Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    RIAltO: A Randomised Investigation of Alternative Ofatumumab-containing regimens in less fit patients with CLL

    Summary
    EudraCT number
    		 2011-000919-22
    Trial protocol
    		 GB  
    Global end of trial date
    24 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2025
    First version publication date
    15 Feb 2025
    Other versions
    Summary report(s)
    		 RIAltO Final Statistical Analysis Report

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    OMB114578
    Additional study identifiers
    ISRCTN number
    		 ISRCTN09988575
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Royal Liverpool Hospital, Liverpool University Hospitals NHS Foundation Trust
    Sponsor organisation address
    4th Floor Linda McCartney, Royal Liverpool Hospital, Prescot Street, Liverpool, United Kingdom, L7 8XP
    Public contact
    Charlotte Rawcliffe, CR:UK Liverpool Cancer Trials Unit, 44 01517948167, c.rawcliffe@liv.ac.uk
    Scientific contact
    Charlotte Rawcliffe, CR:UK Liverpool Cancer Trials Unit, 44 01517948167, c.rawcliffe@liv.ac.uk
    Sponsor organisation name
    The University of Liverpool, Research Support Office,
    Sponsor organisation address
    2nd Floor Block C, Waterhouse Building, 3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
    Public contact
    Charlotte Rawcliffe , CR:UK Liverpool Cancer Trials Unit, 44 01517948285, c.rawcliffe@liv.ac.uk
    Scientific contact
    Charlotte Rawcliffe , CR:UK Liverpool Cancer Trials Unit, 44 01517948285, c.rawcliffe@liv.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 May 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess whether progression free survival (PFS) time (i.e. the length of time during and after medication or treatment during which the disease being treated does not get worse) using ofatumumab plus bendamustine is longer than that using ofatumumab plus chlorambucil.
    Protection of trial subjects
    Risks were minimised by the exclusion of very frail patients with a WHO performance status of more than 3 and those patients with extensive co-morbidity. All patients were screened for significant liver dysfunction, HBsAg and HBcAb (together with antibodies to HIV and hepatitis C), and those who were positive for any of these tests were excluded from the study. In addition, bendamustine was administered at the slightly lower dose (70mg/m2 rather than 90mg/m2) that has been used with good effect as part of immunochemotherapy regimens in previously treated patients. Patients who developped grade 3-4 infection or encounter haematological toxicity of sufficient severity to delay the next cycle of treatment received subsequent cycles at an attenuated dose, with G-CSF support in the event of severe neutropenia.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 521
    Worldwide total number of subjects
    521
    EEA total number of subjects
    0
    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)
    19
    From 65 to 84 years
    476
    85 years and over
    26

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patient notes were screened by the research team prior to the patient being approached. Screening was performed for potential study patients after they had consented to trial participation and within 42 days prior to the first dose of treatment. Patients who fulfilled the screening requirements were eligible for enrolment.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Bendamustine (Including Placebo)
    Arm description
    		 Ofatumumab + Bendamustine (Including Placebo)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Concentrate for solution for infusion , Intravenous use
    Dosage and administration details
    Ofatumumab + Bendamustine (experimental arm) • Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8 cycle 2 onwards: 1000mg iv day 1 • Bendamustine 70mg/m2 iv days 1 and 2 • Cycles to be repeated every 28 days (± 4 days)

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Concentrate for solution for infusion
    Dosage and administration details
    Ofatumumab + Bendamustine (experimental arm) • Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8 cycle 2 onwards: 1000mg iv day 1 • Bendamustine 70mg/m2 iv days 1 and 2 • Cycles to be repeated every 28 days (± 4 days)

    Arm title
    		 Chlorambucil (Including Placebo)
    Arm description
    		 Ofatumumab + Chlorambucil (Including Placebo)
    Arm type
    		 Standard Therapeutic

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Concentrate for solution for infusion , Intravenous use
    Dosage and administration details
    Ofatumumab + Chlorambucil (standard therapeutic arm) • Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8 cycle 2 onwards: 1000mg iv day 1 • Chlorambucil 10mg/m2 po days 1 to 7 • Cycles to be repeated every 28 days (± 4 days)

    Investigational medicinal product name
    Chlorambucil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ofatumumab + Chlorambucil (standard therapeutic arm) • Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8 cycle 2 onwards: 1000mg iv day 1 • Chlorambucil 10mg/m2 po days 1 to 7 • Cycles to be repeated every 28 days (± 4 days)

    Arm title
    		 Idelalisib
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idelalisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Idelalisib will be provided in tablets intended for oral administration. Each tablet contains 150 mg or 100 mg of active idelalisib. The 150 mg tablets will be used for the third and subsequent cycles of therapy; the 100mg tablets are provided for the second cycle of therapy and for use by those subjects who require a dose reduction. The 150 mg tablets are pink, film-coated, and include the following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, polyvinyl alcohol (PVA), and titanium dioxide. The 100 mg tablets are orange, film-coated, and include the following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide.

    Number of subjects in period 1
    		Bendamustine (Including Placebo) Chlorambucil (Including Placebo) Idelalisib
    Started
    223
    225
    73
    Completed
    79
    92
    28
    Not completed
    144
    133
    45
         Adverse event, serious fatal
    64
    54
    16
         Consent withdrawn by subject
    13
    19
    7
         Other
    65
    56
    22
         Lost to follow-up
    2
    4
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Bendamustine (Including Placebo)
    Reporting group description
    		 Ofatumumab + Bendamustine (Including Placebo)

    Reporting group title
    Chlorambucil (Including Placebo)
    Reporting group description
    		 Ofatumumab + Chlorambucil (Including Placebo)

    Reporting group title
    Idelalisib
    Reporting group description
    		 -

    Reporting group values
    		 Bendamustine (Including Placebo) Chlorambucil (Including Placebo) Idelalisib Total
    Number of subjects
    		 223 225 73 521
    Age categorical
    Units: Subjects
        <=70
    		 41 47 16 104
        >70
    		 182 178 57 417
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 76.0 (72.0 to 80.0) 76.0 (72.0 to 79.0) 76.0 (71.0 to 80.0) -
    Gender categorical
    Units: Subjects
        Female
    		 79 82 17 178
        Male
    		 144 143 56 343
    Who Performance Status, n
    Units: Subjects
        0/1
    		 186 187 65 438
        2/3
    		 37 38 8 83
        Missing
    		 0 0 0 0
    Cumulative Illness Rating Score, n
    Units: Subjects
        <=6
    		 173 174 59 406
        >6
    		 50 51 14 115
        Missing
    		 0 0 0 0
    Disease Stage, n
    Units: Subjects
        Stage A
    		 28 26 13 67
        Stage B
    		 73 73 20 166
        Stage C
    		 116 123 40 279
        Missing
    		 6 3 0 9
    VES-13 Assessment, n
    Units: Subjects
        <3
    		 124 131 41 296
        >=3
    		 72 77 24 173
        Missing
    		 27 17 8 52
    GFI Assessment, n
    Units: Subjects
        <4
    		 121 137 37 295
        >=4
    		 72 71 28 171
        Missing
    		 30 17 8 55
    Timed Up & Go Assessment, n
    Units: Subjects
        <10 seconds
    		 84 73 29 186
        >=10 seconds
    		 92 105 30 227
        Missing
    		 47 47 14 108
    IGHV Status, n
    Units: Subjects
        Mutated
    		 67 73 19 159
        Unmutated
    		 71 79 30 180
        Missing
    		 85 73 24 182
    FISH Status, n
    Units: Subjects
        17p-
    		 12 6 3 21
        11q-
    		 23 29 11 63
        +12
    		 46 55 15 116
        13q-
    		 69 64 19 152
        No FISH defect
    		 53 51 20 124
        Missing
    		 20 20 5 45
    Days to treatment since registration
    Units: Days
        median (inter-quartile range (Q1-Q3))
    		 9.0 (6.0 to 17.0) 7.0 (5.0 to 15.0) 8.5 (6.0 to 19.5) -
    Cumulative Illness Rating Score
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 4.0 (2.0 to 6.0) 4.0 (2.0 to 6.0) 4.0 (2.0 to 5.0) -
    VES-13 Assessment
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 1.0 (1.0 to 4.0) 1.0 (1.0 to 3.0) 1.0 (1.0 to 3.0) -
    GFI Assessment
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 3.0 (1.0 to 5.0) 2.0 (1.0 to 4.0) 3.0 (2.0 to 4.0) -
    Timed Up & Go Assessment
    Units: Seconds
        median (inter-quartile range (Q1-Q3))
    		 10.0 (8.2 to 14.4) 10.5 (8.2 to 16.0) 10.0 (7.5 to 12.7) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Bendamustine (Including Placebo)
    Reporting group description
    		 Ofatumumab + Bendamustine (Including Placebo)

    Reporting group title
    Chlorambucil (Including Placebo)
    Reporting group description
    		 Ofatumumab + Chlorambucil (Including Placebo)

    Reporting group title
    Idelalisib
    Reporting group description
    		 -

    Subject analysis set title
    Bendamustine (Including Idelalisib & Placebo) (Randomised)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ofatumumab + Bendamustine (Including Idelalisib & Placebo) (All Randomised)

    Subject analysis set title
    Chlorambucil (Including Idelalisib & Placebo) (Randomised)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ofatumumab + Chlorambucil (Including Idelalisib & Placebo) (All Randomised)

    Subject analysis set title
    Bendamustine (Including Placebo) (Per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Ofatumumab + Bendamustine (Including Placebo) (Per protocol)

    Subject analysis set title
    Chlorambucil (Including Placebo) (Per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Ofatumumab + Chlorambucil (Including Placebo) (Per protocol)

    Subject analysis set title
    Bendamustine (Including Placebo) (Intention-to-treat)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Ofatumumab + Bendamustine (Including Placebo) (Intention-to-treat)

    Subject analysis set title
    Chlorambucil (Including Placebo) (Intention-to-treat)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Ofatumumab + Chlorambucil (Including Placebo) (Intention-to-treat)

    Subject analysis set title
    Bendamustine (Including Placebo) (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Ofatumumab + Bendamustine (Including Placebo) (Safety)

    Subject analysis set title
    Chlorambucil (Including Placebo) (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Ofatumumab + Chlorambucil (Including Placebo) (Safety)

    Subject analysis set title
    Idelalisib (Per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Idelalisib (Per protocol)

    Subject analysis set title
    Placebo (Per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Placebo (Per protocol)

    Subject analysis set title
    Idelalisib (Intention-to-treat)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Idelalisib (Intention-to-treat)

    Subject analysis set title
    Placebo (Intention-to-treat)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Placebo (Intention-to-treat)

    Subject analysis set title
    Idelalisib (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Idelalisib (Safety)

    Subject analysis set title
    Placebo (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Placebo (Safety)

    Primary: Progression Free Survival (PFS) - Primary Analysis - Bendamustine vs. Chlorambucil (Including Placebo)

    		 Close Top of page
    End point title
    		 Progression Free Survival (PFS) - Primary Analysis - Bendamustine vs. Chlorambucil (Including Placebo)
    End point description
    End point type
    Primary
    End point timeframe
    Unless they with withdrew, participants were followed up until progression, death or end of trial.
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    222
    223
    Units: PFS in months
        median (confidence interval 95%)
    37.71 (32.85 to 44.55)
    29.89 (26.38 to 34.66)
    Attachments
    		 PFS - Forest Plot - Subgroup Analysis
    Kaplan Meier Plot: Progression Free Survival
    PFS - Cumulative Illness Rating Score (≤6 vs. >6)
    PFS - Cumulative Illness Rating Score (≤6)
    PFS - Cumulative Illness Rating Score (>6)
    PFS - Performance Status (0 vs. 1 vs. 2 vs. 3)
    PFS - Performance Status (0)
    PFS - Performance Status (1)
    PFS - Performance Status (2)
    PFS - Performance Status (3)
    PFS - VES-13 (<3 vs. ≥3)
    PFS - VES-13 (<3)
    PFS - VES-13 (≥3)
    PFS - GFI (<4 vs. ≥4)
    PFS - GFI (<4)
    PFS - GFI (≥4)
    PFS - Timed Up and Go (<10 vs. ≥10)
    PFS - Timed Up and Go (<10)
    PFS - Timed Up and Go (≥10)
    PFS – IGHV Status
    PFS - IGHV (Mutated)
    PFS - IGHV (Unmutated)
    PFS - FISH Status
    PFS - FISH (17p-)
    PFS - FISH (11q-)
    PFS - FISH (+12)
    PFS - FISH (13q-)
    PFS - FISH (No FISH Defect)
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.9
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Logrank
    Confidence interval

    Secondary: Exploratory Analysis - PFS - Idelalisib vs. Placebo

    		 Close Top of page
    End point title
    		 Exploratory Analysis - PFS - Idelalisib vs. Placebo
    End point description
    End point type
    Secondary
    End point timeframe
    Unless they with withdrew, participants were followed up until progression, death or end of trial.
    End point values
    		 Idelalisib (Intention-to-treat) Placebo (Intention-to-treat)
    Number of subjects analysed
    73
    70
    Units: PFS in months
        median (confidence interval 95%)
    43.46 (32.42 to 59.92)
    26.84 (22.34 to 39.13)
    Attachments
    		 Kaplan Meier Plot: Progression Free Survival
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Idelalisib (Intention-to-treat) v Placebo (Intention-to-treat)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.05
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Idelalisib (Intention-to-treat) v Placebo (Intention-to-treat)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.082
    Method
    		 Logrank
    Confidence interval

    Secondary: Sensitivity Analysis 2 - PFS - All Randomised - Bendamustine vs. Chlorambucil (Including Idelalisib & Placebo)

    		 Close Top of page
    End point title
    		 Sensitivity Analysis 2 - PFS - All Randomised - Bendamustine vs. Chlorambucil (Including Idelalisib & Placebo)
    End point description
    End point type
    Secondary
    End point timeframe
    Unless they with withdrew, participants were followed up until progression, death or end of trial.
    End point values
    		 Bendamustine (Including Idelalisib & Placebo) (Randomised) Chlorambucil (Including Idelalisib & Placebo) (Randomised)
    Number of subjects analysed
    260
    261
    Units: PFS in months
        median (confidence interval 95%)
    41.33 (35.45 to 48.39)
    28.58 (26.38 to 33.67)
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Bendamustine (Including Idelalisib & Placebo) (Randomised) v Chlorambucil (Including Idelalisib & Placebo) (Randomised)
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.83
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Bendamustine (Including Idelalisib & Placebo) (Randomised) v Chlorambucil (Including Idelalisib & Placebo) (Randomised)
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall Survival (OS) - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo)

