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:
    A Phase III, Open Label, Randomized Trial of Ofatumumab Added to Fludarabine-Cyclophosphamide vs. Fludarabine-Cyclophosphamide Combination in Subjects with Relapsed Chronic Lymphocytic Leukemia Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    2008-005811-16
    Trial protocol
    NL   DE   GR   IT   ES   GB   BG   RO  
    Global end of trial date
    25 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Nov 2018
    First version publication date
    04 Nov 2018
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    110913
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00824265
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate and compare PFS of subjects treated with O+FC for the treatment of relapsed CLL to those treated with FC
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Mar 2009
    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
    Brazil: 10
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    India: 29
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 90
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Ukraine: 66
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    365
    EEA total number of subjects
    188
    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)
    231
    From 65 to 84 years
    133
    85 years and over
    1

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Participants (par) were screened within 14 days prior to the start of study drug administration to determine eligibility.

    Pre-assignment
    Screening details
    Eligible par were stratified by Stage (Binet A vs. B vs. C) and number of prior therapies (1-2 vs. ≥3). Par in each stratum were then centrally randomized in a 1:1 ratio to recive intravenous (IV) fludarabine and cyclophosphamide in combination with ofatumumab or IV fludarabine and cyclophosphamide alone.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Arm description
    Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
    Arm type
    Experimental

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

    Arm title
    Fludarabine + Cyclophosphamide_ ITT subjects
    Arm description
    Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
    Arm type
    Active comparator

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

    Number of subjects in period 1
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Started
    183
    182
    Completed
    119
    102
    Not completed
    64
    80
         Physician decision
    6
    12
         Consent withdrawn by subject
    6
    15
         Adverse Event,non-fatal
    50
    52
         Lost to follow-up
    1
    1
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Follow-up phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Arm description
    Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
    Arm type
    Experimental

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

    Arm title
    Fludarabine + Cyclophosphamide_ ITT subjects
    Arm description
    Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
    Arm type
    Active comparator

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

    Number of subjects in period 2
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Started
    172
    160
    Completed
    154
    129
    Not completed
    18
    31
         w/drew consent, no f/u, or MD choice
    18
    31
    Period 3
    Period 3 title
    Survival follow-up phase
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Arm description
    Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
    Arm type
    Experimental

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cycle 1-Day 1 300mg, Cycle 1-Day 8 1000mg, then Cycles 2-6 Day 1 1000mg every 28 days

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

    Arm title
    Fludarabine + Cyclophosphamide_ ITT subjects
    Arm description
    Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
    Arm type
    Active comparator

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine 25mg/m^2 Days 1-3 every 28 days for 6 cycles

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 250 mg/m2 Days 1-3 every 28 days for 6 cycles

    Number of subjects in period 3
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Started
    96
    89
    Completed
    87
    73
    Not completed
    9
    16
         w/drew consent, no f/u, or MD choice
    9
    16

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Reporting group description
    Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

    Reporting group title
    Fludarabine + Cyclophosphamide_ ITT subjects
    Reporting group description
    Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

    Reporting group values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects Total
    Number of subjects
    183 182 365
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    121 110 231
        From 65-84 years
    62 71 133
        85 years and over
    0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.4 ( 8.82 ) 61.6 ( 10.21 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    79 66 145
        Male
    104 116 220
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    3 5 8
        American Indian or Alaska Native
    3 1 4
        Asian - Central/South Asian Heritage
    13 16 29
        Asian - East Asian Heritage
    3 3 6
        Asian - South East Asian Heritage
    3 3 6
        White - Arabic/North African Heritage
    0 1 1
        White - White/Caucasian/European Heritage
    158 153 311
    AgeContinuous
    Units: Years
        arithmetic mean (standard deviation)
    61.4 ( 8.82 ) 61.6 ( 10.21 ) -

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Reporting group description
    Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

    Reporting group title
    Fludarabine + Cyclophosphamide_ ITT subjects
    Reporting group description
    Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
    Reporting group title
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Reporting group description
    Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

    Reporting group title
    Fludarabine + Cyclophosphamide_ ITT subjects
    Reporting group description
    Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.
    Reporting group title
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Reporting group description
    Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

    Reporting group title
    Fludarabine + Cyclophosphamide_ ITT subjects
    Reporting group description
    Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

    Subject analysis set title
    Ofatumumab+Fludarabine+Cyclophosphamide_anti-CLL therapies
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants with relapsed CLL received IV infusions of ofatumumab in combination with fludarabine and cyclophosphamide IV infusions for 6 cycles; each cycle comprised of 28 days. Participants received ofatumumab administered at 300 milligram (mg) on Day 1, 1000 mg on Day 8 of cycle 1 and 1000 mg on Day 1 of cycles 2, 3, 4, 5 and 6. Fludarabine was administered at 25 mg/meter squared [m^2] and cyclophosphamide was administered at 250mg/m^2 on Days 1-3 of each cycles (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

    Subject analysis set title
    Fludarabine+Cyclophosphamide_anti-CLL therapies
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants with relapsed CLL received IV infusions of fludarabine administered at 25 mg/m^2 and cyclophosphamide administered at 250mg/m^2 on Days 1-3 of each cycle (6 cycles). Participants were followed up one month post therapy and every 3 months for 5 years to evaluate survival and disease status.

    Primary: Progression-free survival (PFS), as assessed by the Independent Review Committee (IRC)

    Close Top of page
    End point title
    Progression-free survival (PFS), as assessed by the Independent Review Committee (IRC)
    End point description
    PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression (progressive disease,PD) and the date of death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia (CLL).
    End point type
    Primary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Months
        median (confidence interval 95%)
    28.94 (22.80 to 35.88)
    18.83 (14.42 to 25.82)
    Statistical analysis title
    PFS as assessed by the IRC
    Comparison groups
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0032
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    0.88

    Secondary: Overall survival (OS)

    Close Top of page
    End point title
    Overall survival (OS)
    End point description
    Overall survival is defined as the time from randomization to death due to any cause. Each participant was followed at the time when the last IRC-assessed PFS events occurred. Participants who had not died were censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Months
        median (confidence interval 95%)
    62.65 (44.58 to 999)
    46.23 (37.72 to 56.57)
    Statistical analysis title
    PFS as assessed by IRC
    Comparison groups
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1427
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    1.09

    Secondary: Time to response, as assessed by the IRC

    Close Top of page
    End point title
    Time to response, as assessed by the IRC
    End point description
    Time to response is defined as the time from randomization to the first response. Complete Response/remission(CR) all the criteria at least 2 months after last treatment: no lymphadenopathy(Ly) > 1.5 cm/ hepatomegaly/spleenomegaly/constitutional symptoms; neutrophils >1500 per microliter(µL), platelets(PL) >100,000/µL, hemoglobin(Hb) >11 grams/deciliter(g/dL), lymphocytes(LC) <4000/µL, bone marrow(BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. Incomplete bone marrow recovery(CRi): CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. Partial Remission/response(PR): >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline(BL), Hb >11 g/dL or 50% improvement over BL. Nodular PR(nPR): persistent nodules BM.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    152
    123
    Units: Months
        median (confidence interval 95%)
    0.99 (0.95 to 1.08)
    0.99 (0.95 to 1.18)
    Statistical analysis title
    Time to response as assessed by IRC
    Comparison groups
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.449
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.37

    Secondary: Duration of Response (DOR), as assessed by the IRC

    Close Top of page
    End point title
    Duration of Response (DOR), as assessed by the IRC
    End point description
    DOR is defined as the time from the initial response (CR, CRi, nPR, or PR) to the first documented sign of PD or death due to any cause. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.
    End point type
    Secondary
    End point timeframe
    From time of initial response to disease progression or death, whichever came first (up to 5 years after the last dose of study drug)
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    152
    123
    Units: Months
        median (confidence interval 95%)
    29.63 (25.03 to 41.46)
    24.90 (18.99 to 28.12)
    Statistical analysis title
    Duration of Response as assessed by the IRC
    Comparison groups
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0878
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.05

    Secondary: Time to progression, as assessed by the IRC

    Close Top of page
    End point title
    Time to progression, as assessed by the IRC
    End point description
    Time to progression is defined as the time from the date of randomization to PD. PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlargerd lymph nodes (>1.5 cm) spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site; an increase by 50% or more in the previously noted enlargement of the liver or spleen, an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter, transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukaemia.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after the last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Months
        median (confidence interval 95%)
    42.12 (28.94 to 47.67)
    26.78 (22.51 to 31.87)
    Statistical analysis title
    Time to progression as assessed by the IRC
    Comparison groups
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0036
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    0.87

    Secondary: Time to next therapy

    Close Top of page
    End point title
    Time to next therapy
    End point description
    Time to next therapy is defined as the time from randomization until the start of the next-line of treatment. Data are presented for participants who took anti-cancer therapies and participants in the ITT population.
    End point type
    Secondary
    End point timeframe
    From the start of study drug until the start of the next anti-CLL therapy (up to 5 years after the last dose of study drug)
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects Ofatumumab+Fludarabine+Cyclophosphamide_anti-CLL therapies Fludarabine+Cyclophosphamide_anti-CLL therapies
    Number of subjects analysed
    183
    182
    74
    67
    Units: Months
        median (confidence interval 95%)
    52.96 (43.56 to 62.98)
    40.08 (32.85 to 48.39)
    29.68 (24.97 to 32.66)
    21.03 (16.79 to 28.35)
    Statistical analysis title
    Time to next therapy
    Comparison groups
    Ofatumumab+Fludarabine+Cyclophosphamide_anti-CLL therapies v Fludarabine+Cyclophosphamide_anti-CLL therapies
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    [1]
    P-value
    = 0.0109
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    0.94
    Notes
    [1] - Participants who took anti-cancer therapies
    Statistical analysis title
    Time to next therapy
    Comparison groups
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    [2]
    P-value
    = 0.1143
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.08
    Notes
    [2] - Participants in the ITT population

    Secondary: Number of participants with improvement in Eastern Cooperative Oncology Group (ECOG) performance status

    Close Top of page
    End point title
    Number of participants with improvement in Eastern Cooperative Oncology Group (ECOG) performance status
    End point description
    The ECOG performance status scales and criteria are used by doctors and researchers to assess how a participant's disease is progressing, how the disease affects the daily living, and determines appropriate treatment and prognosis. ECOG performance status are measured at Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1 and Cycle 6 Day1. During follow period, 1 M after study drug therapy, then every 3 month up to 5 year (up to 60 months). Improvement is defined as a decrease from baseline by at least one step on the ECOG performance status scale (yes/no).
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day1, follow up (FU) at 1Month (M) after study drug therapy, 3M, then every 3 month up to 5 year (up to 60 months)
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Participants
        Cycle 2 Day 1, n= 170, 168|
    15
    13
        Cycle 3 Day 1, n= 165,157|
    16
    13
        Cycle 4 Day 1, n= 153, 132|
    19
    13
        Cycle 5 Day 1, n= 135, 118|
    20
    15
        Cycle 6 Day 1, n= 120, 96|
    26
    16
        1 M, FU, n= 159, 145|
    31
    22
        3 M, FU, n= 152, 119|
    31
    21
        6 M, FU, n= 136, 104|
    30
    18
        9 M, FU, n= 127, 96|
    31
    23
        12 M, FU, n= 118, 87|
    30
    20
        15 M, FU, n= 102, 70|
    23
    18
        18 M, FU, n= 96 ,65|
    23
    18
        21 M, FU, n= 92, 59|
    22
    16
        24 M, FU, n= 80, 53|
    20
    15
        27 M, FU, n= 74, 44|
    15
    13
        30 M, FU, n= 69, 35|
    14
    8
        33 M, FU, n= 65, 29|
    15
    7
        36 M, FU, n= 58, 23|
    12
    7
        39 M, FU, n= 51, 18|
    12
    7
        42 M, FU, n= 44, 16|
    11
    6
        45 M, FU, n= 39, 14|
    8
    4
        48 M, FU, n= 37, 12|
    8
    2
        51 M, FU, n= 32, 12|
    7
    3
        54 M, FU, n= 30, 9|
    7
    2
        57 M, FU, n= 26, 9|
    3
    3
        60 M, FU, n= 26, 8|
    3
    3
    No statistical analyses for this end point

    Secondary: Number of Participants with no B-Symptoms or at least one B-symptoms over the time

    Close Top of page
    End point title
    Number of Participants with no B-Symptoms or at least one B-symptoms over the time
    End point description
    Participants with no B-symptoms (B-Sy) (no night sweat, no weight loss, no fever and no extreme fatigue) and at least one indicated B-sy(night sweats, weight loss, fever or extreme fatigue) were presented at Screening, Cycle 1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and during follow up period at 1 M after study drug therapy, then every 3 M up to 5 year (up to 60 months).
    End point type
    Secondary
    End point timeframe
    Screening, Cycle1 Day 1, Cycle 2 Day1, Cycle 3 Day1, Cycle 4 Day1, Cycle 5 Day1, Cycle 6 Day 1 and During at 1M after study drug therapy, 3M, then every 3 M up to 5 year (up to 60 months)
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Participants
        Cycle 5 Day 1, no B-sy, n= 134, 118|
    120
    97
        36 M, FU, no B-sy, n=58, 23|
    56
    23
        Screening, no B-sy, n= 183, 180|
    63
    59
        Screening, one B-sy, n= 183, 180|
    120
    121
        Cycle 1 Day 1, no B-sy, n= 179, 179|
    64
    68
        Cycle 1 Day 1, one B-sy, n= 179, 179|
    115
    111
        Cycle 2 Day 1,no B-sy, n= 168, 170|
    116
    108
        Cycle 2 Day 1, one B-sy, n= 168, 170|
    52
    62
        Cycle 3 Day 1, no B-sy, n= 165, 156|
    131
    116
        Cycle 3 Day 1, one B-sy, n= 165, 156|
    34
    40
        Cycle 4 Day 1, no B-sy, n= 154, 132|
    129
    107
        Cycle 4 Day 1, one B-sy, n= 154, 132|
    25
    25
        Cycle 5 Day 1, one B-sy, n= 134, 118|
    14
    21
        Cycle 6 Day 1, no B-sy, n= 120, 95|
    111
    82
        Cycle 6 Day 1, one B-sy, n= 120, 95|
    9
    13
        1 M, FU, no B-sy, n= 161, 145|
    141
    116
        1 M, FU, one B-sy, n= 161, 145|
    20
    29
        3 M, FU, no B-sy, n= 153, 119|
    136
    105
        3 M, FU, one B-sy, n= 153, 119|
    17
    14
        6 M, FU, no B-sy, n= 138, 107|
    123
    96
        6 M, FU, one B-sy, n= 138, 107|
    15
    11
        9 M, FU, no B-sy, n= 129, 96|
    116
    87
        9 M, FU, one B-sy, n= 129, 96|
    13
    9
        12 M, FU, no B-sy, n= 119, 87|
    108
    74
        12 M, FU, one B-sy, n= 119, 87|
    11
    13
        15 M, FU, no B-sy, n= 103, 71|
    98
    63
        15 M, FU, one B-sy, n= 103, 71|
    5
    8
        18 M, FU, no B-sy, n= 98, 64|
    93
    58
        18 M, FU, one B-sy, n= 98, 64|
    5
    6
        21 M, FU, no B-sy, n= 94, 60|
    87
    55
        21 M, FU, one B-sy , n= 94, 60|
    7
    5
        24 M, FU, no B-sy, n= 80, 52|
    79
    48
        24 M, FU, one B-sy, n= 80, 52|
    1
    4
        27 M, FU, no B-sy, n= 74, 45|
    71
    41
        27 M, FU, one B-syn, n= 74, 45|
    4
    3
        30 M, FU, no B-sy, n= 70, 35|
    68
    33
        30 M, FU, one B-sy, n= 70, 35|
    2
    2
        33 M, FU, no B-sy, n= 66, 29|
    63
    27
        33 M, FU, one B-sy, n= 66, 29|
    3
    2
        36 M, FU, one B-sy, n=58, 23|
    2
    0
        39 M, FU, no B-sy, n=52, 18|
    49
    18
        39 M, FU, one B-sy, n=52, 18|
    3
    0
        42 M, FU, no B-sy, n=45, 16|
    45
    16
        42 M, FU, one B-sy, n=45, 16|
    0
    0
        45 M, FU, no B-sy, n=n=41, 15|
    41
    14
        45 M, FU, one B-sy, n=41, 15|
    0
    1
        48 M, FU, no B-sy, n=37, 13|
    36
    13
        48 M, FU, one B-sy, n=37, 13|
    1
    0
        51 M, FU, no B-sy, n=32, 12|
    32
    11
        51 M, FU, one B-sy, n=32, 12|
    0
    1
        54 M, FU, no B-sy, n=30, 10|
    30
    10
        54 M, FU, one B-sy, n=30, 10|
    0
    0
        57 M, FU, no B-sy, n=26, 9|
    26
    9
        57 M, FU, one B-sy, n=26, 9|
    0
    0
        60 M, FU, no B-sy, n=25, 9|
    24
    9
        60 M, FU, one B-sy, n=25, 9|
    1
    0
    No statistical analyses for this end point

    Secondary: Percentage of participants with the best Overall Response (OR), as assessed by the IRC

    Close Top of page
    End point title
    Percentage of participants with the best Overall Response (OR), as assessed by the IRC
    End point description
    OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Percentage of participants
        CR|
    27
    7
        CRi|
    2
    1
        nPR|
    0
    0
        PR|
    55
    59
        Stable disease|
    11
    28
        Progressive Disease|
    0
    0
        Not Evaluable|
    4
    2
        Missing|
    1
    2
    Statistical analysis title
    Best OR as assessed by IRC
    Comparison groups
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0003
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of participants with the best OR, as assessed by the Investigator

    Close Top of page
    End point title
    Percentage of participants with the best OR, as assessed by the Investigator
    End point description
    OR is defined as the number of participants achieving an objective response (complete response [CR], CR with incomplete bone marrow recovery [CRi], partial response [PR], and nodular PR [nPR]). CR (all the criteria at least 2 months after last treatment): no lymphadenopathy (Ly) > 1.5 cm/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500 per microliter (µL), platelets (PL) >100,000/µL, hemoglobin (Hb) >11 grams/deciliter (g/dL), lymphocytes (LC) <4000/µL, bone marrow (BM) sample must be normocellular for age, <30% LC, no lymphoid nodule. CRi: CR criteria, persistent anemia/thrombocytopenia/neutropenia unrelated to CLL but related to drug toxicity. PR: >=50% decrease in LC, Ly, size of liver and spleen and at least one of the following results: PL >100,000/µL or 50% improvement over Baseline (BL), Hb >11 g/dL or 50% improvement over BL. nPR: persistent nodules BM. Responder = CR + CRi + NPR + PR
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Percentage of participants
        CR|
    45
    24
        CRi|
    12
    4
        nPR|
    2
    8
        PR|
    107
    113
        Stable disease|
    9
    21
        Progressive Disease|
    0
    3
        Missing|
    8
    9
        Responder|
    166
    149
    Statistical analysis title
    Best OR as assessed by Investigator
    Comparison groups
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects v Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0166
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Number of participants who were negative for Minimal Residual Disease (MRD) assessed by IRC

    Close Top of page
    End point title
    Number of participants who were negative for Minimal Residual Disease (MRD) assessed by IRC
    End point description
    MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Participants
        Screening, n= 46, 13|
    0
    0
        Cycle 1 Day 1, n= 2, 0|
    0
    999
        3 M, FU, n= 44, 12|
    21
    7
        6 M, FU, n= 35, 11|
    25
    6
        9 M, FU, n= 29, 8|
    20
    4
        12 M, FU, n= 25, 4|
    16
    1
        15 M, FU, n= 20, 3|
    14
    1
        18 M, FU, n= 16, 2|
    12
    1
        21 M, FU, n= 13, 2|
    9
    1
        24 M, FU, n= 9, 2|
    8
    1
        27 M, FU, n= 9, 1|
    8
    0
        30 M, FU, n= 9, 2|
    8
    2
        33 M, FU, n= 5, 2|
    3
    1
        36 M, FU, n= 5, 2|
    5
    1
        39 M, FU, n= 2, 1|
    2
    1
        42 M, FU, n= 2, 0|
    2
    999
        45 M, FU, n= 1, 1|
    1
    1
        48 M, FU, n= 2, 1|
    2
    1
        51 M, FU, n= 2, 1|
    2
    1
        54 M, FU, n= 2, 1|
    2
    1
    No statistical analyses for this end point

    Secondary: Number of participants who were negative for MRD assessed by investigator

    Close Top of page
    End point title
    Number of participants who were negative for MRD assessed by investigator
    End point description
    MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment at the time the participant achieved a confirmed CR. MRD analysis was performed for the participants who were suspected of achieving a primary endpoint CR. MDR was performed by flow cytometry on a bone marrow or peripheral blood sample taken at least 2 months after final treatment. MRD negative was defined as less than one CLL cell per 10000 leukocytes.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Participants
        Screening, n= 177, 171|
    0
    1
        3 M, FU, n= 120, 76|
    39
    15
        6 M, FU, n= 87, 57|
    48
    11
        9 M, FU, n= 71, 29|
    35
    6
        12 M, FU, n= 55, 18|
    31
    3
        15 M, FU, n= 38, 14|
    23
    2
        18 M, FU, n= 31, 13|
    20
    2
        21 M, FU, n= 27, 9|
    16
    3
        24 M, FU, n= 15, 4|
    13
    2
        27 M, FU, n= 18, 5|
    14
    1
        30 M, FU, n= 15, 3|
    12
    3
        33 M, FU, n= 13, 3|
    8
    2
        36 M, FU, n= 10, 4|
    9
    2
        39 M, FU, n= 7, 3|
    6
    2
        42 M, FU, n= 8, 1|
    7
    1
        45 M, FU, n= 7, 2|
    6
    2
        48 M, FU, n= 6, 3|
    6
    2
        51 M, FU, n= 6, 2|
    5
    1
        54 M, FU, n= 7, 2|
    4
    2
        57 M, FU, n= 4, 3|
    3
    2
        60 M, FU, n= 3, 3|
    3
    2
    No statistical analyses for this end point

    Secondary: Number of participants with any Adverse Event (AE) or Serious Adverse Event (SAE)

    Close Top of page
    End point title
    Number of participants with any Adverse Event (AE) or Serious Adverse Event (SAE)
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
    End point type
    Secondary
    End point timeframe
    From first dose of study medication to 60 Days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    181
    178
    Units: Participants
        AE|
    170
    153
        SAE|
    108
    86
    No statistical analyses for this end point

    Secondary: Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at indicated time points

    Close Top of page
    End point title
    Number of Participants With a Human Anti-human Antibody (HAHA) Positive Result at indicated time points
    End point description
    Serum samples for analysis of HAHA were collected at Baseline (Screening), after 3 cycles were compelted, after 1 M and 6 M post last dose. All samples were first tested in a screening step; positive samples from the screening were further evaluated in a confirmation test. The confirmed positive samples were reported as HAHA-positive.
    End point type
    Secondary
    End point timeframe
    From start of study drug until 60 days after the last dose of study medication
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    181
    178
    Units: Participants
        Screening Visit, n= 179,177|
    8
    1
        Cycle 4 Day 1, n= 151,130|
    0
    2
        1 M, FU, n= 148,132|
    0
    2
        3 M, FU, n= 0,1|
    0
    0
        6 M, FU, n= 130, 99|
    2
    0
        9 M, FU, n= 0, 2|
    0
    0
        30 M, FU, n= 2, 0|
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with Autoimmune Hemolytic Anaemia (AIHA)

    Close Top of page
    End point title
    Number of participants with Autoimmune Hemolytic Anaemia (AIHA)
    End point description
    AIHA is a condition where the body's immune system fails to recognize red blood cells as "self" and begins destroying these red blood cells. The number of participants experienced AIHA are presented.
    End point type
    Secondary
    End point timeframe
    From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    181
    178
    Units: Participants
    3
    2
    No statistical analyses for this end point

    Secondary: Mean level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM

    Close Top of page
    End point title
    Mean level of Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM
    End point description
    Immunoglobulins, or antibodies, are large proteins used by the immune system to identify and neutralize foreign particles such as bacteria and viruses. Their normal blood levels indicate proper immune status. Low levels indicate immuno-suppression. Blood samples were collected from each participant and IgA, IgG, and IgM were measured at Baseline, and 1M and 6M after last dose during follow up period.
    End point type
    Secondary
    End point timeframe
    Baseline, 1M and 6M follow up
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    181
    178
    Units: Gram per liter
    arithmetic mean (standard deviation)
        Cycle 1 Day 1, IgA, n= 179, 175|
    1.0 ( 0.74 )
    0.9 ( 0.68 )
        Cycle 1 Day 1, IgG, n= 179, 175|
    8.7 ( 5.22 )
    8.2 ( 3.86 )
        Cycle 1 Day 1, IgM, n= 179, 175|
    0.6 ( 1.36 )
    0.8 ( 1.77 )
        1 M, FU, IgA, n= 150, 131|
    1.0 ( 0.79 )
    1.0 ( 0.77 )
        1 M, FU, IgG, n= 150, 131|
    7.9 ( 4.05 )
    7.9 ( 3.38 )
        1 M, FU, IgM, n= 150, 131|
    0.5 ( 1.16 )
    0.8 ( 1.88 )
        6 M, FU, IgA, n= 130, 101|
    1.0 ( 0.77 )
    1.0 ( 0.76 )
        6 M, FU, IgG, n= 130, 101|
    7.8 ( 3.97 )
    8.9 ( 4.31 )
        6 M, FU, IgM, n= 130, 101|
    0.4 ( 0.50 )
    1.1 ( 1.98 )
        9 M, FU, IgA, n= 1, 2|
    0.9 ( 999 )
    0.9 ( 0.21 )
        9 M, FU, IgG, n= 1, 2|
    15.2 ( 999 )
    8.8 ( 6.87 )
        9 M, FU, IgM, n= 1, 2|
    0.8 ( 999 )
    0.2 ( 0.04 )
        18 M, FU, IgA, n= 0, 1|
    999 ( 999 )
    2.4 ( 999 )
        18 M, FU, IgG, n= 0, 1|
    999 ( 999 )
    9.1 ( 999 )
        18 M, FU, IgM, n= 0, 1|
    999 ( 999 )
    1.0 ( 999 )
        30 M, FU, IgA, n= 2, 0|
    1.3 ( 1.17 )
    999 ( 999 )
        30 M, FU, IgG, n= 2, 0|
    4.7 ( 0.33 )
    999 ( 999 )
        30 M, FU, IgM, n= 2, 0|
    0.4 ( 0.26 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+

    Close Top of page
    End point title
    Change from baseline in Cluster of Differentiation (CD) Cell Counts, CD5+ and CD19+
    End point description
    CD5+ and CD19+ cells were counted by flow cytometry at Screening (Baseline) on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during the treatment period and after last dose of study drug at 1 M and then every three month follow up up to 45 M. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. day 1 if available, otherwise, screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three months up to 45 M during Follow-up Period
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: cells/uL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1,n=71, 65|
    43180.6 ( 48784.64 )
    53208.7 ( 70944.56 )
        Cycle 1 Day 15, n= 69, 62|
    2656.9 ( 6418.02 )
    9244.0 ( 19610.62 )
        Cycle 2 Day 1, n= 68, 63|
    2057.4 ( 5525.72 )
    10318.8 ( 21453.15 )
        Cycle 2 Day 15, n= 68, 59|
    513.7 ( 1717.65 )
    6874.4 ( 20632.64 )
        Cycle 3 Day 1,n= 68, 59|
    790.0 ( 2953.42 )
    6423.6 ( 19725.57 )
        Cycle 4 Day 1, n= 62, 49|
    402.1 ( 1768.74 )
    2643.2 ( 8092.22 )
        Cycle 5 Day 1,n= 57, 45|
    142.6 ( 472.24 )
    2838.6 ( 8314.08 )
        Cycle 6 Day 1, n= 56, 39|
    109.8 ( 398.77 )
    3862.7 ( 13312.14 )
        1 M, FU, n= 64, 61|
    163.5 ( 685.41 )
    5514.3 ( 17369.97 )
        3 M, FU, n= 69, 47|
    671.3 ( 2786.99 )
    2604.9 ( 9229.90 )
        6 M, FU, n= 61, 42|
    1591.6 ( 8857.22 )
    2275.6 ( 5118.00 )
        9 M, FU, n= 56, 37|
    910.5 ( 2495.85 )
    3408.4 ( 7438.45 )
        12 M, FU, n= 47, 30|
    2303.2 ( 6675.70 )
    2876.5 ( 6252.53 )
        15 M, FU, n= 35, 18|
    3325.8 ( 8006.48 )
    3072.7 ( 9038.23 )
        18 M, FU, n= 22, 12|
    1607.5 ( 2935.82 )
    4549.8 ( 8839.23 )
        21 M, FU, n= 22, 10|
    3830.8 ( 8989.02 )
    5236.9 ( 10537.31 )
        24 M, FU, n= 9, 6|
    1244.6 ( 1300.01 )
    7843.3 ( 11897.55 )
        27 M, FU, n= 7, 4|
    1877.4 ( 2117.84 )
    6128.0 ( 9161.38 )
        30 M, FU, n= 6, 2|
    5029.7 ( 8266.90 )
    6515.5 ( 5916.36 )
        33 M, FU, n= 4, 1|
    14166.8 ( 20166.09 )
    5208.0 ( 999 )
        36 M, FU, n= 3, 1|
    1187.0 ( 1407.79 )
    8184.0 ( 999 )
        39 M, FU, n=1, 0|
    557.0 ( 999 )
    999 ( 999 )
        42 M, FU, n= 1, 0|
    1640.0 ( 999 )
    999 ( 999 )
        45 M, FU, n= 2, 0|
    4689.0 ( 1493.41 )
    999 ( 999 )
        48 M FU, n= 1, 1|
    27755.0 ( 999 )
    29155.0 ( 999 )
        54 M FU, n= 1, 0|
    189849.0 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cell Counts, CD5- CD19+

    Close Top of page
    End point title
    Change from Baseline in Cell Counts, CD5- CD19+
    End point description
    CD5- CD19+ cells were counted by flow cytometry at Screening (baseline) at Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 during treatment period and after last dose of study drug at 1 M and then every three month up to 45 M during follow up period. Flow cytometry is a technique for counting and examining microscopic particles with an electronic detection apparatus. Baseline is defined as the assessment closest to but prior to first dose (e.g. Day 1 if available otherwise screening). Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    Screening, Cycle 1 Day1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1 and after last dose at 1 M and then every three month up to 45 M during Follow-up Period
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    181
    178
    Units: cells/uL
    arithmetic mean (standard deviation)
        Screening, n= 71, 62|
    4817.8 ( 20948.17 )
    6959.1 ( 39980.14 )
        Cycle 1 Day 1,n= 71, 65|
    5996.7 ( 22331.29 )
    2041.3 ( 4418.63 )
        Cycle 1 Day 15, n= 69, 62|
    239.0 ( 1052.19 )
    351.7 ( 1377.56 )
        Cycle 2 Day 1, n= 68, 63|
    115.4 ( 403.09 )
    465.7 ( 1610.05 )
        Cycle 2 Day 15,n= 68, 59|
    35.6 ( 133.75 )
    331.3 ( 1177.18 )
        Cycle 3 Day 1,n= 68, 59|
    39.5 ( 144.64 )
    179.7 ( 520.63 )
        Cycle 4 Day 1, n= 62, 49|
    25.7 ( 92.88 )
    95.3 ( 369.19 )
        Cycle 5 Day 1, n= 57, 45|
    15.9 ( 77.11 )
    195.5 ( 945.34 )
        Cycle 6 Day 1, n= 56, 39|
    10.0 ( 29.85 )
    649.7 ( 3606.28 )
        1 M, FU, n= 64, 61|
    7.5 ( 19.54 )
    863.8 ( 5001.84 )
        3 M, FU, n= 69, 47|
    40.1 ( 238.18 )
    172.0 ( 681.28 )
        6 M, FU, n= 61, 42|
    21.2 ( 58.16 )
    50.7 ( 49.13 )
        9 M, FU, n= 56, 37|
    85.7 ( 359.01 )
    92.0 ( 101.16 )
        12 M, FU, n= 47, 30|
    89.9 ( 226.06 )
    220.1 ( 698.57 )
        15 M, FU, n= 35, 18|
    67.3 ( 59.52 )
    94.6 ( 70.17 )
        18 M, FU, n= 22, 12|
    126.1 ( 188.25 )
    92.3 ( 69.14 )
        21 M, FU, n= 22, 10|
    375.5 ( 1307.35 )
    108.3 ( 95.86 )
        24 M, FU, n= 9, 6|
    74.0 ( 57.46 )
    104.5 ( 70.46 )
        27 M, FU, n= 7, 4|
    73.9 ( 60.40 )
    187.5 ( 200.85 )
        30 M, FU, n= 6, 2|
    74.2 ( 58.82 )
    129.5 ( 5303 )
        33 M, FU, n= 4, 1|
    41.8 ( 40.13 )
    1003.0 ( 999 )
        36 M, FU, n= 3, 1|
    107.3 ( 86.75 )
    1506.0 ( 999 )
        39 M, FU, n= 1, 0|
    13.0 ( 999 )
    999 ( 999 )
        42 M, FU, n= 1, 0|
    13.0 ( 999 )
    999 ( 999 )
        45 M, FU, n= 2, 0|
    166.5 ( 222.74 )
    999 ( 999 )
        48 M, FU, n= 1,1|
    6528.0 ( 999 )
    28.0 ( 999 )
        54 M, FU, n= 1, 0|9
    690.0 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Prognostic and biological markers correlating with clinical response

    Close Top of page
    End point title
    Prognostic and biological markers correlating with clinical response
    End point description
    Blood samples were collected for the assessment of the following prognostic markers at BL: immunoglobulin heavy chain variable region(IgVH) homology; Zeta-Chain-Associated Protein Kinase 70(ZAP70), VH3-21 usage; Cytogenetics (by fluorescent in situ hybridization [FISH]); beta 2 microglobulin. Cox-regression model was used to explore the relationship between progression-free survival and the following explanatory variables: treatment group, cytogenetics (analyzed by FISH included 6q-,11q-, +12q, 17p-, 13q-) , ZAP-70 (positive, negative or intermediate), VH3-21 usage (Yes and No), IgVH homology (>98%, 97%-98% and <97%), beta 2 microglobulin (>3500 microgram per liter [µg/L] and <=3500 µg/L). For each covariate, a hazard ratio <1 indicates a lower risk on the first effect tested compared with the other effects tested. Cytogenetics Group (based on >=20%)=cytogenetics (CY G).
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Participants
        B2 Microglobulin G 1: > 3500 μg/L
    79
    78
        B2 Microglobulin G 1: ≤3500 μg/L, n=51,47|
    22
    26
        CY G 1: 11q-, n=40, 31|
    29
    19
        CY G 1: 17p-, n=7, 13|
    6
    9
        CY G 1: 6q- or +12q or 13q-, n=84, 80|
    38
    48
        CY G 1: no aberration, n=45, 47|
    27
    27
        VH3-21 Usage Flag: Yes, n=9, 7|
    6
    4
        VH3-21 Usage Flag: No, n=159, 162|
    93
    96
        IgVH Homology, <97%, n=40, 43|
    13
    15
        IgVH Homology, 97%-98%, n=12, 10|
    5
    7
        IgVH Homology, >98%, n=115, 116|
    80
    78
        ZAP70 G 1, Negative, n=28, 32|
    14
    13
        ZAP70 G 1, Intermediate, n=54, 46|
    27
    23
        ZAP70, G1 Positive, n=94, 91|
    60
    65
    No statistical analyses for this end point

    Secondary: Changes in Patient Reported Outcome (PRO) measures and scores for European organization for research and treatment of cancer quality of life questionnaire, chronic lymphocytic leukaemia 16 item module (EORTC QLQ-CLL 16)

    Close Top of page
    End point title
    Changes in Patient Reported Outcome (PRO) measures and scores for European organization for research and treatment of cancer quality of life questionnaire, chronic lymphocytic leukaemia 16 item module (EORTC QLQ-CLL 16)
    End point description
    The EORTC QLQ-CLL16 is comprised of 16 questions that address 5 domains of health-related quality of life (HRQoL) important in CLL. There are 4 multi-item scales – fatigue (2 items), treatment side effects ([TSE], 4 items), disease symptoms (disease effects scale [DES], 4 items), and infection scale [IS] (4 items) – and single item scales (social activities [Social Problems (SP) Scale] and future health worries[Future Health (FH) Scale].). These are measured on a four point scale where 1 = not at all and 4 = very much. These scores are transformed to give a rating from 0 – 100, where 0 =no symptoms or problems and 100 = a severe symptoms or problems. EORTC QLQ-CLL16 was assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value was obtained at randomization.
    End point type
    Secondary
    End point timeframe
    Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: scores on a scale
    arithmetic mean (standard deviation)
        FH, 18 M, FU, n=90, 58|
    -15.9 ( 31.69 )
    -18.4 ( 33.72 )
        DES, Cycle 4 Day 1, n=142,125|
    -8.5 ( 18.08 )
    -9.0 ( 17.16 )
        DES, 1 M, FU, n=138, 123|
    -9.7 ( 19.18 )
    -9.8 ( 19.89 )
        DES, 3 M, FU, n=145, 109|
    -8.2 ( 19.48 )
    -10.9 ( 19.07 )
        DES, 6 M, FU, n= 126, 99|
    -9.8 ( 17.99 )
    -11.6 ( 18.05 )
        DES, 9 M, FU, n=115, 85|
    -8.2 ( 20.70 )
    -12.0 ( 17.04 )
        DES. 12 M, FU, n=109, 76|
    -10.1 ( 18.64 )
    -10.2 ( 16.09 )
        DES, 15 M, FU, n=98, 62|
    -8.6 ( 18.08 )
    -10.2 ( 16.91 )
        DES, 18 M, FU, n=90, 59|
    -8.5 ( 18.53 )
    -11.6 ( 18.79 )
        DES, 21 M, FU, n=87, 53|
    -8.2 ( 18.48 )
    -11.3 ( 17.60 )
        DES, 24 M, FU, n=70, 50|
    -7.1 ( 19.93 )
    -13.6 ( 16.18 )
        Fatigue Scale (FS), Cycle 4 Day 1, n=142, 125|
    -7.0 ( 22.57 )
    -7.1 ( 24.16 )
        FS, 1 M, FU, n=139, 123|
    -5.4 ( 29.16 )
    -6.2 ( 28.74 )
        FS, 3 M, FU, n=144, 109|
    -4.4 ( 26.30 )
    -8.3 ( 30.14 )
        FS, 6 M, FU, n=126, 99|
    -7.1 ( 25.94 )
    -12.0 ( 25.98 )
        FS, 9 M, FU, n= 115, 85|
    -6.2 ( 27.08 )
    -10.6 ( 26.95 )
        FS. 12 M, FU, n=109, 76|
    -7.3 ( 27.26 )
    -8.1 ( 25.75 )
        FS, 15 M, FU, n=97, 62|
    -7.6 ( 22.57 )
    -9.9 ( 24.04 )
        FS, 18 M, FU, n=90,59|
    -7.0 ( 23.03 )
    -3.7 ( 33.34 )
        FS, 21 M, FU, n=87, 53|
    -10.3 ( 24.28 )
    -8.2 ( 27.27 )
        FS, 24 M, FU, n=69, 50|
    -8.7 ( 24.19 )
    -8.7 ( 25.48 )
        FH, Cycle 4 Day 1, n=141, 123|
    -11.8 ( 32.89 )
    -10.6 ( 27.76 )
        FH, 1 M, FU, n=139, 120|
    -15.3 ( 35.04 )
    -11.9 ( 29.56 )
        FH, 3 M, FU, n=145, 107|
    -14.3 ( 33.96 )
    -14.0 ( 32.06 )
        FH, 6 M, FU, n=126, 96|
    -13.4 ( 33.98 )
    -17.7 ( 30.57 )
        FH, 9 M, FU, n=113, 81|
    -15.6 ( 33.65 )
    -13.2 ( 34.43 )
        FH. 12 M, FU, n=109, 74|
    -14.1 ( 32.80 )
    -14.9 ( 33.63 )
        FH, 15 M, FU, n=98, 61|
    -14.6 ( 29.14 )
    -14.2 ( 34.13 )
        FH, 21 M, FU, n=87, 52|
    -16.9 ( 28.70 )
    -15.4 ( 29.12 )
        FH, 24 M, FU, n=70, 49|
    -21.0 ( 29.58 )
    -17.7 ( 30.51 )
        IS, Cycle 4 Day 1, n=142,125|
    0.5 ( 17.65 )
    -1.4 ( 18.23 )
        IS, 1 M, FU, n=138, 122|
    2.9 ( 22.79 )
    2.7 ( 24.06 )
        IS, 3 M, FU, n=144, 109|
    0.8 ( 19.42 )
    0.8 ( 20.99 )
        IS, 6 M, FU, n=126, 99|
    -1.2 ( 18.46 )
    -0.9 ( 20.40 )
        IS, 9 M, FU, n=115, 85|
    -1.4 ( 18.81 )
    1.4 ( 22.45 )
        IS. 12 M, FU, n=109, 76|
    0.4 ( 19.22 )
    2.1 ( 20.92 )
        IS, 15 M, FU, n=97, 60|
    0.5 ( 17.56 )
    0.3 ( 18.79 )
        IS, 18 M, FU, n=89, 59|
    -2.0 ( 16.04 )
    0.9 ( 19.04 )
        IS, 21 M, FU, n=87, 53|
    -2.5 ( 18.13 )
    2.5 ( 22.09 )
        IS, 24 M, FU, n=69, 49|
    -0.5 ( 18.85 )
    0.5 ( 21.34 )
        SP Scale Cycle 4 Day 1, n=141, 125|
    1.9 ( 25.44 )
    0.3 ( 26.94 )
        SP Scale, 1 M, FU, n=137, 121|
    3.2 ( 34.51 )
    0.0 ( 35.22 )
        SP Scale, 3 M, FU, n=143, 109|
    -1.9 ( 33.04 )
    -4.3 ( 35.75 )
        SP Scale, 6 M, FU, n=124, 98|
    -5.6 ( 31.73 )
    -10.9 ( 30.56 )
        SP Scale, 9 M, FU, n=114, 85|
    -5.0 ( 30.15 )
    -11.0 ( 31.45 )
        SP Scale. 12 M, FU, n=107, 75|
    -7.2 ( 31.06 )
    -7.6 ( 34.47 )
        SP Scale, 15 M, FU, n=95, 61|
    -6.7 ( 30.21 )
    -13.7 ( 30.05 )
        SP Scale, 18 M, FU, n=89, 59|
    -7.1 ( 31.57 )
    -8.5 ( 40.40 )
        SP Scale, 21 M, FU, n=86, 53|
    -8.1 ( 31.07 )
    -7.5 ( 37.92 )
        SP Scale, 24 M, FU, n=68, 50|
    -11.8 ( 24.27 )
    -8.7 ( 36.15 )
        TSE, Cycle 4 Day 1, n=142, 125|
    -4.7 ( 16.15 )
    -4.0 ( 16.78 )
        TSE, 1 M, FU, n=139, 123|
    -5.0 ( 18.09 )
    -3.2 ( 19.08 )
        TSE, 3 M, FU, n=145,109|
    -3.7 ( 19.41 )
    -4.3 ( 17.03 )
        TSE, 6 M, FU, n=126, 99|
    -6.0 ( 15.25 )
    -4.8 ( 16.96 )
        TSE, 9 M, FU, n=115, 85|
    -4.3 ( 17.22 )
    -5.1 ( 16.38 )
        TSE. 12 M, FU, n=109, 76|
    -5.2 ( 16.44 )
    -3.2 ( 13.94 )
        TSE, 15 M, FU, n=98, 62|
    -4.0 ( 14.92 )
    -4.2 ( 13.73 )
        TSE, 18 M, FU, n=90, 60|
    -4.4 ( 17.10 )
    -3.6 ( 19.18 )
        TSE, 21 M, FU, n=87, 54|
    -4.7 ( 16.63 )
    -4.0 ( 15.91 )
        TSE, 24 M, FU, n=70, 50|
    -5.4 ( 17.52 )
    -6.5 ( 14.12 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Patient Reported Outcome (PRO) as assessed by EuroQoL Five-Dimension (EQ-5D) score at indicated visit

    Close Top of page
    End point title
    Change from Baseline in Patient Reported Outcome (PRO) as assessed by EuroQoL Five-Dimension (EQ-5D) score at indicated visit
    End point description
    EQ-5D is comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score. The utility score measures mobility, self-care, usual activities, pain, discomfort, and anxiety/depression. Responses to each of the 5 health states are measured on a 3-point scale (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = unable, or extreme problems). Responses are typically converted into health utilities or valuations on a scale ranging from 0 (death) to 1 (perfect health). The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A Negative health status describes health state worse than death.Baseline is the most recent, non-missing value prior to or on the first study drug dose date.
    End point type
    Secondary
    End point timeframe
    Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Score on a scale
    arithmetic mean (standard deviation)
        UT, Cycle 4 Day 1, n=136, 121|
    0.0 ( 0.27 )
    0.0 ( 0.21 )
        UT, 1 M, FU, n=133, 117|
    0.1 ( 0.22 )
    0.0 ( 0.28 )
        UT, 3 M, FU, n=141, 102|
    0.0 ( 0.27 )
    0.1 ( 0.23 )
        UT, 6 M, FU, n=122, 96|
    0.1 ( 0.24 )
    0.1 ( 0.24 )
        UT, 9 M, FU, n=110, 81|
    0.1 ( 0.26 )
    0.1 ( 0.24 )
        UT. 12 M, FU, n=107, 71|
    0.1 ( 0.21 )
    0.1 ( 0.22 )
        UT, 15 M, FU, n=96, 58|
    0.0 ( 0.23 )
    0.1 ( 0.24 )
        UT, 18 M, FU, n=88, 57|
    0.1 ( 0.21 )
    0.0 ( 0.34 )
        UT, 21 M, FU, n= 87, 52|
    0.1 ( 0.21 )
    0.1 ( 0.26 )
        UT, 24 M, FU, n=68, 47|
    0.1 ( 0.19 )
    0.1 ( 0.28 )
        VAS Cycle 4 Day 1, n=137, 122|
    6.1 ( 17.68 )
    5.6 ( 17.64 )
        VAS, 1 M, FU, n=138, 122|
    5.6 ( 20.73 )
    5.9 ( 22.83 )
        VAS, 3 M, FU, n=141, 107|
    5.7 ( 19.92 )
    9.6 ( 20.88 )
        VAS, 6 M, FU, n=124, 99|
    8.2 ( 18.84 )
    11.1 ( 19.08 )
        VAS, 9 M, FU, n=114, 85|
    8.1 ( 18.33 )
    11.9 ( 20.59 )
        VAS. 12 M, FU, n=108, 75|
    7.0 ( 21.93 )
    10.3 ( 21.21 )
        VAS, 15 M, FU, n=95, 62|
    8.0 ( 17.52 )
    13.1 ( 21.06 )
        VAS, 18 M, FU, n=89, 60|
    9.4 ( 17.86 )
    11.1 ( 25.40 )
        VAS, 21 M, FU, n=87, 53|
    8.1 ( 16.42 )
    11.3 ( 24.16 )
        VAS, 24 M, FU, n=69, 50|
    8.8 ( 19.50 )
    15.2 ( 21.88 )
    No statistical analyses for this end point

    Secondary: Change from baseline in the European organization for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30) score

    Close Top of page
    End point title
    Change from baseline in the European organization for the research and treatment of cancer quality of life questionnaire core 30 (EORTC QLQ-C30) score
    End point description
    EORTC QLQ-C30, a self-reported, cancer-specific instrument assessing 15 domains: physical, role, emotional, cognitive and social functioning, pain,fatigue, nausea and vomiting, insomnia, loss of appetite, constipation, diarrhea, and dyspnea, financial difficulties and a global health status/quality of life (QOF). Functional and symptoms scales were measured on four point Likert scale where 1 = not at all and 4 = very much. Pat. assessed at Screening; Cycle 4 Day 1 and during follow-up 1 M and every 3 M up to 24 months. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Clinically meaningful changes or minimally important differences (MIDs)have been previously established for the EORTC QLQ C30, and categorized as ‘small’ if the mean change in scores is 5-10 points, ‘moderate’ if 10-20 points, and ‘large’ if >20points.
    End point type
    Secondary
    End point timeframe
    Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Diarrhoea, 6 M, FU, n=124, 98|
    0.0 ( 20.38 )
    -3.1 ( 16.64 )
        Financial Difficulties, 6 M, FU, n=126, 98|
    -5.8 ( 24.61 )
    -8.8 ( 26.89 )
        Global Health Status, 6 M, FU, n=125, 97|
    7.5 ( 21.57 )
    13.7 ( 23.01 )
        Appetite Loss, Cycle 4 Day 1, n=140, 124|
    0.5 ( 25.60 )
    -1.9 ( 26.65 )
        Appetite Loss, 1 M, FU, n=136, 119|
    -0.2 ( 26.14 )
    -3.9 ( 28.52 )
        Appetite Loss, 3 M, FU, n=142, 108|
    -0.7 ( 26.77 )
    -7.4 ( 28.22 )
        Appetite Loss, 6 M, FU, n=123, 97|
    -6.0 ( 23.00 )
    -12.4 ( 26.05 )
        Appetite Loss, 9 M, FU, n=112, 83|
    -3.9 ( 20.38 )
    -9.6 ( 25.25 )
        Appetite Loss. 12 M, FU, n=107, 72|
    -4.0 ( 22.76 )
    -6.0 ( 27.59 )
        Appetite Loss, 15 M, FU, n=96, 60|
    -3.8 ( 23.13 )
    -9.4 ( 28.19 )
        Appetite Loss, 18 M, FU, n=89, 60|
    -7.9 ( 20.11 )
    -9.4 ( 30.12 )
        Appetite Loss, 21 M, FU, n=87, 52|
    -3.4 ( 20.36 )
    -7.7 ( 27.70 )
        Appetite Loss, 24 M, FU, n=69, 48|
    -3.9 ( 22.53 )
    -12.5 ( 29.68 )
        Cognitive Functioning, Cycle 4 Day 1, n=142, 126|
    3.4 ( 18.25 )
    2.5 ( 18.39 )
        Cognitive Functioning, 1 M, FU, n=139, 122|
    -0.4 ( 18.40 )
    3.0 ( 19.87 )
        Cognitive Functioning, 3 M, FU, n= 145, 109|
    0.0 ( 18.74 )
    2.3 ( 21.69 )
        Cognitive Functioning, 6 M, FU, n=126, 99|
    1.7 ( 18.95 )
    2.7 ( 20.99 )
        Cognitive Functioning, 9 M, FU, n=115, 85|
    -0.6 ( 20.58 )
    2.4 ( 19.61 )
        Cognitive Functioning. 12 M, FU, n=110, 76|
    -2.1 ( 19.17 )
    -1.8 ( 21.36 )
        Cognitive Functioning, 15 M, FU, n=97, 62|
    -1.0 ( 17.97 )
    0.3 ( 20.58 )
        Cognitive Functioning, 18 M, FU, n=89, 61|
    -0.9 ( 20.00 )
    -0.3 ( 22.67 )
        Cognitive Functioning, 21 M, FU, n=88, 53|
    -1.9 ( 21.65 )
    -1.9 ( 21.84 )
        Cognitive Functioning, 24 M, FU, n=70, 50|
    1.0 ( 20.83 )
    -1.3 ( 21.25 )
        Constipation, Cycle 4 Day 1, n=142, 126|
    2.1 ( 21.46 )
    0.8 ( 18.60 )
        Constipation, 1 M, FU, n=139, 122|
    -0.7 ( 19.02 )
    0.3 ( 18.92 )
        Constipation, 3 M, FU, n= 145, 109|
    -2.1 ( 19.33 )
    -0.9 ( 20.01 )
        Constipation, 6 M, FU, n=125, 98|
    -3.5 ( 19.32 )
    0.3 ( 18.22 )
        Constipation, 9 M, FU, n=115, 85|
    -1.2 ( 19.71 )
    0.4 ( 18.18 )
        Constipation. 12 M, FU, n=109, 76|
    -0.0 ( 23.13 )
    0.4 ( 19.24 )
        Constipation, 15 M, FU, n=96, 62|
    -1.7 ( 21.29 )
    -3.8 ( 20.11 )
        Constipation, 18 M, FU, n=90, 61|
    -0.4 ( 21.49 )
    -1.1 ( 24.32 )
        Constipation, 21 M, FU, n=87, 53|
    -1.9 ( 22.93 )
    -3.8 ( 23.26 )
        Constipation, 24 M, FU, n=70, 50|
    0.0 ( 21.23 )
    -3.3 ( 21.56 )
        Diarrhoea, Cycle 4 Day 1,n= 141, 125|
    0.2 ( 19.72 )
    -2.4 ( 17.54 )
        Diarrhoea, 1 M, FU, n=135, 121|
    -3.5 ( 20.87 )
    0.8 ( 21.28 )
        Diarrhoea, 3 M, FU, n=143, 109|
    1.6 ( 22.49 )
    1.5 ( 20.98 )
        Diarrhoea, 9 M, FU, n=114, 85|
    0.3 ( 20.56 )
    -2.7 ( 17.97 )
        Diarrhoea. 12 M, FU, n=108, 76|
    -3.4 ( 15.75 )
    -2.2 ( 19.12 )
        Diarrhoea, 15 M, FU, n=96, 61|
    -1.7 ( 19.57 )
    -4.4 ( 20.62 )
        Diarrhoea, 18 M, FU, n=89, 61|
    -1.9 ( 17.67 )
    -1.1 ( 17.18 )
        Diarrhoea, 21 M, FU, n=87, 53|
    -2.3 ( 18.88 )
    0.6 ( 21.17 )
        Diarrhoea, 24 M, FU, n=68, 50|
    -2.9 ( 17.02 )
    -0.7 ( 20.75 )
        Dyspnoea Cycle 4 Day 1,n= 138, 124|
    -4.6 ( 22.85 )
    -4.6 ( 23.41 )
        Dyspnoea, 1 M, FU, n=139, 121|
    -1.0 ( 26.60 )
    -2.8 ( 25.67 )
        Dyspnoea, 3 M, FU, n=141, 108|
    -3.1 ( 26.40 )
    -1.5 ( 25.53 )
        Dyspnoea, 6 M, FU, n=124, 97|
    -2.7 ( 21.92 )
    -7.2 ( 24.17 )
        Dyspnoea, 9 M, FU, n=113, 83|
    -2.7 ( 26.03 )
    -6.4 ( 23.55 )
        Dyspnoea. 12 M, FU, n=108, 73|
    -3.4 ( 24.52 )
    -4.1 ( 22.87 )
        Dyspnoea, 15 M, FU, n=95, 60|
    -2.5 ( 20.77 )
    -2.2 ( 26.66 )
        Dyspnoea, 18 M, FU, n=90, 59|
    -3.0 ( 24.81 )
    -2.8 ( 29.22 )
        Dyspnoea, 21 M, FU, n=87, 52|
    -3.4 ( 24.92 )
    -1.9 ( 21.30 )
        Dyspnoea, 24 M, FU, n=69, 49|
    -2.4 ( 26.39 )
    -4.8 ( 24.53 )
        Emotional Functioning Cycle 4 Day 1, n=142, 125|
    4.4 ( 17.91 )
    5.4 ( 19.59 )
        Emotional Functioning, 1 M, FU, n=139, 122|
    5.4 ( 20.26 )
    7.2 ( 24.08 )
        Emotional Functioning, 3 M, FU, n=145, 109|
    5.7 ( 20.93 )
    7.8 ( 20.90 )
        Emotional Functioning, 6 M, FU, n=126, 99|
    4.8 ( 22.57 )
    8.9 ( 22.34 )
        Emotional Functioning, 9 M, FU, n=115, 85|
    3.4 ( 22.95 )
    6.7 ( 18.52 )
        Emotional Functioning. 12 M, FU, n=110, 76|
    3.9 ( 22.11 )
    8.0 ( 21.92 )
        Emotional Functioning, 15 M, FU, n=98, 62|
    5.1 ( 21.54 )
    6.5 ( 21.15 )
        Emotional Functioning, 18 M, FU, n=90, 61|
    5.1 ( 22.94 )
    6.5 ( 26.35 )
        Emotional Functioning, 21 M, FU, n=88, 52|
    5.3 ( 22.43 )
    7.7 ( 23.56 )
        Emotional Functioning, 24 M, FU, n=70, 50|
    7.1 ( 23.02 )
    7.1 ( 26.16 )
        Fatigue Cycle 4 Day 1, n=142, 126|
    -4.3 ( 21.37 )
    -6.3 ( 22.66 )
        Fatigue, 1 M, FU, n=138, 122|
    -7.4 ( 25.16 )
    -4.5 ( 28.64 )
        Fatigue, 3 M, FU, n=145, 109|
    -5.4 ( 24.01 )
    -9.3 ( 27.83 )
        Fatigue, 6 M, FU, n=126, 99|
    -8.2 ( 23.64 )
    -12.2 ( 22.43 )
        Fatigue, 9 M, FU, n=115, 86|
    -8.8 ( 23.80 )
    -9.8 ( 24.56 )
        Fatigue. 12 M, FU, n=110, 76|
    -6.8 ( 25.28 )
    -10.3 ( 23.44 )
        Fatigue, 15 M, FU, n=97, 76|
    -7.6 ( 19.83 )
    -8.9 ( 27.61 )
        Fatigue, 18 M, FU, n=90, 62|
    -7.0 ( 22.25 )
    -6.1 ( 30.15 )
        Fatigue, 21 M, FU, n=88, 53|
    -9.6 ( 20.44 )
    -9.1 ( 25.34 )
        Fatigue, 24 M, FU, n=70, 50|
    -9.1 ( 23.01 )
    -11.7 ( 25.30 )
        Financial Difficulties Cycle 4 Day 1, n=141, 126|
    -4.5 ( 23.98 )
    -6.1 ( 29.93 )
        Financial Difficulties, 1 M, FU, n=136, 122|
    -5.9 ( 26.57 )
    -5.2 ( 26.07 )
        Financial Difficulties, 3 M, FU, n=145, 108|
    -4.1 ( 28.30 )
    -9.0 ( 29.40 )
        Financial Difficulties, 9 M, FU, n=114, 84|
    -6.1 ( 27.54 )
    -8.7 ( 27.44 )
        Financial Difficulties. 12 M, FU, n=110, 76|
    -6.4 ( 24.93 )
    -9.6 ( 28.71 )
        Financial Difficulties, 15 M, FU, n=96, 62|
    -8.3 ( 23.69 )
    -9.7 ( 27.91 )
        Financial Difficulties, 18 M, FU, n=90, 60|
    -4.1 ( 24.39 )
    -12.2 ( 30.04 )
        Financial Difficulties, 21 M, FU, n=88, 51|
    -10.6 ( 22.34 )
    -11.1 ( 28.02 )
        Financial Difficulties, 24 M, FU, n=70, 50|
    -6.2 ( 24.93 )
    -12.0 ( 27.57 )
        Nausea and Vomiting Cycle 4 Day 1, n=142, 126|
    2.0 ( 16.06 )
    3.7 ( 18.37 )
        Nausea and Vomiting, 1 M, FU, n=139, 122|
    1.0 ( 14.85 )
    0.1 ( 19.22 )
        Nausea and Vomiting, 3 M, FU, n=145, 109|
    0.1 ( 15.90 )
    -2.9 ( 14.49 )
        Nausea and Vomiting, 6 M, FU, n=126, 99|
    -2.8 ( 13.12 )
    -2.5 ( 14.36 )
        Nausea and Vomiting, 9 M, FU, n=115, 86|
    -1.3 ( 13.81 )
    -1.2 ( 15.08 )
        Nausea and Vomiting. 12 M, FU, n=110, 76|
    -2.9 ( 13.52 )
    -1.8 ( 12.35 )
        Nausea and Vomiting, 15 M, FU, n=97, 62|
    -3.3 ( 11.45 )
    -2.7 ( 11.76 )
        Nausea and Vomiting, 18 M, FU, n=90, 61|
    -3.3 ( 12.03 )
    -2.5 ( 10.02 )
        Nausea and Vomiting, 21 M, FU, n=88, 53|
    -4.0 ( 13.37 )
    1.3 ( 11.72 )
        Nausea and Vomiting, 24 M, FU, n=70, 50|
    -2.4 ( 13.69 )
    -0.3 ( 11.90 )
        Pain Cycle 4 Day 1, n=142, 126|
    -3.6 ( 20.64 )
    -4.2 ( 20.43 )
        Pain, 1 M, FU, n=139, 122|
    -2.8 ( 23.02 )
    -5.5 ( 22.31 )
        Pain, 3 M, FU, n=145, 109|
    -3.8 ( 25.13 )
    -2.1 ( 24.44 )
        Pain, 6 M, FU, n=126, 99|
    -5.3 ( 23.54 )
    -6.6 ( 20.59 )
        Pain, 9 M, FU, n=115, 86|
    -4.2 ( 23.86 )
    -4.8 ( 22.12 )
        Pain. 12 M, FU, n=110, 76|
    -3.5 ( 24.43 )
    -3.7 ( 21.01 )
        Pain, 15 M, FU, n=98, 62|
    -2.9 ( 23.08 )
    -3.5 ( 22.00 )
        Pain, 18 M, FU, n=90, 61|
    -3.3 ( 19.39 )
    0.5 ( 28.05 )
        Pain, 21 M, FU, n=88, 53|
    -5.9 ( 19.74 )
    -0.9 ( 25.82 )
        Pain, 24 M, FU, n=70, 50|
    -1.7 ( 23.25 )
    -3.0 ( 24.67 )
        Physical Functioning Cycle 4 Day 1, n=141, 124|
    1.2 ( 14.50 )
    0.6 ( 16.81 )
        Physical Functioning, 1 M, FU, n=139, 122|
    0.4 ( 19.52 )
    -0.7 ( 21.15 )
        Physical Functioning, 3 M, FU, n=142, 108|
    0.9 ( 18.66 )
    0.9 ( 19.68 )
        Physical Functioning, 6 M, FU, n=124, 98|
    3.2 ( 16.41 )
    5.7 ( 17.01 )
        Physical Functioning, 9 M, FU, n=113, 83|
    3.9 ( 17.30 )
    6.2 ( 17.25 )
        Physical Functioning. 12 M, FU, n=109, 73|
    2.4 ( 17.98 )
    3.5 ( 17.52 )
        Physical Functioning, 15 M, FU, n=96, 60|
    3.8 ( 14.65 )
    2.7 ( 18.46 )
        Physical Functioning, 18 M, FU, n=90, 60|
    4.1 ( 16.65 )
    0.1 ( 22.09 )
        Physical Functioning, 21 M, FU, n=88, 52|
    4.7 ( 17.14 )
    2.1 ( 18.88 )
        Physical Functioning, 24 M, FU, n=69, 49|
    5.3 ( 17.44 )
    3.7 ( 20.57 )
        Global Health Status Cycle 4 Day 1, n=140, 122|
    6.4 ( 23.46 )
    6.8 ( 17.54 )
        Global Health Status, 1 M, FU, n=136, 119|
    6.5 ( 24.23 )
    6.9 ( 26.32 )
        Global Health Status, 3 M, FU, n=142, 105|
    5.0 ( 21.45 )
    12.3 ( 21.15 )
        Global Health Status, 9 M, FU, n=112, 83|
    7.6 ( 23.24 )
    11.7 ( 22.35 )
        Global Health Status. 12 M, FU, n=110, 74|
    7.6 ( 23.64 )
    12.2 ( 21.77 )
        Global Health Status, 15 M, FU, n=93, 61|
    7.6 ( 20.40 )
    12.7 ( 22.29 )
        Global Health Status, 18 M, FU, n= 89, 60|
    9.2 ( 23.03 )
    10.4 ( 27.00 )
        Global Health Status, 21 M, FU, n=87, 53|
    10.8 ( 20.26 )
    12.7 ( 21.53 )
        Global Health Status, 24 M, FU, n=68, 48|
    12.1 ( 24.28 )
    12.3 ( 24.31 )
        Role Functioning Cycle 4 Day 1,n=140, 124|
    1.4 ( 23.27 )
    0.1 ( 24.83 )
        Role Functioning, 1 M, FU, n= 138, 120|
    -0.1 ( 25.83 )
    -0.7 ( 27.53 )
        Role Functioning, 3 M, FU, n=141, 107|
    0.5 ( 25.19 )
    0.9 ( 28.94 )
        Role Functioning, 6 M, FU, n=124, 97|
    4.3 ( 25.49 )
    5.5 ( 26.54 )
        Role Functioning, 9 M, FU, n=113, 83|
    4.1 ( 26.21 )
    6.2 ( 25.60 )
        Role Functioning. 12 M, FU, n=109, 72|
    2.1 ( 26.46 )
    3.9 ( 24.78 )
        Role Functioning, 15 M, FU, n=96, 60|
    3.8 ( 24.84 )
    1.9 ( 25.13 )
        Role Functioning, 18 M, FU, n=90, 60|
    7.0 ( 24.09 )
    -0.0 ( 28.95 )
        Role Functioning, 21 M, FU, n=88, 51|
    5.3 ( 22.82 )
    2.6 ( 26.74 )
        Role Functioning, 24 M, FU, n=69, 49|
    5.8 ( 25.54 )
    3.7 ( 30.10 )
        Social Functioning Cycle 4 Day 1, n=142, 126|
    3.1 ( 20.30 )
    -0.9 ( 23.50 )
        Social Functioning, 1 M, FU, n=138, 122|
    0.4 ( 25.98 )
    0.8 ( 27.93 )
        Social Functioning, 3 M, FU, n=145, 109|
    0.8 ( 23.76 )
    4.3 ( 26.29 )
        Social Functioning, 6 M, FU, n= 126, 99|
    3.4 ( 22.04 )
    6.1 ( 26.24 )
        Social Functioning, 9 M, FU, n=115, 84|
    2.3 ( 21.84 )
    4.2 ( 25.46 )
        Social Functioning. 12 M, FU, n= 110, 76|
    3.0 ( 23.04 )
    3.3 ( 21.95 )
        Social Functioning, 15 M, FU, n=96, 62|
    6.2 ( 18.30 )
    1.6 ( 27.61 )
        Social Functioning, 18 M, FU, n=90, 61|
    6.5 ( 19.78 )
    2.7 ( 29.69 )
        Social Functioning, 21 M, FU, n=88, 52|
    6.6 ( 18.83 )
    4.5 ( 24.72 )
        Social Functioning, 24 M, FU, n=70, 50|
    7.9 ( 19.60 )
    7.7 ( 24.56 )
        Insomnia Cycle 4 Day 1, n=138, 123|
    -3.1 ( 26.07 )
    -8.7 ( 26.94 )
        Insomnia, 1 M, FU, n=135, 120|
    -5.9 ( 29.04 )
    -11.1 ( 27.78 )
        Insomnia, 3 M, FU, n=139, 108|
    -6.2 ( 29.64 )
    -13.3 ( 28.07 )
        Insomnia, 6 M, FU, n=121, 98|
    -5.2 ( 26.18 )
    -17.0 ( 25.88 )
        Insomnia, 9 M, FU, n=112, 81|
    -3.0 ( 30.53 )
    -13.2 ( 31.04 )
        Insomnia. 12 M, FU, n=106, 73|
    -6.9 ( 25.91 )
    -10.5 ( 29.33 )
        Insomnia, 15 M, FU, n=96, 59|
    -5.9 ( 29.02 )
    -17.5 ( 26.52 )
        Insomnia, 18 M, FU, n=89, 59|
    -7.5 ( 28.32 )
    -15.3 ( 28.58 )
        Insomnia, 21 M, FU, n=86, 52|
    -8.5 ( 25.15 )
    -10.3 ( 34.64 )
        Insomnia, 24 M, FU, n=68, 49|
    -1.5 ( 33.30 )
    -13.6 ( 35.95 )
    No statistical analyses for this end point

    Secondary: Mean of Health Change Questionnaire (HCQ)

    Close Top of page
    End point title
    Mean of Health Change Questionnaire (HCQ)
    End point description
    The HCQ consists of a single question in which the participant is asked if he/she has experienced any change in his/her health overall since beginning the study. For HCQ, values from 1 to 9 were assigned to the 9 responses in the HCQ questionnaire, ranging from 1 for ‘my health is a great deal better’ to 9 for ‘my health is a great deal worse’ since the beginning of the study. Lower scores represent better conditions.
    End point type
    Secondary
    End point timeframe
    Screening, Cycle 3 Day 1, and 1 M and every 3 month post last dose up to 24 month.
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    182
    Units: Unit on a scale
    arithmetic mean (standard deviation)
        Cycle 4 Day 1, n=139, 124|
    2.6 ( 1.62 )
    2.8 ( 1.59 )
        1 M, FU, n=138, 121|
    3.0 ( 2.05 )
    3.2 ( 2.30 )
        3 M, FU, n=141, 108|
    3.0 ( 2.11 )
    2.8 ( 1.86 )
        6 M, FU, n=124, 98|
    2.6 ( 1.76 )
    2.6 ( 1.82 )
        9 M, FU, n=112, 85|
    2.5 ( 1.78 )
    2.4 ( 1.57 )
        12 M, FU, n=108, 74|
    2.5 ( 1.80 )
    2.5 ( 1.78 )
        15 M, FU, n=96, 61|
    2.2 ( 1.57 )
    2.3 ( 1.68 )
        18 M, FU, n=88, 58|
    2.4 ( 1.67 )
    2.7 ( 2.01 )
        21 M, FU, n= 87, 52|
    2.3 ( 1.50 )
    2.3 ( 1.52 )
        24 M, FU, n=69, 49|
    2.3 ( 1.76 )
    2.6 ( 1.89 )
    No statistical analyses for this end point

    Secondary: Mean area under the time-concentration curve (AUC) curve over the dosing interval (AUC[0-tau]) of ofatumumab

    Close Top of page
    End point title
    Mean area under the time-concentration curve (AUC) curve over the dosing interval (AUC[0-tau]) of ofatumumab [3]
    End point description
    Area under the time-concentration curve (AUC) over the dosing interval (AUC[0-tau]) was evaluated. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).
    End point type
    Secondary
    End point timeframe
    Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5,6
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: descriptive statistics
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    Units: hour*nanogram/mililiter (h*ng/mL)
    geometric mean (confidence interval 95%)
        cycle 1, week 1, n=158|
    3554.910 (3224.844 to 3918.759)
        cycle 1, week 2, n=129|
    34109.67 (30042.08 to 38728.00)
        cycle 2, n=147|
    67069.79 (59485.45 to 75621.13)
        cycle 3, n=129|
    84620.05 (76209.86 to 93958.35)
        cycle 4, 107|
    89091.35 (78326.34 to 101335.9)
        cycle 5, n=97|
    96829.23 (84488.81 to 110972.1)
        cycle 6, n=91|
    104798.0 (90904.74 to 120814.6)
    No statistical analyses for this end point

    Secondary: Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) of Ofatumumab

    Close Top of page
    End point title
    Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) of Ofatumumab [4]
    End point description
    Blood samples were collected to assess the plasma concentration of ofatumumab.Cmax and Ctrough were determined. Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, predose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, and 6 (Days 29, 57, 113, and 141).
    End point type
    Secondary
    End point timeframe
    Cycle 1 Week 1, Cycle 1 Week 2, Cycles 2,3,4,5
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: descriptive statistics
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    Units: Micrograms per milliliter
    geometric mean (confidence interval 95%)
        Cmax cycle 1, week 1, n=154|
    61.355 (55.444 to 67.897)
        Cmax cycle 1, week 2, n=159|
    241.192 (210.492 to 276.369)
        Cmax cycle 4, n=140|
    312.745 (287.708 to 339.961)
        Ctrough cycle 1, week 1, n=167|
    3.551 (2.417 to 5.217)
        Ctrough cycle 1, week 2, n=165|
    9.496 (6.565 to 13.736)
        Ctrough cycle 2, n=162|
    24.281 (17.953 to 32.840)
        Ctrough cycle 3,n=150|
    25.632 (18.884 to 34.791)
        Ctrough cycle 4,n=130|
    58.640 (44.465 to 77.333)
        Ctrough cycle 5, n=113|
    70.398 (55.257 to 89.686)
    No statistical analyses for this end point

    Secondary: Time of occurrence of Cmax (Tmax) of ofatumumab

    Close Top of page
    End point title
    Time of occurrence of Cmax (Tmax) of ofatumumab [5]
    End point description
    Blood samples were collected from participants who received ofatumumab plus fludarabine and cyclophosphamide predose and 0.5 h after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Week 1, Cycle 1 Week 2, Cycle 4
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: descriptive statistics
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    183
    Units: Hour
    geometric mean (confidence interval 95%)
        cycle 1, week 1,n=154|
    6.106 (5.789 to 6.442)
        cycle 1, week 2, n=159|
    5.004 (4.896 to 5.114)
        cycle 4, n=140|
    4.878 (4.661 to 5.105)
    No statistical analyses for this end point

    Secondary: Number of participants with drug related infections reported as AEs and SAEs of maximum severity of Grade 3 or Higher

    Close Top of page
    End point title
    Number of participants with drug related infections reported as AEs and SAEs of maximum severity of Grade 3 or Higher
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Maximum severity grades were evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).
    End point type
    Secondary
    End point timeframe
    From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    181
    178
    Units: Participants
        AE|
    19
    11
        SAE|
    25
    21
    No statistical analyses for this end point

    Secondary: Number of participants with at least one Grade 3/Grade 4 myelosuppression adverse events

    Close Top of page
    End point title
    Number of participants with at least one Grade 3/Grade 4 myelosuppression adverse events
    End point description
    Participants with at least one Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented. Myelosuppression is defined as the decrease in the ability of the bone marrow to produce blood cells. AEs were graded according to NCI common terminology criteria for adverse events (CTCAE) grade, version 3.0 (1, mild; 2, moderate; 3, severe; 4, life-threatening/disabling; 5, death).
    End point type
    Secondary
    End point timeframe
    From first dose of study medication to 60 days after the last dose of study medication (for an AE), or up to 5 years after the last dose of study drug or until the time of the next anti-CLL therapy (for SAE)
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    181
    178
    Units: Participants
    126
    118
    No statistical analyses for this end point

    Secondary: Number of participants who received no transfusion or at Least one transfusion during the study

    Close Top of page
    End point title
    Number of participants who received no transfusion or at Least one transfusion during the study
    End point description
    Participants who received no transfusion and at least one transfusion during the study are presented. Participants who took any blood products or blood supportive care product are included.
    End point type
    Secondary
    End point timeframe
    From randomization up to 5 years after last dose of study drug
    End point values
    Ofatumumab + Fludarabine + Cyclophosphamide_ ITT subjects Fludarabine + Cyclophosphamide_ ITT subjects
    Number of subjects analysed
    181
    178
    Units: Participants
        At least one transfusion|
    125
    99
        No transfusions|
    56
    79
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 8.5 years.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Ofatumumab + Fludarabine + Cyclophosphamide
    Reporting group description
    Ofatumumab + Fludarabine + Cyclophosphamide

    Reporting group title
    Fludarabine + Cyclophosphamide
    Reporting group description
    Fludarabine + Cyclophosphamide

    Serious adverse events
    Ofatumumab + Fludarabine + Cyclophosphamide Fludarabine + Cyclophosphamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    108 / 181 (59.67%)
    86 / 178 (48.31%)
         number of deaths (all causes)
    40
    42
         number of deaths resulting from adverse events
    11
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    3 / 181 (1.66%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    2 / 2
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder papilloma
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopharyngeal cancer
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Melanoma recurrent
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic vasculitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombophlebitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 181 (4.97%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    4 / 9
    3 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    3 / 181 (1.66%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         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
    Respiratory failure
         subjects affected / exposed
    3 / 181 (1.66%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    1 / 1
    Dyspnoea
         subjects affected / exposed
    3 / 181 (1.66%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (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
    Hip fracture
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Epidermolysis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 181 (1.10%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 181 (1.10%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 181 (0.00%)
    4 / 178 (2.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Angina pectoris
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Extrasystoles
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid arteriosclerosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Demyelinating polyneuropathy
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (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
    Febrile neutropenia
         subjects affected / exposed
    18 / 181 (9.94%)
    15 / 178 (8.43%)
         occurrences causally related to treatment / all
    15 / 24
    12 / 24
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Neutropenia
         subjects affected / exposed
    17 / 181 (9.39%)
    14 / 178 (7.87%)
         occurrences causally related to treatment / all
    17 / 21
    15 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Anaemia
         subjects affected / exposed
    11 / 181 (6.08%)
    12 / 178 (6.74%)
         occurrences causally related to treatment / all
    2 / 12
    12 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombocytopenia
         subjects affected / exposed
    7 / 181 (3.87%)
    10 / 178 (5.62%)
         occurrences causally related to treatment / all
    3 / 7
    7 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancytopenia
         subjects affected / exposed
    5 / 181 (2.76%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    4 / 5
    3 / 6
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    2 / 181 (1.10%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 181 (1.10%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplasia pure red cell
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 181 (1.66%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    2 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 181 (1.66%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatitis
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (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
    Renal failure
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    5 / 181 (2.76%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (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
    Pneumonia
         subjects affected / exposed
    28 / 181 (15.47%)
    29 / 178 (16.29%)
         occurrences causally related to treatment / all
    14 / 34
    9 / 32
         deaths causally related to treatment / all
    1 / 4
    3 / 11
    Urinary tract infection
         subjects affected / exposed
    6 / 181 (3.31%)
    6 / 178 (3.37%)
         occurrences causally related to treatment / all
    1 / 11
    3 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 181 (2.21%)
    8 / 178 (4.49%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 8
         deaths causally related to treatment / all
    1 / 4
    0 / 4
    Neutropenic sepsis
         subjects affected / exposed
    4 / 181 (2.21%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    3 / 5
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 181 (2.21%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    6 / 181 (3.31%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 181 (1.66%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 181 (0.55%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cellulitis
         subjects affected / exposed
    2 / 181 (1.10%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 181 (0.55%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 181 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acinetobacter bacteraemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anal abscess
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical mycobacterial infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atypical pneumonia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal candidiasis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella sepsis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic mycosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B reactivation
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Starvation
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (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
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Ofatumumab + Fludarabine + Cyclophosphamide Fludarabine + Cyclophosphamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    149 / 181 (82.32%)
    123 / 178 (69.10%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    12 / 181 (6.63%)
    5 / 178 (2.81%)
         occurrences all number
    14
    9
    Vascular disorders
    Hypotension
         subjects affected / exposed
    11 / 181 (6.08%)
    4 / 178 (2.25%)
         occurrences all number
    12
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 181 (8.29%)
    6 / 178 (3.37%)
         occurrences all number
    18
    7
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    38 / 181 (20.99%)
    55 / 178 (30.90%)
         occurrences all number
    50
    69
    Neutropenia
         subjects affected / exposed
    93 / 181 (51.38%)
    62 / 178 (34.83%)
         occurrences all number
    192
    126
    Leukopenia
         subjects affected / exposed
    27 / 181 (14.92%)
    10 / 178 (5.62%)
         occurrences all number
    38
    29
    Anaemia
         subjects affected / exposed
    24 / 181 (13.26%)
    38 / 178 (21.35%)
         occurrences all number
    40
    51
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    26 / 181 (14.36%)
    15 / 178 (8.43%)
         occurrences all number
    40
    18
    Asthenia
         subjects affected / exposed
    13 / 181 (7.18%)
    16 / 178 (8.99%)
         occurrences all number
    15
    16
    Fatigue
         subjects affected / exposed
    15 / 181 (8.29%)
    11 / 178 (6.18%)
         occurrences all number
    19
    12
    Chills
         subjects affected / exposed
    14 / 181 (7.73%)
    3 / 178 (1.69%)
         occurrences all number
    19
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    45 / 181 (24.86%)
    36 / 178 (20.22%)
         occurrences all number
    75
    73
    Vomiting
         subjects affected / exposed
    19 / 181 (10.50%)
    22 / 178 (12.36%)
         occurrences all number
    23
    28
    Diarrhoea
         subjects affected / exposed
    14 / 181 (7.73%)
    19 / 178 (10.67%)
         occurrences all number
    17
    22
    Constipation
         subjects affected / exposed
    8 / 181 (4.42%)
    11 / 178 (6.18%)
         occurrences all number
    8
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 181 (8.29%)
    10 / 178 (5.62%)
         occurrences all number
    20
    12
    Dyspnoea
         subjects affected / exposed
    15 / 181 (8.29%)
    3 / 178 (1.69%)
         occurrences all number
    22
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    23 / 181 (12.71%)
    8 / 178 (4.49%)
         occurrences all number
    30
    11
    Pruritus
         subjects affected / exposed
    19 / 181 (10.50%)
    2 / 178 (1.12%)
         occurrences all number
    23
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 181 (7.18%)
    8 / 178 (4.49%)
         occurrences all number
    15
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 181 (7.18%)
    8 / 178 (4.49%)
         occurrences all number
    14
    8

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Apr 2014
    Study Name and Logo added. Name of Physician Study Leader updated. Investigator Agreement Page updated. SAEs no longer reported after commencement of subsequent anti-CLL therapy. Prohibited concomitant medication, Glucocorticoid dosing amended. Requirement to collect anticancer and anti-infectious concomitant medications after 1 month follow-up amended to collect only if associated with an SAE and only until subsequent anti-CLL therapy is initiated. Details regarding reporting of study results to investigators, to a publically available register, and for publication updated. Investigator responsibilities with regard to Quality Compliance and Quality Assurance updated. Minor clarifications and typographical errors addressed.
    30 Sep 2014
    Clinical Investigational Leader and associated contact information updated. Introduction updated with current published data. Statistical assumptions for event rate projection updated.
    20 Feb 2015
    Name of Physician Project Lead and Sponsor Signatory updated. The requirement to report SAEs after commencement of subsequent anti-CLL therapy has been reinstated in India only, to comply with changed country-specific requirements.
    08 Mar 2016
    Delete or replace references to GSK or its staff with that of Novartis/Novartis and its authorized agents. Make administrative changes to align with Novartis processes and procedures.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    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-Sun May 04 14:30:42 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA