
    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
    29 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to demonstrate superiority in progression-free survival (PFS) with obinutuzumab (GA101) plus cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (G-CHOP), compared with rituximab plus chemotherapy (R-CHOP) in previously untreated subjects with CD20-positive diffuse large B-cell lymphoma (DLBCL), based on investigator-assessed PFS.
    Protection of trial subjects
    Each subject, or the subject's representative, signed an informed consent form prior to screening.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jul 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 78 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 252
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Japan: 111
    Country: Number of subjects enrolled
    Korea, Republic of: 59
    Country: Number of subjects enrolled
    Thailand: 86
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Panama: 4
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Hungary: 68
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Russian Federation: 31
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Canada: 120
    Country: Number of subjects enrolled
    United States: 96
    Country: Number of subjects enrolled
    Australia: 22
    Country: Number of subjects enrolled
    South Africa: 8
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Switzerland: 21
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    Spain: 79
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Italy: 259
    Country: Number of subjects enrolled
    Czech Republic: 74
    Worldwide total number of subjects
    1418
    EEA total number of subjects
    565
    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)
    850
    From 65 to 84 years
    566
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Eleven subjects withdrew from the study after randomization but prior to receiving study treatment.

    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
    		 Rituximab+Chemotherapy
    Arm description
    		 Subjects received eight 21-day cycles of rituximab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera, Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab at a dose of 375 milligrams per square metre (mg/m^2), administered by intravenous (IV) infusion on Day 1 of each 21-day cycle for 8 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 750 mg/m^2, administered intravenously (IV) on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 50 mg/m^2 IV, administered on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine 1.4 mg/m^2 (maximum 2 mg) IV, administered on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 100 mg (or equivalent prednisolone or methylprednisolone), administered orally on Days 1-5 of each 21-day cycle.

    Arm title
    		 Obinutuzumab+Chemotherapy
    Arm description
    		 Subjects received eight 21-day cycles of obinutuzumab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    GA101, RO5072759
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Obinutuzumab 1000 mg IV infusion, administered on Day 1 of each 21-day cycle for 8 cycles. During Cycle 1, obinutuzumab was also infused on Days 8 and 15.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 750 milligrams per square metre (mg/m^2), administered intravenously (IV) on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 50 mg/m^2 IV, administered on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine 1.4 mg/m^2 (maximum 2 mg) IV, administered on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 100 mg (or equivalent prednisolone or methylprednisolone), administered orally on Days 1-5 of each 21-day cycle.

    Number of subjects in period 1
    		Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Started
    712
    706
    Completed
    0
    0
    Not completed
    712
    706
         Adverse event, serious fatal
    31
    38
         Physician decision
    12
    19
         Continued in the study
    446
    455
         Adverse event, non-fatal
    3
    4
         Non-compliance
    2
    3
         Withdrawal by Subject
    25
    22
         Protocol Violation
    1
    -
         Lost to follow-up
    5
    8
         Progressive disease
    173
    148
         Reason not specified
    14
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab+Chemotherapy
    Reporting group description
    		 Subjects received eight 21-day cycles of rituximab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy.

    Reporting group title
    Obinutuzumab+Chemotherapy
    Reporting group description
    		 Subjects received eight 21-day cycles of obinutuzumab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy.

    Reporting group values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy Total
    Number of subjects
    		 712 706 1418
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 432 418 850
        Elderly (From 65-84 years)
    		 280 286 566
        Elderly 85 years and over
    		 0 2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.1 ± 13.6 59.4 ± 13.3 -
    Gender categorical
    Units: Subjects
        Female
    		 329 337 666
        Male
    		 383 369 752

    End points

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    End points reporting groups
    Reporting group title
    Rituximab+Chemotherapy
    Reporting group description
    		 Subjects received eight 21-day cycles of rituximab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy.

    Reporting group title
    Obinutuzumab+Chemotherapy
    Reporting group description
    		 Subjects received eight 21-day cycles of obinutuzumab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy.

    Primary: Progression-Free Survival (PFS), Investigator-Assessed

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    End point title
    		 Progression-Free Survival (PFS), Investigator-Assessed
    End point description
    Progression-free survival was defined as the time from randomization until the first documented day of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments according to the Revised Response Criteria for Malignant Lymphoma. Progression was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumor measurements were obtained by computed tomography (CT) or magnetic resonance imaging (MRI). The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
        number (not applicable)
    30.2
    28.5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy
    Number of subjects included in analysis
    1418
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3868 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.11
    Notes
    [1] - Stratified by International Prognostic Index (IPI) score (low/low−intermediate (excluding participants having an IPI score 0 without bulky disease).

    Secondary: Progression-Free Survival (PFS), Independent Review Committee (IRC)-Assessed

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    End point title
    		 Progression-Free Survival (PFS), Independent Review Committee (IRC)-Assessed
    End point description
    Progression-free survival was defined as the time from randomization until the first documented day of disease progression or death from any cause, whichever occurred first, on the basis of IRC assessments according to the Revised Response Criteria for Malignant Lymphoma. Progression was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumor measurements were obtained by CT/MRI. An FDG-PET was mandatory where a PET scanner was available. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
        number (not applicable)
    26.1
    24.2
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Rituximab+Chemotherapy v Obinutuzumab+Chemotherapy
    Number of subjects included in analysis
    1418
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2736 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.1
    Notes
    [2] - Stratified by International Prognostic Index (IPI) score (low/low−intermediate (excluding participants having an IPI score 0 without bulky disease).

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival in the overall study population was defined as the time from the date of randomization to the date of death from any cause. Reported is the percentage of subjects with event. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
        number (not applicable)
    17.7
    17.8
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR), Investigator-Assessed

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    End point title
    		 Overall Response Rate (ORR), Investigator-Assessed
    End point description
    Overall response was determined on the basis of investigator assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma, 2007. Tumor assessments were performed with CT/MRI with or without PET. Overall response was defined as the disappearance of all evidence of disease, regression of measurable disease, and no new sites. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
    number (not applicable)
        Without PET (n= 712, 706)
    80.3
    81.7
        With PET (n=665, 669)
    77.9
    77.4
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR), IRC-Assessed

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    End point title
    		 Overall Response Rate (ORR), IRC-Assessed
    End point description
    Overall response was determined on the basis of IRC assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma, 2007. Tumor assessments were performed with CT/MRI with or without PET. Overall response was defined as the disappearance of all evidence of disease, regression of measurable disease, and no new sites. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
    number (not applicable)
        Without PET (n= 712, 706)
    80.2
    82.3
        With PET (n=665, 669)
    81.1
    82.1
    No statistical analyses for this end point

    Secondary: Complete Response (CR) at the End of Treatment, Investigator-Assessed

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    End point title
    		 Complete Response (CR) at the End of Treatment, Investigator-Assessed
    End point description
    Percentage of subjects with complete response was determined on the basis of investigator assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma, 2007. Tumor assessments were performed with CT/MRI with or without PET. Complete response was defined as the disappearance of all evidence of disease. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
    number (not applicable)
        Without PET (n= 712, 706)
    33.8
    35.1
        With PET (n=665, 669)
    59.5
    56.7
    No statistical analyses for this end point

    Secondary: Complete Response (CR) at the End of Treatment, IRC-Assessed

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    End point title
    		 Complete Response (CR) at the End of Treatment, IRC-Assessed
    End point description
    Percentage of subjects with complete response was determined on the basis of IRC assessments according to the International Working Group (IWG) Revised Response Criteria for Malignant Lymphoma, 2007. Tumor assessments were performed with CT/MRI with or without PET. Complete response was defined as the disappearance of all evidence of disease. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
    number (not applicable)
        Without PET (n= 712, 706)
    34.4
    39.1
        With PET (n=665, 669)
    65.3
    66.7
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS), Investigator-Assessed

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    End point title
    		 Event-Free Survival (EFS), Investigator-Assessed
    End point description
    Event-free survival was defined as the time from the date of randomization until the date of disease progression, relapse, initiation of a new non–protocol-specified anti-lymphoma treatment, or death from any cause on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Disease progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Tumor measurements were obtained by CT/MRI. Reported is the percentage of subjects with event.
    End point type
    Secondary
    End point timeframe
    Baseline up to death or disease progression, or initiation of new anti-lymphoma treatment (NALT), whichever occurred first, to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
        number (not applicable)
    35.1
    33.4
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS), Investigator-Assessed

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    End point title
    		 Disease-Free Survival (DFS), Investigator-Assessed
    End point description
    Disease-free survival was defined as the time from the date of the first occurrence of a documented CR to the date of disease progression/relapse or death from any cause on the basis of investigator assessments with the use of Revised Response Criteria for Malignant Lymphoma. Tumor assessments were performed with CT/MRI. CR was defined as disappearance of all target lesions. Progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. Reported is the percentage of subjects with event. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to death or disease progression, whichever occurred first, to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    369
    397
    Units: percentage of subjects with event
        number (not applicable)
    17.3
    19.4
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR), Investigator-Assessed

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    End point title
    		 Duration of Response (DOR), Investigator-Assessed
    End point description
    DOR: the time from first occurrence of a documented CR or PR to disease progression/relapse, or death from any cause for subjects with a response of CR or PR. Tumor assessments were performed with CT/MRI. CR: disappearance of all target lesions. PR: >/=50% decrease target lesions in up to six dominant lesions identified at baseline, no new lesions and no increase in the size of the liver, spleen, or other nodes. Splenic and hepatic nodules must have regressed by >/= 50%. Progression/relapse was defined as at least 50% increase in nodal lesions or >/=50% increase in any node > 1 centimeter (cm) or >/= 50% increase in other target measurable lesions (e.g., splenic or hepatic nodules) and/or appearance of any new bone marrow involvement and/or appearance of any new lesion > 1.5 cm or >/= 50% increase in any previously involved node with a diameter </= 1 cm such that it is now >1.5 cm. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to death or disease progression, whichever occurs first, to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    642
    659
    Units: percentage of subjects with event
        number (not applicable)
    26.8
    26.7
    No statistical analyses for this end point

    Secondary: Time to Next Anti-Lymphoma Treatment (TTNALT)

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    End point title
    		 Time to Next Anti-Lymphoma Treatment (TTNALT)
    End point description
    Time to next anti-lymphoma treatment was defined as the time from the date of randomization to the start date of the next anti-lymphoma treatment or death from any cause. Reported is the percentage of subjects with event. The intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to start of next anti-lymphoma treatment or death due to any cause, whichever occurred first, to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: percentage of subjects with event
        number (not applicable)
    32.3
    30.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs)
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event 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 adverse events. The safety analysis population included all subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to data cut-off (up to approximately 4 years and 9 months)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    703
    704
    Units: percentage of subjects
        number (not applicable)
    94.9
    97.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Human Anti-Human Antibodies (HAHAs) to Obinutuzumab

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    End point title
    		 Percentage of Subjects With Human Anti-Human Antibodies (HAHAs) to Obinutuzumab [3]
    End point description
    The presence of HAHAs to obinutuzumab was assessed in the first 100 randomized subjects. The safety analysis population included all subjects who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) on Cycle (C) 1 Day (D) 1, C4D1, at end of treatment/early termination (up to Month 6), every 6 months thereafter for 30 months (cycle length = 21 days)
    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: This endpoint was assessed in the reported arm only.
    End point values
    		 Obinutuzumab+Chemotherapy
    Number of subjects analysed
    100
    Units: percentage of subjects
    number (not applicable)
        Screening (n=70)
    2.9
        Cycle 1 Day 1 (n=29)
    0
        Cycle 4 Day 1 (n=89)
    0
        Study Completion / Early Discontinuation (n=67)
    0
        Follow-Up Month 6 (n=41)
    0
        Follow-Up Month 12 (n=40)
    0
        Follow-Up Month 18 (n=27)
    0
        Follow-Up Month 24 (n=25)
    0
        Follow-Up Month 30 (n=19)
    0
        Follow-Up Completion/ Early Discontinuation (n=6)
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale Score

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    End point title
    		 Change From Baseline in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) Subscale Score
    End point description
    The FACT-Lym subscale was developed to assess health-related quality of life in patients with non-Hodgkin lymphoma. The score range is 0-60, with higher scores indicating better outcomes. A positive change from baseline indicates an improvement. The intent-to-treat (ITT) population included all randomized subjects. 9999=NE=Not estimable based on 0 or 1 subject evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose [Hour 0] on C1D1), C3D1, end of treatment (up to Month 6), every 12 months thereafter up to data cut-off, up to approximately 4 years and 9 months, (cycle length = 21 days)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: Unitless score
    arithmetic mean (standard deviation)
        Baseline (n=607, 641)
    45.36 ± 10.15
    45.12 ± 9.96
        Score Change, Cycle 3 Day 1 (n=553, 565)
    3.84 ± 8.69
    3.74 ± 9.23
        Score Change, Study Compl./Discont. (n=526, 529)
    5.04 ± 10.26
    4.43 ± 11.09
        Score Change, Follow-Up Month 12 (n=370, 412)
    6.38 ± 10.13
    6.21 ± 10.49
        Score Change, Follow-Up Month 24 (n=232, 248)
    7.79 ± 10.26
    5.95 ± 10.38
        Score Change, Follow-Up Month 30 (n=0, 1)
    99999 ± 99999
    25 ± 99999
        Score Change, Follow-Up Month 36 (n=94, 100)
    7.13 ± 10.18
    6.88 ± 10.74
        Score Change, Follow-Up Month 48 (n=6, 10)
    3.06 ± 4.67
    4 ± 7.8
        Score Change, Follow-Up Term./Compl. (n=50, 48)
    3.54 ± 12.57
    3.6 ± 11.49
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) Domain Scores

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) Domain Scores
    End point description
    The EORTC QLQ-C30 is a health-related quality of life questionnaire. A higher score indicates better quality of life, with changes of 5 to 10 points considered to be a minimally important difference to subjects. The intent-to-treat (ITT) population included all randomized subjects. 9999=NE=Not estimable based on 0 or 1 subject evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose [Hour 0] on C1D1), C3D1, end of treatment (up to Month 6), every 12 months thereafter up to data cut-off, up to approximately 4 years and 9 months, (cycle length = 21 days)
    End point values
    		 Rituximab+Chemotherapy Obinutuzumab+Chemotherapy
    Number of subjects analysed
    712
    706
    Units: Unitless score
    arithmetic mean (standard deviation)
        Baseline (n=610, 643)
    59.78 ± 24.47
    58.51 ± 25.22
        Change Baseline, Cycle 1 Day 1 (n=0, 0)
    99999 ± 99999
    99999 ± 99999
        Change Baseline, Cycle 3 Day 1 (n=555, 567)
    6.28 ± 24.08
    7.52 ± 25.95
        Change Baseline, Study Completion (n=526, 532)
    9.97 ± 26.14
    10.29 ± 30.16
        Change Baseline, Follow-Up Month 12 (n=370, 414)
    12.73 ± 26.32
    13.89 ± 30.02
        Change Baseline, Follow-Up Month 24 (n=234, 247)
    16.84 ± 26.3
    14.74 ± 29.57
        Change Baseline, Follow-Up Month 30 (n=0, 1)
    99999 ± 99999
    58.33 ± 99999
        Change Baseline, Follow-Up Month 36 (n=94, 99)
    14.36 ± 31.4
    14.31 ± 31.34
        Change Baseline, Follow-Up Month 48 (n=7, 10)
    -4.76 ± 39.04
    14.17 ± 33.34
        Change Baseline, Follow-Up Completion (n=50, 48)
    1.17 ± 33.25
    -0.69 ± 24.06
    No statistical analyses for this end point

    Secondary: Serum Concentrations of Obinutuzumab in Japanese Participants with Diffuse Large B-Cell Lymphoma (DLBCL)

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    End point title
    		 Serum Concentrations of Obinutuzumab in Japanese Participants with Diffuse Large B-Cell Lymphoma (DLBCL) [4]
    End point description
    Serum samples for assessment of obinutuzumab serum concentrations were collected only from a subset of Japanese subjects following administration of 1000 mg obinutuzumab.
    End point type
    Secondary
    End point timeframe
    C1: D1 post-infusion and 20-28 and 66-80 hours after end of infusion, D8 and D15 pre-and post-infusion; C2: D1 pre- and post-infusion; C4: D1 pre- and post-infusion; C6: D1 pre- and post-infusion; C8: D1 pre- and post-infusion (cycle length = 21 days)
    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: This endpoint was assessed in the reported arm only.
    End point values
    		 Obinutuzumab+Chemotherapy
    Number of subjects analysed
    40
    Units: micrograms per milliliter (μg/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1, Day 8 pre-infusion
    174 ± 38.7
        Cycle 1, Day 15 pre-infusion
    320 ± 39.2
        Cycle 2, Day 1 pre-infusion
    431 ± 39.8
        Cycle 4, Day 1 pre-infusion
    352 ± 42.1
        Cycle 6, Day 1 pre-infusion
    378 ± 45.9
        Cycle 8, Day 1 pre-infusion
    478 ± 43.9
        Cycle 1, Day 1 post-infusion
    435 ± 32.3
        Cycle 1, Day 1 20-28 hours after end of infusion
    259 ± 56.3
        Cycle 1, Day 1 66-80 hours after end of infusion
    219 ± 51.2
        Cycle 1, Day 8 post-infusion
    578 ± 37.8
        Cycle 1, Day 15 post-infusion
    718 ± 32.9
        Cycle 2, Day 1 post-infusion
    938 ± 31.3
        Cycle 4, Day 1 post-infusion
    817 ± 28.6
        Cycle 6, Day 1 post-infusion
    813 ± 32.6
        Cycle 8, Day 1 post-infusion
    881 ± 35.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 years and 9 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Obinutuzumab+Chemotherapy
    Reporting group description
    		 Subjects received eight 21-day cycles of obinutuzumab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy.

    Reporting group title
    Rituximab+Chemotherapy
    Reporting group description
    		 Subjects received eight 21-day cycles of rituximab, combined with six or eight cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone (CHOP) chemotherapy (21-day cycles). Prior to study start, study centers chose whether they planned to administer 6 or 8 cycles of CHOP chemotherapy.

    Serious adverse events
    		 Obinutuzumab+Chemotherapy Rituximab+Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    300 / 704 (42.61%)
    264 / 703 (37.55%)
         number of deaths (all causes)
    126
    122
         number of deaths resulting from adverse events
    17
    19
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Colorectal cancer
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Liposarcoma
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    3 / 704 (0.43%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Marginal zone lymphoma
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary cystadenoma lymphomatosum
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 704 (0.28%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour perforation
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 704 (0.43%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous occlusion
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 704 (0.28%)
    4 / 703 (0.57%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Axillary pain
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 704 (0.43%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 3
    2 / 2
    Extravasation
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 704 (0.57%)
    5 / 703 (0.71%)
         occurrences causally related to treatment / all
    1 / 4
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    17 / 704 (2.41%)
    11 / 703 (1.56%)
         occurrences causally related to treatment / all
    11 / 23
    10 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 704 (0.14%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Alveolitis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 704 (0.43%)
    4 / 703 (0.57%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 704 (0.57%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 704 (0.71%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 704 (0.57%)
    4 / 703 (0.57%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emotional distress
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIV antibody positive
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscence
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Facial bones fracture
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         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
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    8 / 704 (1.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney rupture
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve injury
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (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
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    3 / 704 (0.43%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 704 (0.14%)
    5 / 703 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    9 / 704 (1.28%)
    4 / 703 (0.57%)
         occurrences causally related to treatment / all
    3 / 10
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Cardiac failure
         subjects affected / exposed
    7 / 704 (0.99%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    3 / 7
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    3 / 704 (0.43%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac perforation
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 704 (0.43%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular flutter
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 704 (0.43%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    Depressed level of consciousness
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 704 (0.43%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iiird nerve paralysis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 704 (0.00%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Transient ischaemic attack
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 704 (1.28%)
    6 / 703 (0.85%)
         occurrences causally related to treatment / all
    7 / 10
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    81 / 704 (11.51%)
    72 / 703 (10.24%)
         occurrences causally related to treatment / all
    97 / 103
    86 / 89
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histiocytosis haematophagic
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    10 / 704 (1.42%)
    5 / 703 (0.71%)
         occurrences causally related to treatment / all
    10 / 10
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    52 / 704 (7.39%)
    40 / 703 (5.69%)
         occurrences causally related to treatment / all
    55 / 59
    41 / 42
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    8 / 704 (1.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    9 / 11
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacrimation increased
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (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
    4 / 704 (0.57%)
    6 / 703 (0.85%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 704 (0.28%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 704 (0.57%)
    6 / 703 (0.85%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastric perforation
         subjects affected / exposed
    1 / 704 (0.14%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (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 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 704 (0.28%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematemesis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal perforation
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Inguinal hernia
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 704 (0.28%)
    4 / 703 (0.57%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Intestinal perforation
         subjects affected / exposed
    3 / 704 (0.43%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Large intestine polyp
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 704 (0.43%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 704 (0.28%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Acute prerenal failure
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis glandularis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Goitre
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 704 (0.28%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Costochondritis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 704 (0.14%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 704 (0.14%)
    4 / 703 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Candida sepsis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    2 / 704 (0.28%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    3 / 704 (0.43%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fungal infection
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 704 (0.43%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    4 / 704 (0.57%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective glossitis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 704 (0.43%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    6 / 704 (0.85%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Measles
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis cryptococcal
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 704 (0.43%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (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 / 704 (0.14%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    40 / 704 (5.68%)
    32 / 703 (4.55%)
         occurrences causally related to treatment / all
    26 / 42
    24 / 36
         deaths causally related to treatment / all
    2 / 5
    4 / 6
    Pneumonia bacterial
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 704 (0.28%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    15 / 704 (2.13%)
    10 / 703 (1.42%)
         occurrences causally related to treatment / all
    9 / 16
    8 / 10
         deaths causally related to treatment / all
    1 / 1
    2 / 3
    Sepsis syndrome
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    12 / 704 (1.70%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    6 / 12
    2 / 3
         deaths causally related to treatment / all
    3 / 6
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis of central nervous system
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 704 (0.43%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (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
    Cachexia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 704 (0.14%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 704 (0.71%)
    4 / 703 (0.57%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 704 (0.00%)
    3 / 703 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 704 (0.14%)
    0 / 703 (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
    2 / 704 (0.28%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 704 (0.00%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 704 (0.00%)
    1 / 703 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 704 (0.14%)
    2 / 703 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Obinutuzumab+Chemotherapy Rituximab+Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    642 / 704 (91.19%)
    604 / 703 (85.92%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    249 / 704 (35.37%)
    164 / 703 (23.33%)
         occurrences all number
    312
    195
    Vascular disorders
    Hypertension
         subjects affected / exposed
    40 / 704 (5.68%)
    27 / 703 (3.84%)
         occurrences all number
    45
    34
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    47 / 704 (6.68%)
    27 / 703 (3.84%)
         occurrences all number
    52
    32
    Dysgeusia
         subjects affected / exposed
    44 / 704 (6.25%)
    37 / 703 (5.26%)
         occurrences all number
    53
    41
    Headache
         subjects affected / exposed
    73 / 704 (10.37%)
    56 / 703 (7.97%)
         occurrences all number
    81
    68
    Neuropathy peripheral
         subjects affected / exposed
    87 / 704 (12.36%)
    88 / 703 (12.52%)
         occurrences all number
    96
    94
    Paraesthesia
         subjects affected / exposed
    55 / 704 (7.81%)
    51 / 703 (7.25%)
         occurrences all number
    65
    54
    Peripheral sensory neuropathy
         subjects affected / exposed
    54 / 704 (7.67%)
    56 / 703 (7.97%)
         occurrences all number
    61
    60
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    88 / 704 (12.50%)
    96 / 703 (13.66%)
         occurrences all number
    135
    123
    Febrile neutropenia
         subjects affected / exposed
    52 / 704 (7.39%)
    44 / 703 (6.26%)
         occurrences all number
    68
    58
    Leukopenia
         subjects affected / exposed
    109 / 704 (15.48%)
    84 / 703 (11.95%)
         occurrences all number
    272
    222
    Neutropenia
         subjects affected / exposed
    304 / 704 (43.18%)
    261 / 703 (37.13%)
         occurrences all number
    676
    671
    Thrombocytopenia
         subjects affected / exposed
    47 / 704 (6.68%)
    16 / 703 (2.28%)
         occurrences all number
    61
    17
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    71 / 704 (10.09%)
    73 / 703 (10.38%)
         occurrences all number
    89
    83
    Chills
         subjects affected / exposed
    131 / 704 (18.61%)
    36 / 703 (5.12%)
         occurrences all number
    141
    37
    Fatigue
         subjects affected / exposed
    133 / 704 (18.89%)
    120 / 703 (17.07%)
         occurrences all number
    181
    147
    Mucosal inflammation
         subjects affected / exposed
    45 / 704 (6.39%)
    37 / 703 (5.26%)
         occurrences all number
    56
    42
    Oedema peripheral
         subjects affected / exposed
    35 / 704 (4.97%)
    40 / 703 (5.69%)
         occurrences all number
    38
    48
    Pyrexia
         subjects affected / exposed
    129 / 704 (18.32%)
    73 / 703 (10.38%)
         occurrences all number
    170
    91
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    47 / 704 (6.68%)
    46 / 703 (6.54%)
         occurrences all number
    52
    56
    Abdominal pain upper
         subjects affected / exposed
    35 / 704 (4.97%)
    39 / 703 (5.55%)
         occurrences all number
    43
    43
    Constipation
         subjects affected / exposed
    165 / 704 (23.44%)
    171 / 703 (24.32%)
         occurrences all number
    189
    209
    Diarrhoea
         subjects affected / exposed
    110 / 704 (15.63%)
    89 / 703 (12.66%)
         occurrences all number
    146
    112
    Dyspepsia
         subjects affected / exposed
    44 / 704 (6.25%)
    42 / 703 (5.97%)
         occurrences all number
    51
    46
    Nausea
         subjects affected / exposed
    206 / 704 (29.26%)
    197 / 703 (28.02%)
         occurrences all number
    323
    270
    Stomatitis
         subjects affected / exposed
    46 / 704 (6.53%)
    63 / 703 (8.96%)
         occurrences all number
    57
    80
    Vomiting
         subjects affected / exposed
    102 / 704 (14.49%)
    72 / 703 (10.24%)
         occurrences all number
    141
    99
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    83 / 704 (11.79%)
    60 / 703 (8.53%)
         occurrences all number
    94
    69
    Dyspnoea
         subjects affected / exposed
    52 / 704 (7.39%)
    31 / 703 (4.41%)
         occurrences all number
    57
    31
    Oropharyngeal pain
         subjects affected / exposed
    41 / 704 (5.82%)
    37 / 703 (5.26%)
         occurrences all number
    46
    39
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    145 / 704 (20.60%)
    142 / 703 (20.20%)
         occurrences all number
    148
    145
    Rash
         subjects affected / exposed
    16 / 704 (2.27%)
    45 / 703 (6.40%)
         occurrences all number
    19
    47
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    76 / 704 (10.80%)
    58 / 703 (8.25%)
         occurrences all number
    78
    63
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    57 / 704 (8.10%)
    42 / 703 (5.97%)
         occurrences all number
    70
    49
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    43 / 704 (6.11%)
    46 / 703 (6.54%)
         occurrences all number
    55
    53
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    96 / 704 (13.64%)
    70 / 703 (9.96%)
         occurrences all number
    120
    80
    Hypokalaemia
         subjects affected / exposed
    60 / 704 (8.52%)
    49 / 703 (6.97%)
         occurrences all number
    83
    74

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2011
    Protocol Amendment 1 included the following: an early futility analysis of the end-of-treatment complete response rate for the first 200 randomized subjects; inclusion of fluorodeoxyglucose positron-emission tomography (FDG-PET) information for determination of the overall response rate and complete response rate at the end of treatment for subjects for whom FDG-PET information was available; inclusion of a pharmacokinetic sampling schedule and analysis plan for a subset of up to 40 Japanese subjects enrolled and treated in the obinutuzumab+chemotherapy arm.
    31 Aug 2012
    Protocol Amendment 2 included updated guidelines for dose-delays and modifications due to toxicities to make the modifications more consistent with standard practice.
    22 May 2013
    Protocol Amendment 3 included the following: removal of the existing cap on the recruitment of subjects with occult or prior hepatitis B infection; progression-free survival (PFS), as assessed by the independent review committee (IRC), was added to the primary outcome measure to clarify that it would be analyzed to support the primary analysis and that, in the United States, IRC-assessed PFS would be the basis for regulatory decisions.
    24 Mar 2014
    Protocol Amendment 4 included new guidelines regarding the management of subjects with thrombocytopenia, especially during the first cycle of obinutuzumab, including those subjects receiving concomitant anticoagulants or platelet inhibitors.

    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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