    		 Close Top of page
    End point title
    		 Overall Survival (OS) - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo)
    End point description
    End point type
    Secondary
    End point timeframe
    Unless they withdrew, participants were followed up until death or end of trial.
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    222
    223
    Units: OS in months
        median (confidence interval 95%)
    75.03 (63.45 to 90.07)
    70.10 (59.93 to 93.13)
    Attachments
    		 Kaplan Meier Plot: Overall Survival
    OS - Forest Plot - Subgroup Analysis
    OS - Cumulative Illness Rating Score (≤6 vs. >6)
    OS - Cumulative Illness Rating Score (≤6)
    OS - Cumulative Illness Rating Score (>6)
    OS - Performance Status (0 vs. 1 vs. 2 vs. 3)
    OS - Performance Status (0)
    OS - Performance Status (1)
    OS - Performance Status (2)
    OS - Performance Status (3)
    OS - VES-13 (<3 vs. ≥3)
    OS - VES-13 (<3)
    OS - VES-13 (≥3)
    OS - GFI (<4 vs. ≥4)
    OS - GFI (<4)
    OS - GFI (≥4)
    OS - Timed Up and Go (<10 vs. ≥10)
    OS - Timed Up and Go (<10)
    OS - Timed Up and Go (≥10)
    OS - IGHV Status
    OS - IGHV (Mutated)
    OS - IGHV (Unmutated)
    OS - FISH Status
    OS - FISH (17p-)
    OS - FISH (11q-)
    OS - FISH (+12)
    OS - FISH (13q-)
    OS - FISH (No FISH Defect)
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.48
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall Survival (OS) - Exploratory Analysis – Idelalisib vs. Placebo

    		 Close Top of page
    End point title
    		 Overall Survival (OS) - Exploratory Analysis – Idelalisib vs. Placebo
    End point description
    End point type
    Secondary
    End point timeframe
    Unless they withdrew, participants were followed up until death or end of trial.
    End point values
    		 Idelalisib (Intention-to-treat) Placebo (Intention-to-treat)
    Number of subjects analysed
    73
    70
    Units: No. OS events
    20
    26
    Attachments
    		 Kaplan Meier Plot: Overall Survival
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Idelalisib (Intention-to-treat) v Placebo (Intention-to-treat)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.29
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Idelalisib (Intention-to-treat) v Placebo (Intention-to-treat)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.251
    Method
    		 Logrank
    Confidence interval

    Secondary: Response Including MRD Negativity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Overall Response

    		 Close Top of page
    End point title
    		 Response Including MRD Negativity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Overall Response
    End point description
    Overall Response (Complete Remission & Partial Remission)
    End point type
    Secondary
    End point timeframe
    Response was assessed at end of treatment.
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    143
    141
    Units: Events
    112
    102
    Statistical analysis title
    		 Logistic regression model
    Statistical analysis description
    Overall Response (Complete Remission & Partial Remission) - Logistic Regression Model
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.334
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 2.26

    Secondary: Duration of Response - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo)

    		 Close Top of page
    End point title
    		 Duration of Response - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo)
    End point description
    End point type
    Secondary
    End point timeframe
    Unless they withdrew, participants were followed up until progression or end of trial.
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    112
    102
    Units: Response duration in months
        median (confidence interval 95%)
    44.44 (32.57 to 49.80)
    30.20 (23.19 to 34.90)
    Attachments
    		 Kaplan Meier Plot: Duration of Response
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.84
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to Treatment Failure (TTF) - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo)

    		 Close Top of page
    End point title
    		 Time to Treatment Failure (TTF) - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo)
    End point description
    Unless they withdrew, participants were followed up until treatment failure or end of trial.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    215
    219
    Units: TTF in months
        median (confidence interval 95%)
    37.73 (32.76 to 44.61)
    28.09 (26.18 to 33.59)
    Attachments
    		 Kaplan Meier Plot: Time to Treatment Failure
    TTF - Forest Plot - Subgroup Analysis
    TTF - Cumulative Illness Rating Score (≤6 vs. >6)
    TTF - Cumulative Illness Rating Score (≤6)
    TTF - Cumulative Illness Rating Score (>6)
    TTF - Performance Status (0 vs. 1 vs. 2 vs. 3)
    TTF - Performance Status (0)
    TTF - Performance Status (1)
    TTF - Performance Status (2)
    TTF - Performance Status (3)
    TTF - VES-13 (<3 vs. ≥3)
    TTF - VES-13 (<3)
    TTF - VES-13 (≥3)
    TTF - GFI (<4 vs. ≥4)
    TTF - GFI (<4)
    TTF - GFI (≥4)
    TTF - Timed Up and Go (<10 vs. ≥10)
    TTF - Timed Up and Go (<10)
    TTF - Timed Up and Go (≥10)
    TTF - IGHV Status
    TTF - IGHV (Mutated)
    TTF - IGHV (Unmutated)
    TTF - FISH Status
    TTF - FISH (17p-)
    TTF - FISH (11q-)
    TTF - FISH (+12)
    TTF - FISH (No FISH Defect)
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.86
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Logrank
    Confidence interval

    Secondary: Toxicity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Toxicity Summary

    		 Close Top of page
    End point title
    		 Toxicity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Toxicity Summary
    End point description
    End point type
    Secondary
    End point timeframe
    Toxicity reported up to 28 days after last dose of treatment except for grade 3 and 4 infection which was reported until 6 months after last dose of treatment.
    End point values
    		 Bendamustine (Including Placebo) (Safety) Chlorambucil (Including Placebo) (Safety)
    Number of subjects analysed
    215
    219
    Units: Events
        Grade 3+ AE
    108
    102
        SAE
    139
    127
        Either Grade 3+ AE or SAE
    175
    166
    No statistical analyses for this end point

    Secondary: Toxicity - Exploratory Analysis – Idelalisib vs. Placebo - Toxicity Summary

    		 Close Top of page
    End point title
    		 Toxicity - Exploratory Analysis – Idelalisib vs. Placebo - Toxicity Summary
    End point description
    End point type
    Secondary
    End point timeframe
    Toxicity reported up to 28 days after last dose of treatment except for grade 3 and 4 infection which was reported until 6 months after last dose of treatment.
    End point values
    		 Idelalisib (Safety) Placebo (Safety)
    Number of subjects analysed
    72
    67
    Units: Events
        Grade 3+ AE
    41
    37
        SAE
    60
    38
        Either Grade 3+ AE or SAE
    69
    56
    No statistical analyses for this end point

    Secondary: Toxicity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Adverse Events by Severity

    		 Close Top of page
    End point title
    		 Toxicity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Adverse Events by Severity
    End point description
    End point type
    Secondary
    End point timeframe
    Toxicity reported up to 28 days after last dose of treatment except for grade 3 and 4 infection which was reported until 6 months after last dose of treatment.
    End point values
    		 Bendamustine (Including Placebo) (Safety) Chlorambucil (Including Placebo) (Safety)
    Number of subjects analysed
    215
    219
    Units: Adverse Events
        Severity 1
    1162
    1105
        Severity 2
    694
    704
        Severity 3
    219
    222
        Severity 4
    43
    32
        Severity 5
    0
    1
        Missing
    17
    19
    No statistical analyses for this end point

    Secondary: Toxicity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Serious Adverse Events by Severity

    		 Close Top of page
    End point title
    		 Toxicity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Serious Adverse Events by Severity
    End point description
    End point type
    Secondary
    End point timeframe
    Toxicity reported up to 28 days after last dose of treatment except for grade 3 and 4 infection which was reported until 6 months after last dose of treatment.
    End point values
    		 Bendamustine (Including Placebo) (Safety) Chlorambucil (Including Placebo) (Safety)
    Number of subjects analysed
    215
    219
    Units: Serious Adverse Events
        Severity 1
    58
    41
        Severity 2
    89
    69
        Severity 3
    93
    85
        Severity 4
    18
    18
        Severity 5
    9
    3
        Missing
    40
    18
    No statistical analyses for this end point

    Secondary: Toxicity - Exploratory Analysis – Idelalisib vs. Placebo - Adverse Events by Severity

    		 Close Top of page
    End point title
    		 Toxicity - Exploratory Analysis – Idelalisib vs. Placebo - Adverse Events by Severity
    End point description
    End point type
    Secondary
    End point timeframe
    Toxicity reported up to 28 days after last dose of treatment except for grade 3 and 4 infection which was reported until 6 months after last dose of treatment.
    End point values
    		 Idelalisib (Safety) Placebo (Safety)
    Number of subjects analysed
    72
    67
    Units: Adverse Events
        Severity 1
    460
    493
        Severity 2
    259
    278
        Severity 3
    114
    80
        Severity 4
    14
    7
        Severity 5
    1
    0
        Missing
    2
    6
    No statistical analyses for this end point

    Secondary: Toxicity - Exploratory Analysis – Idelalisib vs. Placebo - Serious Adverse Events by Severity

    		 Close Top of page
    End point title
    		 Toxicity - Exploratory Analysis – Idelalisib vs. Placebo - Serious Adverse Events by Severity
    End point description
    End point type
    Secondary
    End point timeframe
    Toxicity reported up to 28 days after last dose of treatment except for grade 3 and 4 infection which was reported until 6 months after last dose of treatment.
    End point values
    		 Idelalisib (Safety) Placebo (Safety)
    Number of subjects analysed
    72
    67
    Units: Serious Adverse Events
        Severity 1
    32
    15
        Severity 2
    42
    38
        Severity 3
    34
    23
        Severity 4
    9
    4
        Severity 5
    4
    1
        Missing
    20
    18
    No statistical analyses for this end point

    Secondary: Response Including MRD Negativity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Response by Treatment

    		 Close Top of page
    End point title
    		 Response Including MRD Negativity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - Response by Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Response was assessed at end of treatment.
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    143
    141
    Units: Patients
        Complete Remission
    1
    1
        Partial Remission
    111
    101
        Stable Disease
    23
    36
        Progressive Disease
    8
    3
    No statistical analyses for this end point

    Secondary: Response Including MRD Negativity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - MRD by Treatment

    		 Close Top of page
    End point title
    		 Response Including MRD Negativity - Primary Analysis – Bendamustine vs. Chlorambucil (Including Placebo) - MRD by Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Response was assessed at end of treatment.
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    79
    88
    Units: Patients
        MRD+ve
    59
    84
        MRD-ve
    20
    4
    No statistical analyses for this end point

    Other pre-specified: Sensitivity Analysis 1 - PFS - Per Protocol Set - Bendamustine vs. Chlorambucil (Including Placebo)

    		 Close Top of page
    End point title
    		 Sensitivity Analysis 1 - PFS - Per Protocol Set - Bendamustine vs. Chlorambucil (Including Placebo)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Unless they with withdrew, participants were followed up until progression, death or end of trial.
    End point values
    		 Bendamustine (Including Placebo) (Per protocol) Chlorambucil (Including Placebo) (Per protocol)
    Number of subjects analysed
    134
    158
    Units: PFS in months
        median (confidence interval 95%)
    37.71 (32.29 to 48.39)
    28.32 (25.53 to 34.86)
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Bendamustine (Including Placebo) (Per protocol) v Chlorambucil (Including Placebo) (Per protocol)
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.99
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Bendamustine (Including Placebo) (Per protocol) v Chlorambucil (Including Placebo) (Per protocol)
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042
    Method
    		 Logrank
    Confidence interval

    Post-hoc: Additional Analysis - Time to Second Line Treatment - Bendamustine vs. Chlorambucil (Including Placebo)

    		 Close Top of page
    End point title
    		 Additional Analysis - Time to Second Line Treatment - Bendamustine vs. Chlorambucil (Including Placebo)
    End point description
    End point type
    Post-hoc
    End point timeframe
    Time to Second Line Treatment (From Initiation of Study Treatment)
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    79
    108
    Units: Events in months
        median (confidence interval 95%)
    27.93 (23.52 to 35.59)
    26.32 (21.45 to 29.87)
    Attachments
    		 Time to Second Line Treatment
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.98
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034
    Method
    		 Logrank
    Confidence interval

    Post-hoc: Additional Analysis - Time to Third Line Treatment (From Randomisation) - Bendamustine vs. Chlorambucil (Including Placebo)

    		 Close Top of page
    End point title
    		 Additional Analysis - Time to Third Line Treatment (From Randomisation) - Bendamustine vs. Chlorambucil (Including Placebo)
    End point description
    End point type
    Post-hoc
    End point timeframe
    Time to Third Line Treatment (From Randomisation)
    End point values
    		 Bendamustine (Including Placebo) (Intention-to-treat) Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects analysed
    222
    223
    Units: Events
    21
    37
    Attachments
    		 Time to Third Line Treatment
    Statistical analysis title
    		 Stratified Cox PH model
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.84
    Statistical analysis title
    		 Stratified log rank test
    Comparison groups
    Bendamustine (Including Placebo) (Intention-to-treat) v Chlorambucil (Including Placebo) (Intention-to-treat)
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Logrank
    Confidence interval

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Toxicity reported up to 28 days after last dose of treatment except for grade 3 and 4 infection which was reported until 6 months after last dose of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Bendamustine
    Reporting group description
    		 Adverse events are reported for the safety set (SS) which consists of all patients who received any trial treatment. For "Total number of deaths (all causes)", the number provided is for the Intention-to-treat set rather than the Safety set.

    Reporting group title
    Chlorambucil
    Reporting group description
    		 Adverse events are reported for the safety set (SS) which consists of all patients who received any trial treatment. For "Total number of deaths (all causes)", the number provided is for the Intention-to-treat set rather than the Safety set.

    Serious adverse events
    		 Bendamustine Chlorambucil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    139 / 215 (64.65%)
    127 / 219 (57.99%)
         number of deaths (all causes)
    83
    76
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma stage I
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer stage II
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    5 / 215 (2.33%)
    7 / 219 (3.20%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    5 / 215 (2.33%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer fatigue
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia transformation
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    External ear neoplasm malignant
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    3 / 215 (1.40%)
    3 / 219 (1.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder cancer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    3 / 215 (1.40%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myeloproliferative neoplasm
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    3 / 215 (1.40%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleomorphic malignant fibrous histiocytoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Second primary malignancy
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    4 / 215 (1.86%)
    3 / 219 (1.37%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    12 / 215 (5.58%)
    8 / 219 (3.65%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral neoplasm
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery embolism
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    11 / 215 (5.12%)
    5 / 219 (2.28%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Amyloidosis senile
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactoid reaction
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media allergy
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    3 / 215 (1.40%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular swelling
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    3 / 215 (1.40%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    3 / 215 (1.40%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    3 / 215 (1.40%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    X-ray with contrast upper gastrointestinal tract
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Expired product administered
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    25 / 215 (11.63%)
    21 / 219 (9.59%)
         occurrences causally related to treatment / all
    0 / 27
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematuria
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block right
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    5 / 215 (2.33%)
    9 / 219 (4.11%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplasia pure red cell
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    9 / 215 (4.19%)
    7 / 219 (3.20%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    4 / 219 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    3 / 219 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         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
    Angioedema
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperhidrosis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichen planus
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psoriasis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    4 / 219 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    3 / 215 (1.40%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    3 / 219 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis viral
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster oticus
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    7 / 215 (3.26%)
    5 / 219 (2.28%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    22 / 215 (10.23%)
    13 / 219 (5.94%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    19 / 215 (8.84%)
    13 / 219 (5.94%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    13 / 215 (6.05%)
    5 / 219 (2.28%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    9 / 215 (4.19%)
    4 / 219 (1.83%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    4 / 219 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    3 / 219 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (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
    Alcohol intolerance
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemic syndrome
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
    Additional description: Relatedness has not been included in the report Fatalities number not included in the report
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Bendamustine Chlorambucil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    180 / 215 (83.72%)
    184 / 219 (84.02%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    6 / 219 (2.74%)
         occurrences all number
    6
    6
    Vascular disorders
    Flushing
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 219 (0.91%)
         occurrences all number
    2
    2
    Haematoma
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Hot flashes
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Hypertension
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    5 / 219 (2.28%)
         occurrences all number
    3
    5
    Hypotension
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    6 / 215 (2.79%)
    9 / 219 (4.11%)
         occurrences all number
    6
    9
    Phlebitis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Thromboembolic event
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 219 (0.91%)
         occurrences all number
    2
    4
    Vascular disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Chills
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    15 / 215 (6.98%)
    18 / 219 (8.22%)
         occurrences all number
    18
    21
    Edema face
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Edema limbs
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    21 / 215 (9.77%)
    13 / 219 (5.94%)
         occurrences all number
    22
    14
    Fatigue
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    70 / 215 (32.56%)
    80 / 219 (36.53%)
         occurrences all number
    91
    100
    Fever
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    26 / 215 (12.09%)
    10 / 219 (4.57%)
         occurrences all number
    30
    14
    Flu like symptoms
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    11 / 215 (5.12%)
    5 / 219 (2.28%)
         occurrences all number
    11
    6
    Gait disturbance
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    General disorders and administration site conditions - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    17 / 215 (7.91%)
    22 / 219 (10.05%)
         occurrences all number
    24
    29
    Infusion related reaction
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    63 / 215 (29.30%)
    65 / 219 (29.68%)
         occurrences all number
    84
    101
    Infusion site extravasation
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Injection site reaction
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Localized edema
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    1
    2
    Malaise
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    3 / 219 (1.37%)
         occurrences all number
    2
    3
    Neck edema
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    4 / 219 (1.83%)
         occurrences all number
    1
    4
    Oedema
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    15 / 215 (6.98%)
    10 / 219 (4.57%)
         occurrences all number
    17
    11
    Pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    30 / 215 (13.95%)
    17 / 219 (7.76%)
         occurrences all number
    32
    29
    Immune system disorders
    Allergic reaction
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    20 / 215 (9.30%)
    25 / 219 (11.42%)
         occurrences all number
    23
    32
    Anaphylaxis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences all number
    2
    1
    Reproductive system and breast disorders
    Genital edema
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    3 / 219 (1.37%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Cough
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    52 / 215 (24.19%)
    34 / 219 (15.53%)
         occurrences all number
    60
    45
    Dyspnea
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    25 / 215 (11.63%)
    32 / 219 (14.61%)
         occurrences all number
    27
    34
    Epistaxis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    3 / 219 (1.37%)
         occurrences all number
    3
    3
    Hoarseness
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    3 / 219 (1.37%)
         occurrences all number
    2
    4
    Hypoxia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Laryngeal inflammation
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    1
    2
    Nasal congestion
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences all number
    2
    1
    Pleural effusion
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    3
    0
    Pneumonitis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 219 (0.91%)
         occurrences all number
    2
    2
    Postnasal drip
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    1
    2
    Productive cough
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    3 / 219 (1.37%)
         occurrences all number
    8
    3
    Respiratory, thoracic and mediastinal disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    17 / 215 (7.91%)
    7 / 219 (3.20%)
         occurrences all number
    18
    7
    Sinus disorder
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Sneezing
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Sore throat
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    13 / 215 (6.05%)
    12 / 219 (5.48%)
         occurrences all number
    13
    15
    Voice alteration
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Wheezing
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Anxiety
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    4 / 219 (1.83%)
         occurrences all number
    3
    6
    Confusion
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    0 / 219 (0.00%)
         occurrences all number
    3
    0
    Delirium
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Depression
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    4 / 219 (1.83%)
         occurrences all number
    4
    4
    Hallucinations
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    1
    2
    Insomnia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    8 / 215 (3.72%)
    11 / 219 (5.02%)
         occurrences all number
    8
    15
    Libido decreased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Psychiatric disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    2 / 219 (0.91%)
         occurrences all number
    3
    3
    Alkaline phosphatase increased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    6 / 219 (2.74%)
         occurrences all number
    5
    6
    Aspartate aminotransferase increased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    3 / 219 (1.37%)
         occurrences all number
    0
    3
    Blood bilirubin increased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    2 / 219 (0.91%)
         occurrences all number
    6
    2
    CPK increased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Creatinine increased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    8 / 219 (3.65%)
         occurrences all number
    8
    8
    GGT increased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    1
    2
    Investigations - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    4 / 219 (1.83%)
         occurrences all number
    9
    4
    Lymphocyte count decreased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    1 / 219 (0.46%)
         occurrences all number
    3
    1
    Lymphocyte count increased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    6 / 215 (2.79%)
    2 / 219 (0.91%)
         occurrences all number
    6
    2
    Neutrophil count decreased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    148 / 215 (68.84%)
    144 / 219 (65.75%)
         occurrences all number
    245
    250
    Platelet count decreased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    105 / 215 (48.84%)
    92 / 219 (42.01%)
         occurrences all number
    189
    178
    Weight gain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Weight loss
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    5 / 219 (2.28%)
         occurrences all number
    7
    5
    White blood cell decreased
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    6 / 215 (2.79%)
    7 / 219 (3.20%)
         occurrences all number
    6
    9
    Injury, poisoning and procedural complications
    Bruising
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    3 / 219 (1.37%)
         occurrences all number
    3
    4
    Fall
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    4 / 219 (1.83%)
         occurrences all number
    7
    5
    Fracture
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    3 / 219 (1.37%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    2 / 219 (0.91%)
         occurrences all number
    4
    2
    Wrist fracture
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Cardiac disorders
    Aortic valve disease
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    4 / 219 (1.83%)
         occurrences all number
    4
    4
    Atrial flutter
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    8 / 219 (3.65%)
         occurrences all number
    3
    8
    Chest pain - cardiac
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    2 / 219 (0.91%)
         occurrences all number
    3
    2
    Heart failure
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Palpitations
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    3 / 219 (1.37%)
         occurrences all number
    3
    3
    Sinus bradycardia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences all number
    2
    1
    Sinus tachycardia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    3 / 219 (1.37%)
         occurrences all number
    2
    3
    Ventricular tachycardia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Central nervous system necrosis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Concentration impairment
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Dizziness
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    14 / 215 (6.51%)
    14 / 219 (6.39%)
         occurrences all number
    15
    14
    Dysarthria
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Dysesthesia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    4 / 219 (1.83%)
         occurrences all number
    7
    4
    Extrapyramidal disorder
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Headache
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    15 / 215 (6.98%)
    13 / 219 (5.94%)
         occurrences all number
    19
    19
    Lethargy
         subjects affected / exposed
    13 / 215 (6.05%)
    17 / 219 (7.76%)
         occurrences all number
    14
    19
    Memory impairment
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Movements involuntary
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Nervous system disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    6 / 215 (2.79%)
    7 / 219 (3.20%)
         occurrences all number
    7
    8
    Olfactory nerve disorder
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Paresthesia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    2 / 219 (0.91%)
         occurrences all number
    5
    2
    Peripheral motor neuropathy
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Peripheral sensory neuropathy
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    10 / 219 (4.57%)
         occurrences all number
    4
    14
    Presyncope
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Sinus pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Somnolence
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Syncope
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    3 / 219 (1.37%)
         occurrences all number
    1
    4
    Transient ischemic attacks
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Tremor
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    6 / 219 (2.74%)
         occurrences all number
    2
    6
    Vasovagal reaction
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    71 / 215 (33.02%)
    58 / 219 (26.48%)
         occurrences all number
    112
    85
    Blood and lymphatic system disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    13 / 215 (6.05%)
    26 / 219 (11.87%)
         occurrences all number
    23
    40
    Febrile neutropenia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    1
    2
    Haemolysis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Haemolytic uremic syndrome
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Leukocytosis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    6 / 215 (2.79%)
    2 / 219 (0.91%)
         occurrences all number
    7
    2
    Lymph node pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Thrombotic thrombocytopenic purpura
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    9 / 219 (4.11%)
         occurrences all number
    8
    11
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    4 / 219 (1.83%)
         occurrences all number
    1
    5
    Ear pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    4 / 219 (1.83%)
         occurrences all number
    3
    4
    External ear inflammation
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Hearing impaired
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    3 / 219 (1.37%)
         occurrences all number
    0
    3
    Vertigo
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    1 / 219 (0.46%)
         occurrences all number
    4
    1
    Vestibular disorder
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    0 / 219 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Blurred vision
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    3 / 219 (1.37%)
         occurrences all number
    1
    3
    Cataract
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Conjunctivitis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    2 / 219 (0.91%)
         occurrences all number
    4
    2
    Dry eye
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Eye disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    4 / 219 (1.83%)
         occurrences all number
    7
    4
    Eye pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Eyelid function disorder
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Flashing lights
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences all number
    0
    2
    Watering eyes
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    3 / 219 (1.37%)
         occurrences all number
    0
    3
    Abdominal pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    17 / 215 (7.91%)
    16 / 219 (7.31%)
         occurrences all number
    21
    17
    Anal pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Anal ulcer
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Bloating
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    1 / 219 (0.46%)
         occurrences all number
    4
    2
    Colitis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Colonic hemorrhage
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Constipation
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    54 / 215 (25.12%)
    34 / 219 (15.53%)
         occurrences all number
    75
    43
    Dental caries
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Diarrhea
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    52 / 215 (24.19%)
    46 / 219 (21.00%)
         occurrences all number
    73
    69
    Dry mouth
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    11 / 215 (5.12%)
    5 / 219 (2.28%)
         occurrences all number
    12
    6
    Dyspepsia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    4 / 219 (1.83%)
         occurrences all number
    1
    4
    Dysphagia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Esophageal pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Flatulence
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Gastroesophageal reflux disease
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    2 / 219 (0.91%)
         occurrences all number
    3
    2
    Gastrointestinal disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    15 / 215 (6.98%)
    7 / 219 (3.20%)
         occurrences all number
    18
    7
    Gastrointestinal pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Haemorrhoids
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Mucositis oral
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    5 / 219 (2.28%)
         occurrences all number
    7
    5
    Nausea
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    71 / 215 (33.02%)
    74 / 219 (33.79%)
         occurrences all number
    95
    104
    Oral dysesthesia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Oral pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    9 / 219 (4.11%)
         occurrences all number
    4
    9
    Rectal hemorrhage
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Salivary duct inflammation
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Stomach pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    4 / 219 (1.83%)
         occurrences all number
    1
    5
    Toothache
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    3 / 219 (1.37%)
         occurrences all number
    0
    3
    Vomiting
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    31 / 215 (14.42%)
    39 / 219 (17.81%)
         occurrences all number
    39
    50
    Hepatobiliary disorders
    Hepatic pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Portal vein thrombosis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    9 / 219 (4.11%)
         occurrences all number
    4
    11
    Body odor
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Dry skin
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    13 / 215 (6.05%)
    8 / 219 (3.65%)
         occurrences all number
    15
    9
    Erythema multiforme
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    1 / 219 (0.46%)
         occurrences all number
    4
    1
    Hyperhidrosis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    6 / 219 (2.74%)
         occurrences all number
    5
    6
    Palmar-plantar erythrodysesthesia syndrome
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    1 / 219 (0.46%)
         occurrences all number
    3
    2
    Pruritus
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    24 / 215 (11.16%)
    13 / 219 (5.94%)
         occurrences all number
    27
    13
    Purpura
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Rash Macular
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    0 / 219 (0.00%)
         occurrences all number
    4
    0
    Rash acneiform
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 219 (0.91%)
         occurrences all number
    2
    2
    Rash erythematous
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    5 / 219 (2.28%)
         occurrences all number
    5
    5
    Rash generalized
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    12 / 215 (5.58%)
    9 / 219 (4.11%)
         occurrences all number
    15
    11
    Rash maculo-papular
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    31 / 215 (14.42%)
    29 / 219 (13.24%)
         occurrences all number
    35
    32
    Rash pruritic
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    41 / 215 (19.07%)
    34 / 219 (15.53%)
         occurrences all number
    61
    56
    Skin ulceration
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    3 / 219 (1.37%)
         occurrences all number
    2
    3
    Urticaria
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    6 / 219 (2.74%)
         occurrences all number
    2
    6
    Renal and urinary disorders
    Acute kidney injury
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    1
    2
    Cystitis noninfective
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Haematuria
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Renal and urinary disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Renal calculi
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Urinary frequency
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    7 / 219 (3.20%)
         occurrences all number
    5
    7
    Urinary retention
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Urinary tract obstruction
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Urinary tract pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Endocrine disorders
    Endocrine disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    1 / 219 (0.46%)
         occurrences all number
    5
    1
    Arthritis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Back pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    15 / 215 (6.98%)
    25 / 219 (11.42%)
         occurrences all number
    15
    28
    Bone pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Chest wall pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    4 / 219 (1.83%)
         occurrences all number
    2
    4
    Generalized muscle weakness
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences all number
    0
    2
    Joint effusion
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Muscle weakness left-sided
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Muscle weakness lower limb
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    3 / 219 (1.37%)
         occurrences all number
    2
    3
    Muscle weakness upper limb
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorder - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    9 / 215 (4.19%)
    12 / 219 (5.48%)
         occurrences all number
    11
    14
    Myalgia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    1 / 219 (0.46%)
         occurrences all number
    3
    1
    Neck pain
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    3 / 219 (1.37%)
         occurrences all number
    2
    3
    Pain in extremity
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    5 / 219 (2.28%)
         occurrences all number
    6
    5
    Infections and infestations
    Bladder infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Bronchial infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    6 / 215 (2.79%)
    11 / 219 (5.02%)
         occurrences all number
    6
    13
    Device related infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Eye infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    3 / 219 (1.37%)
         occurrences all number
    5
    3
    Hepatic infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    29 / 215 (13.49%)
    29 / 219 (13.24%)
         occurrences all number
    32
    37
    Lip infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Lung infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    8 / 215 (3.72%)
    13 / 219 (5.94%)
         occurrences all number
    10
    13
    Mucosal infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    2
    2
    Otitis media
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Papulopustular rash
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Penile infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    1
    2
    Phlebitis infective
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Rash pustular
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    2 / 219 (0.91%)
         occurrences all number
    0
    2
    Rhinitis infective
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Sepsis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Sinusitis
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    2 / 219 (0.91%)
         occurrences all number
    3
    2
    Skin infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    7 / 219 (3.20%)
         occurrences all number
    7
    7
    Soft tissue infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Tooth infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 219 (0.91%)
         occurrences all number
    2
    2
    Upper respiratory infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    13 / 215 (6.05%)
    11 / 219 (5.02%)
         occurrences all number
    14
    12
    Urinary tract infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    7 / 215 (3.26%)
    11 / 219 (5.02%)
         occurrences all number
    9
    16
    Vaginal infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences all number
    2
    1
    Vulval infection
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    Metabolism and nutrition disorders
    Anorexia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    25 / 215 (11.63%)
    14 / 219 (6.39%)
         occurrences all number
    26
    16
    Hypercalcemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Hyperglycemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    7 / 219 (3.20%)
         occurrences all number
    5
    16
    Hyperkalemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    5 / 219 (2.28%)
         occurrences all number
    4
    5
    Hypernatremia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 219 (0.46%)
         occurrences all number
    0
    1
    Hyperuricemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    6 / 219 (2.74%)
         occurrences all number
    1
    8
    Hypoalbuminemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    0 / 219 (0.00%)
         occurrences all number
    7
    0
    Hypocalcemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    5 / 215 (2.33%)
    2 / 219 (0.91%)
         occurrences all number
    5
    2
    Hypoglycemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    0 / 219 (0.00%)
         occurrences all number
    2
    0
    Hypokalemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    5 / 219 (2.28%)
         occurrences all number
    5
    7
    Hypomagnesemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    2 / 215 (0.93%)
    1 / 219 (0.46%)
         occurrences all number
    2
    2
    Hyponatremia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    3 / 215 (1.40%)
    5 / 219 (2.28%)
         occurrences all number
    8
    8
    Hypophosphatemia
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 219 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders - Other, specify
    alternative dictionary used: CTCAE 4
         subjects affected / exposed
    4 / 215 (1.86%)
    2 / 219 (0.91%)
         occurrences all number
    6
    2

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Sep 2011
    Amended version submitted in response to grounds for non-acceptance from MHRA. Main changes from Version 1: Date: 28.06.2011: Changes and clarification to Exclusion criteria Yellow fever vaccine and hypersensitivity to the active substance and its excipients have been added as exclusion criterion. In addition a note of justification for the lower neutrophil and platelet exclusion criteria which are contradictory to the Bendamustine SmPC has been included. Addition of justification for the Ofatumumab in study rationale The rationale for the dosage of ofatumumab in the trial population has now been explicitly stated within the study rationale. (section 2.2) Addition of specific surveillance activities during the study The requirement for surveillance of patients for suicidality (MS patients only), bowel obstruction and PML before and during treatment have been addressed throughout the protocol.
    05 Oct 2011
    Main changes from Version 2: Date: 06.09.2011: Changes to Sample Collection Requirements for Central Pathological Review (CPR) - Volume of blood for CPR has been increased from 5ml to 6ml due to the lack of a suitable 5ml collection tube. - Addition of a blood sample for CPR at 2 months post treatment - Inclusion of option to retain bone marrow trephine samples for future research should the patients give their consent. Changes to Study Schedule - Inclusion of standard sodium, total protein and gamma-GT biochemistry tests at all visits where safety samples are collected. - Height and weight to be performed initially at screening rather baseline for the purposes of ordering drug supply immediately following randomisation. - Monitoring for suicidality, bowel obstruction and PML has been redefined as a toxicity rather than a physical examination assessment. Changes to Pharmacovigilance Reporting Procedure Pharmacovigilance reporting procedures were revised to reflect the introduction of remote data entry for PV reporting within the LCTC to replace the previous system of faxing hard copy forms.
    11 Jun 2012
    Main changes from Version 3: Date: 05/10/2011: Changes to Eligibility - Inclusion of patients with SLL. - Addition of clarification regarding which prior CLL therapies are excluded. - Addition of clarification and further guidance regarding patients with seropositivity for HBV. Changes to Study Schedule - CIRS: Additional guidance added regarded scoring of haematopoietic category. - Removal of baseline weight measurement. - Clarification regarding follow up assessments to be performed by patient’s post-disease progression. - Removal of chloride and haptoglobin from the list of required laboratory tests. - Format changes to study schedule table to clarify post-PD follow up for overall survival assessments and to also separate out the clinical assessments from the lab assessments. Trial Treatment - Inclusion of wording allowing a delay in the commencement of chlorambucil/bendamustine until day 2 if practical reasons preclude commencement on day 1 of the treatment cycle. - Addition of geriatric assessments 2 months post treatment. - Addition of EORTC QLQ-CLL16 questionnaire every 3 months for duration of trial. - Inclusion of guidance regarding dose reduction of allopurinol for renal impairment. - Inclusion of wording allowing sites to use alternative glucocorticoid, antiemetic and hyperuricemia prophylaxis in accordance with local practice. - Inclusion of wording allowing the omission of baseline, 2 months post treatment and progression bone marrow samples under specific circumstances at the discretion of the chief investigator. Other - Change of Manufacturer name for free Ofatumumab and Bendamustine supply. - Addition of wording regarding acknowledgement of receipt of SAEs. - Administrative and typographical changes.
    29 Jan 2013
    Main changes from Version 4: Date: 11/06/2012: Eligibility Criteria - Additional of inclusion criterion 1e in line with NCI/IWCLL 2008 criteria. This was omitted from previous version protocols in error. - Change to inclusion criteria 1a and 1d, in line with NCI/IWCLL 2008 criteria - Inclusion of patients who have received prior localised radiotherapy for CLL (inclusion criteria #2). Sampling: - Revision of sampling schedule for Biobank samples - changed to visit-led rather than time-led schedule with first post treatment samples collected 6 months post treatment end. - Extension of MRD blood sampling (4ml) out to every 3 months in follow up from 9 months post treatment end until end of trial, progression or commencement of second line therapy. - Removal of bicarbonate, gamma GT and from the biochemistry profile as these are deemed non-essential for safety purposes. - Inclusion of paraprotein screen as part of immunoglobulin tests at baseline only. - Addition of clarification regarding the provision of archived diagnostic material from those patients who have already had bone marrow samples taken prior to trial entry (and who do not wish to undergo repeat sampling for trial purposes) and the wish to retain part of this material for research purposes providing that the patient and local Trust consents. - Addition of clarification regarding collection of sequential biobanking samples until 100 complete patient sets are received. Also updates to Quality of Life Questionnaires, Treatment and Safety sections
    17 Jul 2013
    Main changes from version: 5 Date: 29/01/2013: Exclusion Criteria: - Addition of exclusion criteria points 7 to 13 in line with Gilead’s protocol. - Change in exclusion criteria 8 from ongoing drug induced pneumonitis to history drug of pneumonitis - Exclusion criteria 16 updated to include hypersensitivity to idelalisib. - Change in exclusion criteria 6 from bilirubin more than twice the ULN to more than 1.5 the ULN Study Schematic: - Updated to include unacceptable toxicity Intervention: - Additional double blinded randomisation using a factorial design to include idelalisib / placebo. Rationale: - Update to rationale section to include data on idelalisib and to support the new trial design. Objectives: - Update to objectives to include idelalisib - Addition of objective to investigate the effect of adding idelalisib to ofatumumab-containing chemo-immunotherapy. Potential Risks and Benefits: - Addition of side effects associated with idelalisib. - Addition of the benefits associated with adding idelalisib. Enrolment & randomisation: - Addition of information allowing eligibility assessments that have been performed over the 42 day window at the discretion of the Chief Investigator. Trial Treatment: - Additional treatment arm idelalisib/placebo, patients will now be allocated to one of the four treatment arms: - Arm A + idelalisib - Arm A + placebo - Arm B + idelalisib - Arm B + placebo - Update to the treatment overview section, now separated into induction and maintenance phase. - Addition of guidance for patients treated as per protocol v.5. - Guidance provided on the sequencing of study drugs. - Addition of information on how idelalisisb / placebo will be assigned using an IWRS. - Addition of information on the formation of idelalisib and placebo Also update to Assessment & Procedures section
    18 Dec 2015
    Recrtuiment size reduced from 670 to 600 - Recruitment extended until April 2017 - Overall study extended until April 2020 - Contact details updated
    24 Feb 2016
    Urgent Safety Measure changes: - Omission of idelalisib from cycle 1. - Commencement of idelalisib at attenuated dose (100 mg bd) from cycle 2 with escalation to full dose (150 mg bd) in subsequent cycles if there are no ongoing grade ≥2 toxicities attributed to idelalisib/placebo. - Inclusion of a full blood count in the day 15 safety assessments that are required for cycles 1-3. - Extension of the day 15 safety assessments beyond cycle 3 if the final dose of idelalisib/placebo has not been reached or if the previous day 15 assessment showed grade ≥3 toxicity. - Routine G-CSF support for each subsequent cycle of the induction phase in the event of: 1. Grade ≥3 infection or febrile neutropenia 2. Grade ≥3 neutropenia when the next cycle is due 3. Grade 4 neutropenia occurring at any time during the treatment cycle - Routine antimicrobial prophylaxis with co-trimoxazole for all patients. - *** Subject to tolerance, co-trimoxazole (or equivalent) should be administered during the induction phase and for the first 12 weeks of the maintenance/follow up phase. Thereafter, co-trimoxazole (or equivalent) may be discontinued if the patient has not experienced grade 3-4 neutropenia or infection for a period of 12 weeks. Additonal changes: - Clarity on the follow up assessments for patients not entering the maintenance phase. - Time point references changed from months to weeks throughout for study assessments
    15 Apr 2016
    All references to idelalisib/placebo treatment removed, background and references to effects of idelalisib removed and schedule of assessments amended accordingly - Patient recruitment target reduced from 600 to 504. - Annual CT scans no longer necessary. - Day 15 assessments required during cycle 1 for all patients (not during cycles 2 and 3). - Co-trimoxazole and G-CSF treatment requirements updated and clarified. - References to maintenance treatment removed as idelalisib/placebo no longer applicable. - References to ‘induction treatment’ replaced by ‘treatment’ as there is no ‘maintenance phase’.
    01 Sep 2016
    Corrected section 8.1 ‘Schedule of Assessments’: 1) Toxicity assessment removed from ‘Screening’ column as already included in ‘Baseline’ column. 2) ‘Interim Assessments’ column header corrected to state correct timing of interim assessments – this was incorrectly entered in the last version of the protocol – as such, no new assessments have been added and the ones that were missing have been re-added. 3) ‘Interim Assessments’ column corrected to include demographics, physical examination, WHO performance status, serum immunoglobulins and removed serum biochemistry. These changes were incorrectly made in the last version of the protocol and as such, no new assessments have been added. ‘Post-treatment’ column corrected to include CLL-related symptoms and physical examination - These changes were incorrectly made in the last version of the protocol and as such, no new assessments have been added. - Concomitant medication information no longer required after the formal response assessment at week 12 for all patients. Section 7.2.10 and section 20.7 of appendix M updated accordingly (in addition to Schedule of Assessments) (except for SAE reports). - Section 10.5 – Generic bendamustine may be used for patients (previously this had been Levact only). The RSI used for this study will remain as Levact. - References to GSK replaced with Novartis throughout. - 8.1.4: Reworded section on planned assessments during the follow up phase for clarity. No new assessments added. Separated patients who have received 2 cycles of treatment or more and patients who have not received 2 cycles of treatment, using headers and how they are to be managed. - GP letter updated to remove references to idelalisib/placebo and CYP3A inducers and CYP3A substrates (as treatment no longer offered on this study following the previous substantial amendment). - Patient contact card updated to remove references to idelalisib/placebo
    31 May 2017
    Increased recruitment target to 565 - Extended end date of recruitment to 30/04/2018 (study to end 30/04/2021) - Statistics section updated - Re-included physical examination and CLL related symptoms in the schedule of assessments table as omitted in error and re-included reminder that interim response assessments are to be performed within 7 days of the next treatment cycle - Removed reference to ofatumumab being supplied free of charge as this may change prior to the end of the recruitment period - Expanded window for collection of MRD and Biobank samples - Updated TSC membership - Removed reference to reporting SAEs online - Removed ofatumumab IB section reference of IB for RSI information
    09 Oct 2017
    - Minor protocol clarifications added/changes/corrections made to reflect already approved changes (RSI details, SAE reporting methods, translational sample window in schedule of assessments tables, references to REC)
    03 Apr 2018
    Minor protocol update regarding the methods of statistical analysis. This related to the patients treated with idelalisib. (Section 9.4 Sample Size)
    18 Feb 2020
    Removal of ‘Appendix M’ - this appendix covered the treatment and follow-up schedule for patients randomised to the Protocol v5 or earlier i.e. pre-idelalisib treatment (O+B vs. O+Chl). - Trial Centre personnel updates and alteration to addresses, namely the address trial samples should be sent to. - Rebranding of LCTU to LCTC. The Liverpool Cancer Trials Unit has merged with the Medicines for Children Clinical Trials Research Centre. As a collective, we are now the Liverpool Clinical Trials Centre. - Clarification of length of follow-up sections 8.1.5 (Translational) and 8.1.7 Assessments for patients who are withdrawn from trial treatment. the Protocol stipulated that patients would remain on study until the last patient had completed 3 years of follow-up. However, this is Statistical term whereby ‘follow-up’ is considered to be a patient’s entire length of participation in the study. The last patient was randomised in April 2018; the trial is due to end is April 2021, meaning for this patient, participation in the follow-up phase itself will be a maximum of 2 years.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Mar 2016
    Recruitment was closed for 4 months from mid-March 2016 to mid-July 2016 due to safety concerns which led to the withdrawal of idealisib.
    14 Jul 2016

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Secondary outcomes, Quality of Life, Analysis of Frailty and Co-Morbidity and Predictive Value of Biomarkers, are not included in this summary of results but results are provided in the attached report.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Thu May 01 05:44:22 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA