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    Clinical Trial Results:
    A phase III, open label, randomized, multicenter trial of Ofatumumab added to Chlorambucil vs. Chlorambucil Monotherapy in previously untreated patients with 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
    2008-004932-19
    Trial protocol
    NL   IE   DE   ES   SE   BE   CZ   FR   IT   GR   GB  
    Global end of trial date
    17 May 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    31 May 2019
    First version publication date
    13 Nov 2014
    Other versions
    v1 (removed from public view)
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    COMB157B2301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00748189
    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, Novartis.email@novartis.com
    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
    17 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate PFS of ofatumumab added to chlorambucil for previously untreated (front-line) CLL compared to chlorambucil monotherapy.
    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
    22 Dec 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    United Kingdom: 58
    Country: Number of subjects enrolled
    United States: 38
    Country: Number of subjects enrolled
    Belgium: 60
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Greece: 21
    Country: Number of subjects enrolled
    India: 42
    Country: Number of subjects enrolled
    Ireland: 15
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 41
    Country: Number of subjects enrolled
    Russian Federation: 28
    Worldwide total number of subjects
    447
    EEA total number of subjects
    329
    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)
    139
    From 65 to 84 years
    301
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Eligible participants (par.) were stratified by age (<65 years vs. >=65years), stage (Binet A vs. B vs. C) and Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2). Participants in each stratum were then centrally randomized in a 1:1 ratio to receive ofatumumab plus chlorambucil (O+CHL) or chlorambucil alone (CHL).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Chlorambucil
    Arm description
    Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
    Arm type
    Active comparator

    Investigational medicinal product name
    Chlorambucil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Chlorambucil was administered as 2-mg tablets. The treatment dose was 10 mg/m² given on Days 1-7 every 28 days. For patients suffering from nausea or vomiting, dose splitting to 2 or 3 daily administrations was permitted. Dose delays or reductions were allowed in the event of toxicity

    Arm title
    Ofatumumab + Chlorambucil
    Arm description
    Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    OMB157
    Other name
    Pharmaceutical forms
    Cutaneous liquid, Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ofatumumab (GSK1841157) was provided as clear, colorless, liquid 100-mg/mL concentrate in 5-mL glass vials. The ofatumumab infusions were prepared in 1000 mL sterile, to yield a 0.3 mg/mL ofatumumab concentration for the first 300-mg infusion and to yield a 1 mg/mL concentration for subsequent 1000-mg infusions. Ofatumumab was infused IV on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by infusions of 1000 mg on the first day of each subsequent 28-day cycle.

    Investigational medicinal product name
    Chlorambucil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    hlorambucil was administered as 2-mg tablets. The treatment dose was 10 mg/m² given on Days 1-7 every 28 days. For patients suffering from nausea or vomiting, dose splitting to 2 or 3 daily administrations was permitted. Dose delays or reductions were allowed in the event of toxicity

    Number of subjects in period 1
    Chlorambucil Ofatumumab + Chlorambucil
    Started
    226
    221
    Completed
    10
    9
    Not completed
    216
    212
         Physician decision
    16
    5
         Adverse event, serious fatal
    99
    84
         Study terminated by Sponsor
    70
    79
         Consent withdrawn by subject
    23
    29
         Lost to follow-up
    8
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chlorambucil
    Reporting group description
    Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Reporting group title
    Ofatumumab + Chlorambucil
    Reporting group description
    Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Reporting group values
    Chlorambucil Ofatumumab + Chlorambucil Total
    Number of subjects
    226 221 447
    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)
    70 69 139
        From 65-84 years
    151 150 301
        85 years and over
    5 2 7
    Sex: Female, Male
    Units: Subjects
        Female
    86 79 165
        Male
    140 142 282
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    2 4 6
        American Indian or Alaskan Native
    1 0 1
        Asian - Central/South Asian Heritage
    22 19 41
        Asian - Mixed Race
    0 2 2
        White
    201 196 397
    AgeCategoricalOther
    Units: Years
        median (full range (min-max))
    70 (36 to 91) 69 (35 to 92) -

    End points

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    End points reporting groups
    Reporting group title
    Chlorambucil
    Reporting group description
    Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Reporting group title
    Ofatumumab + Chlorambucil
    Reporting group description
    Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Subject analysis set title
    Chlorambucil
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Subject analysis set title
    Ofatumumab + Chlorambucil
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Subject analysis set title
    Study OMB110911: Ofatumumab + Chlorambucil
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Subject analysis set title
    Study LEUA1001: Chlorambucil
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with CLL, Non-Hodgkin’s lymphoma or other refractory malignancies received three different formulations of a 0.2 mg/kilogram(kg) chlorambucil tablet orally with a two-day interval between drug administration.

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

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    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 (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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event or death occurred after extensive lost-to-follow-up time or if new anti-cancer therapy was started were censored at the date of the last visit with adequate assessment.
    End point type
    Primary
    End point timeframe
    From randomization to the date of first documented disease progression or death due to any cause, whichever occured first, reported between day of first patient randomized up to about 49 months
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    226
    221
    Units: Months
        median (confidence interval 95%)
    13.1 (10.6 to 13.8)
    22.4 (19.0 to 25.2)
    Statistical analysis title
    PFS as assessed by IRC
    Comparison groups
    Chlorambucil v Ofatumumab + Chlorambucil
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    0.72

    Secondary: Number of participants with the best overall response (OR), as assessed by the IRC

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    End point title
    Number 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 until the 259th PFS event occurred, up to about 49 months
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    226
    221
    Units: Participants
        CR
    3
    27
        CRi
    0
    5
        nPR
    0
    1
        PR
    152
    149
    No statistical analyses for this end point

    Secondary: Number of participants who were negative for minimal residual disease (MRD)

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    End point title
    Number of participants who were negative for minimal residual disease (MRD)
    End point description
    MRD 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 until the 259th PFS event occurred (Median follow-up approximately 28.9 months)
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    226
    221
    Units: Participants
        MRD negative, irrespective of response
    8
    26
        MRD negative, with an IRC-assessed CR
    0
    10
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    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 total 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 about 111 months
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    226
    221
    Units: Months
        median (confidence interval 95%)
    84.67 (74.25 to 999)
    999 (84.50 to 999)
    Statistical analysis title
    Overall survival
    Statistical analysis description
    hazard ratios are obtained using the Pike estimator. A hazard ratio <1 indicates a lower risk with O+CHL treatment compared with chlorambucil
    Comparison groups
    Chlorambucil v Ofatumumab + Chlorambucil
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.363
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.17

    Secondary: Time to response, as assessed by the IRC

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    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 (CR, CRi, nPR, or PR). 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. Participants with unknown or missing responses were considered as non-responders. Only responders (CR, CRi, PR, nPR) were included in the analysis.
    End point type
    Secondary
    End point timeframe
    From randomization uo to about 27 months
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    154
    182
    Units: Months
        median (confidence interval 95%)
    1.9 (1.2 to 1.9)
    1.2 (1.0 to 1.9)
    No statistical analyses for this end point

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

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    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 enlarged 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. Par. who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time (>= 12 weeks) were censored at the date of the last visit with adequate assessment. Par. with unknown or missing responses were considered as non-responders.
    End point type
    Secondary
    End point timeframe
    From randomization up to about 43 months
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    154
    182
    Units: Months
        median (confidence interval 95%)
    13.2 (10.8 to 16.4)
    22.1 (19.1 to 24.6)
    No statistical analyses for this end point

    Secondary: Time to progression, as assessed by the IRC

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    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 disease progression (PD). PD requires at least one of the following: lymphadenopathy, appearance of any new lesion such as enlarged 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. Participants who were alive and had not progressed at the time of analysis or if a progression event occurred after extensive lost-to-follow-up time were censored at the date of the last visit with adequate assessment.
    End point type
    Secondary
    End point timeframe
    From randomization up to about 49 months
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    226
    221
    Units: Months
        median (confidence interval 95%)
    13.6 (11.2 to 14.6)
    23.1 (21.2 to 25.8)
    No statistical analyses for this end point

    Secondary: Time to next therapy

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    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.
    End point type
    Secondary
    End point timeframe
    From randomization up to about 49 months
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    99
    64
    Units: Months
        median (confidence interval 95%)
    24.67 (22.57 to 29.08)
    39.82 (34.69 to 48.79)
    No statistical analyses for this end point

    Secondary: Number of participants with improvement in ECOG performance status of 0 or 1

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    End point title
    Number of participants with improvement in ECOG performance status of 0 or 1
    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. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead. Participants with an ECOG performance status of 0 or 1 are shown..
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 3 Day 1, 1 month Follow-up
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    227
    217
    Units: Participants
        ECOG (0, 1) at Baseline
    209
    200
        ECOG (0, 1) at Cycle 3 Day 1
    184
    189
        ECOG (0, 1) 1 Month Follow-up
    183
    191
    No statistical analyses for this end point

    Secondary: Number of participants with improvement in constitutional symptoms (CS)

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    End point title
    Number of participants with improvement in constitutional symptoms (CS)
    End point description
    Assessment for the presence of the following symptoms were performed at Screening, Day 1 of each treatment cycle and at every Follow-up visit: night sweats (without signs of infection); unexplained, unintentional weight loss >= 10% within the previous 6 months; recurrent, unexplained fever of greater than 38 degrees celsius or 100.5 degrees fahrenheit for 2 weeks; and extreme fatigue. The best response refers to overall best response in terms of CR, CRi, PR or nPR. Data are presented for constitutional response= yes and no.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 3 Day 1, and 1 month Follow-up
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    226
    221
    Units: Participants
        CS present, Baseline, n=226, 221
    120
    118
        CS present, Cycle 3 Day 1, n=198, 199
    44
    33
        CS present, 1 Month Follow-up, n=198, 200
    23
    22
    No statistical analyses for this end point

    Secondary: Number of participants with a human anti-human antibody (HAHA) positive result

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    End point title
    Number of participants with a human anti-human antibody (HAHA) positive result
    End point description
    Serum samples for analysis of HAHA were collected at Baseline (Screening), Cycle 4 Day 1 (after 3 months of treatment), and at 1 month and 6 months post last dose of ofatumumab. 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 and further evaluated in the titration test to obtain a titer of HAHA.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 4 Day 1, 1 Month Follow-up, and 6 Month Follow-up
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    0 [1]
    202
    Units: Participants
    0
    Notes
    [1] - not analyzed for anti-ofatumumab antibody.
    No statistical analyses for this end point

    Secondary: Cmax and Ctrough of ofatumumab

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    End point title
    Cmax and Ctrough of ofatumumab
    End point description
    Blood samples were collected to assess the plasma concentration of ofatumumab. Maximum concentration (Cmax) and observed drug concentration prior to the next dose (Ctrough) were determined. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of treatment.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1,Cycle 1 Day 8, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, and Cycle 9 Day 1
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    0 [2]
    193
    Units: Micrograms/Milliliter (µg/mL)
    geometric mean (geometric coefficient of variation)
        Cmax, Cycle 1 Day 1, n=0, 176
    ±
    51.8 ± 1.03
        Cmax, Cycle 1 Day 8, n=0, 193
    ±
    241 ± 0.46
        Cmax, Cycle 4 Day 1, n=0, 169
    ±
    285 ± 0.44
        Ctrough, Cycle 1 Day 8, n=0, 99
    ±
    2.5 ± 5.85
        Ctrough, Cycle 2 Day 1, n=0, 138
    ±
    5.2 ± 15.37
        Ctrough, Cycle 3 Day 1, n=0, 142
    ±
    6.2 ± 17.06
        Ctrough, Cycle 4 Day 1, n=0, 147
    ±
    15.5 ± 7.99
        Ctrough, Cycle 5 Day 1, n=0, 149
    ±
    33.5 ± 3.61
        Ctrough, Cycle 6 Day 1, n=0, 155
    ±
    45.9 ± 2.77
        Ctrough, Cycle 9 Day 1, n=0, 56
    ±
    55.6 ± 3.50
    Notes
    [2] - Cmax and Ctrough were not collected for this arm.
    No statistical analyses for this end point

    Secondary: Total plasma clearance (CL) of ofatumumab

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    End point title
    Total plasma clearance (CL) of ofatumumab
    End point description
    Plasma clearance is defined as the plasma volume which is totally cleared of drug per unit of time. Blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    0 [3]
    183
    Units: Milliliter/hour (mL/h)
        geometric mean (geometric coefficient of variation)
    ±
    15.4 ± 0.73
    Notes
    [3] - total plasma clearance was not collected for this arm/drug.
    No statistical analyses for this end point

    Secondary: AUC(0-tau) of ofatumumab

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    End point title
    AUC(0-tau) of ofatumumab
    End point description
    Area under the concentration time curve over the dosing interval [AUC(0-tau)] is a measure of drug exposure over time. AUC(0-tau) is defined as the area under the ofatumumab plasma concentration-time curve from dosing to time tau, where tau is the length of the dosing interval of ofatumumab. For estimation of AUC(0-tau), blood samples were collected from participants who received ofatumumab plus chlorambucil at pre-dose and 0.5 hous after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to the ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on duration of treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    0 [4]
    208
    Units: µg x hours/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1, n=0, 193
    ±
    2621 ± 0.76
        Cycle 1 Day 8, n=0, 208
    ±
    25369 ± 0.87
        Cycle 4 Day 1, n=0, 183
    ±
    65100 ± 0.73
    Notes
    [4] - AUC was not collected for this arm/drug
    No statistical analyses for this end point

    Secondary: Volume of distribution at steady state (Vss) of ofatumumab

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    End point title
    Volume of distribution at steady state (Vss) of ofatumumab
    End point description
    Volume of distribution at steady state (Vss) is defined as the distribution of a drug between plasma and the rest of the body at steady state. Blood samples were collected from participants who received ofatumumab plus chlorambucil at predose and 0.5 hour after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 4 Day 1
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    0 [5]
    208
    Units: Liters
    geometric mean (geometric coefficient of variation)
        Vss, Cycle 1 Day 1, n=0, 193
    ±
    7.78 ± 0.55
        Vss, Cycle 1 Day 8, n=0, 208
    ±
    7.77 ± 0.54
        Vss, Cycle 4 Day 1, n=0, 183
    ±
    8.06 ± 0.53
    Notes
    [5] - Vss was not collected for this arm/drug.
    No statistical analyses for this end point

    Secondary: Plasma half life (t1/2) of ofatumumab

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    End point title
    Plasma half life (t1/2) of ofatumumab
    End point description
    The terminal half-life (t1/2) of ofatumumab is defined as the time required for the plasma concentration of ofatumumab to reach half of its original concentration. Blood samples were collected to assess the plasma half-life of ofatumumab. Blood samples were collected from participants who received ofatumumab plus chlorambucil pre-dose and 0.5 hours after the end of the ofatumumab infusion at treatment Cycle 1 and Cycle 4 (Days 1, 8, and 85). In addition, pre-dose samples were collected prior to ofatumumab administration at Cycles 2, 3, 5, 6, 9 and 12 (Days 29, 57, 113, 141, 225 and 309), depending on the duration of the treatment. Samples were also collected during clinic visits on Day 15 (during Cycle 1) and Day 43 (during Cycle 2) and at 1, 3, and 6 months post-treatment.
    End point type
    Secondary
    End point timeframe
    Cycle 4 Day 1
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    0 [6]
    183
    Units: hours
        geometric mean (geometric coefficient of variation)
    ±
    445 ± 1.05
    Notes
    [6] - t1/2 was not collected for this arm/drug
    No statistical analyses for this end point

    Secondary: Dose-normalized Cmax of chlorambucil and phenylacetic acid mustard (PAAM)

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    End point title
    Dose-normalized Cmax of chlorambucil and phenylacetic acid mustard (PAAM)
    End point description
    Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The maximum observed concentration (Cmax) of chlorambucil and PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].
    End point type
    Secondary
    End point timeframe
    Cycle 3 Day 1
    End point values
    Study OMB110911: Ofatumumab + Chlorambucil Study LEUA1001: Chlorambucil
    Number of subjects analysed
    7
    12
    Units: nanograms per milliliter per milligram
    geometric mean (standard deviation)
        Chlorambucil Cmax/Dose
    27.1 ± 0.32
    38.4 ± 0.36
        PAAM Cmax/Dose
    19.3 ± 0.23
    24.3 ± 0.30
    Statistical analysis title
    Dose-normalized Cmax of chlorambucil and PAAM
    Comparison groups
    Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    [7]
    Method
    Parameter type
    Ratio of Cmax/Dose
    Point estimate
    0.71
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    0.94
    Notes
    [7] - Comparability of dose-normalized chlorambucil Cmax values with ofatumumab in current study and without ofatumumab in prior study
    Statistical analysis title
    Dose-normalized Cmax of chlorambucil and PAAM
    Comparison groups
    Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    [8]
    Method
    Parameter type
    Ratio of Cmax/Dose
    Point estimate
    0.79
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    0.99
    Notes
    [8] - Comparability of dose-normalized PAAM Cmax values with ofatumumab in current study and without ofatumumab in prior study

    Secondary: Dose-normalized AUC(0-6) and AUC(0-inf) of chlorambucil and dose-normalized AUC(0-6) of phenylacetic acid mustard (PAAM)

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    End point title
    Dose-normalized AUC(0-6) and AUC(0-inf) of chlorambucil and dose-normalized AUC(0-6) of phenylacetic acid mustard (PAAM)
    End point description
    Blood samples for the determination of serum concentrations of chlorambucil and its metabolite PAAM were collected from participants in a substudy on Cycle 3 Day 1. The area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) and over 6 hours (AUC[0-6]) of chlorambucil and AUC(0-6) of PAAM normalized to the administered dose was determined as a measure of exposure and compared to reference data from a prior study (LEUA1001) [No NCT number available for this study; GlaxoSmithKline Document Number RM1998/00449/00].
    End point type
    Secondary
    End point timeframe
    Cycle 3 Day 1
    End point values
    Study OMB110911: Ofatumumab + Chlorambucil Study LEUA1001: Chlorambucil
    Number of subjects analysed
    7
    12
    Units: Hours*nanogram/milliliter/milligram
    geometric mean (standard deviation)
        Chlorambucil AUC(0-6)/Dose
    67.84 ± 0.24
    65.43 ± 0.44
        Chlorambucil AUC(0-inf)/Dose
    74.42 ± 0.23
    67.10 ± 0.45
        PAAM AUC(0-6)/Dose
    71.52 ± 0.26
    80.32 ± 0.26
    Statistical analysis title
    Dose-normalized AUC of PAAM
    Comparison groups
    Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    [9]
    Method
    Parameter type
    Ratio of AUC(0-6)/Dose
    Point estimate
    1.04
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.4
    Notes
    [9] - Comparability of dose-normalized chlorambucil AUC(0-6) values with ofatumumab in current study and without ofatumumab in prior study
    Statistical analysis title
    Dose-normalized AUC of PAAM
    Comparison groups
    Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    [10]
    Method
    Parameter type
    Ratio of AUC(0-inf)/Dose
    Point estimate
    1.11
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.5
    Notes
    [10] - Comparability of dose-normalized chlorambucil AUC(0-inf) values with ofatumumab in current study and without ofatumumab in prior study
    Statistical analysis title
    Dose-normalized AUC of PAAM
    Comparison groups
    Study OMB110911: Ofatumumab + Chlorambucil v Study LEUA1001: Chlorambucil
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    [11]
    Method
    Parameter type
    Ratio of AUC(0-6)/Dose
    Point estimate
    0.89
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.1
    Notes
    [11] - Comparability of dose-normalized PAAM AUC(0-6) values with ofatumumab in current study and without ofatumumab in prior study

    Secondary: Change from Baseline in health related quality of life (HRQOL)

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    End point title
    Change from Baseline in health related quality of life (HRQOL)
    End point description
    HRQOL was assessed using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTCQLQC30), Chronic Lymphocytic Leukemia module (EORTC QLQ-CLL16), EuorQoL-Five Dimension (EQ-5D), and HCQ. Period (P)1 (Day 85, Day 169, Day 253) and P2 (scheduled follow-up (FU) and withdrawal visits) analysis were considered. Baseline (BL) for P1 was defined as score from screening visit and BL for P2 was defined as the last on-treatment score. The 2 principal QoL outcomes were pre-specified as the Global Health scale (GHS/QOL) of the EORTC QLQ-C30 and fatigue scale of the EORTC QLQ-CLL16. For EORTC QLQ-C30,GHS/Qol, the possible scale range was 0-100 (with 100 being 'best') and a positive difference from BL is indicative of better functioning (range -100 to +100). For the EORTC QLQ-CLL16 fatigue scale, the possible scale range was 0-100 (with 0 being 'best') and a negative difference from BL represents an improvement in fatigue (range -100 to +100).
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 4 day 1, cycle 7 day 1, 1 month follow-up, 6 month follow-up, 12 month follow-up
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    226
    221
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        P1, Cycle 4 Day 1, QLQC30 GHS/QoL score, n=139,159
    1.92 ± 21.22
    6.08 ± 21.08
        P1, Cycle 7 Day 1, QLQC30 GHS/QoL score, n=52, 55
    8.01 ± 22.20
    6.97 ± 17.55
        P1,Cycle 4 Day 1,QLQCLL16 fatigue score, n=145,163
    -4.71 ± 27.48
    -4.60 ± 24.23
        P1, Cycle 7 Day 1,QLQCLL16 fatigue score, n=55,57
    -1.21 ± 25.43
    -9.36 ± 22.93
        P2,1 month FU, QLQC30 GHS/QoL score, n=118, 150
    4.79 ± 23.13
    0.56 ± 18.31
        P2, 6 month FU, QLQC30 GHS/QoL score, n=83, 129
    3.01 ± 22.07
    3.75 ± 20.83
        P2, 12 month FU, QLQC30 GHS/QoL score, n=48, 96
    3.82 ± 18.27
    1.22 ± 17.69
        P2, 1 month FU, QLQCLL16 fatigue score, n=121, 152
    -1.24 ± 21.75
    -0.33 ± 19.13
        P2, 6 month FU, QLQCLL16 fatigue score, n=85, 131
    -7.06 ± 18.96
    -2.93 ± 19.34
        P2, 12 month FU, QLQCLL16 fatigue score, n=51, 95
    -2.94 ± 17.86
    0.88 ± 16.91
    No statistical analyses for this end point

    Secondary: Number of participants with any adverse event (AE) or serious adverse event (SAE)

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    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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
    End point type
    Secondary
    End point timeframe
    From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    227
    217
    Units: Participants
        Any AE
    205
    208
        Any SAE
    84
    97
    No statistical analyses for this end point

    Secondary: Number of participants with AEs and SAEs of maximum severity of grade 3 or higher

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    End point title
    Number of participants with 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. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs. 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 the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    227
    217
    Units: Participants
        Any AE, Grade 3
    54
    67
        Any AE, Grade 4
    31
    36
        Any AE, Grade 5
    25
    36
        Any SAE, Grade 3
    36
    34
        Any SAE, Grade 4
    13
    19
        Any SAE, Grade 5
    25
    36
    No statistical analyses for this end point

    Secondary: Number of participants with at least one Grade 3/Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia)

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    End point title
    Number of participants with at least one Grade 3/Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia)
    End point description
    Participants with a Grade 3 or Grade 4 myelosuppression (anemia, neutropenia, and thrombocytopenia) are presented by treatment cycle. 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 the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    227
    217
    Units: Participants
    92
    83
    No statistical analyses for this end point

    Secondary: Number of participants with autoimmune hemolytic anaemia (AIHA) disease

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    End point title
    Number of participants with autoimmune hemolytic anaemia (AIHA) disease
    End point description
    AIHA is a disease 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 diagnosed with AIHA are presented.
    End point type
    Secondary
    End point timeframe
    From the first dose of study medication to 60 days after the last dose of study medication and until follow-up for SAEs unless initiation of subsequent anti-CLL therapy
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    227
    217
    Units: Participants
    6
    4
    No statistical analyses for this end point

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

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    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 are counted in this table.
    End point type
    Secondary
    End point timeframe
    From start of treatment to the last study visit/withdrawal visit (Median follow-up approximately 28.9 months)
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    227
    217
    Units: Participants
        No transfusions
    159
    168
        At least one transfusion
    68
    49
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in the Immunoglobulin (Ig) antibodies IgA, IgG, and IgM

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    End point title
    Mean change from Baseline in the 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. IgA, IgG, and IgM were measured in the blood samples of the participants. Baseline IgA, IgG, and IgM values are the last pre-dose assessment values performed on Cycle 1 Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
    End point type
    Secondary
    End point timeframe
    From start of treatment up to 30 days after last treatment
    End point values
    Chlorambucil Ofatumumab + Chlorambucil
    Number of subjects analysed
    227
    217
    Units: Gram per liter
    arithmetic mean (standard deviation)
        IgA, n=175, 186
    0.047 ± 0.5706
    0.048 ± 0.4257
        IgG, n=175, 186
    -0.458 ± 3.6177
    -0.268 ± 2.5430
        IgM n=175, 186
    -0.398 ± 4.7864
    -0.031 ± 0.2507
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events and Serious Adverse Events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 111 months
    Adverse event reporting additional description
    All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of 111 months.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Chlorambucil
    Reporting group description
    Participants with previously untreated chronic lymphocytic leukemia (CLL) received chlorambucil monotherapy 10 milligram (mg)/meter squared (m^2) orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Reporting group title
    Ofatumumab 1000 mg + Chlorambucil
    Reporting group description
    Participants with CLL received intravenous (IV) infusions of ofatumumab on Day 1 (300 mg) and Day 8 (1000 mg) in the first cycle, followed by IV infusions of 1000 mg on the first day of each subsequent 28-day cycle in combination with chlorambucil 10 mg/m^2 orally on Days 1-7 of every 28-day cycle for a minimum of 3 cycles until best response or a maximum of 12 cycles.

    Reporting group title
    Total
    Reporting group description
    All patients.

    Serious adverse events
    Chlorambucil Ofatumumab 1000 mg + Chlorambucil Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    57 / 227 (25.11%)
    53 / 217 (24.42%)
    110 / 444 (24.77%)
         number of deaths (all causes)
    99
    84
    183
         number of deaths resulting from adverse events
    2
    3
    5
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Inflammation
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 227 (0.44%)
    5 / 217 (2.30%)
    6 / 444 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular stent restenosis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Traumatic ulcer
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mycobacterium test
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 217 (0.92%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 217 (0.92%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 227 (0.88%)
    2 / 217 (0.92%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 227 (1.76%)
    2 / 217 (0.92%)
    6 / 444 (1.35%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 217 (0.92%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 227 (0.00%)
    4 / 217 (1.84%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 227 (2.20%)
    3 / 217 (1.38%)
    8 / 444 (1.80%)
         occurrences causally related to treatment / all
    6 / 6
    4 / 4
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    3 / 227 (1.32%)
    0 / 217 (0.00%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 227 (2.20%)
    3 / 217 (1.38%)
    8 / 444 (1.80%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 3
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 217 (0.46%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    2 / 227 (0.88%)
    0 / 217 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 227 (1.76%)
    6 / 217 (2.76%)
    10 / 444 (2.25%)
         occurrences causally related to treatment / all
    4 / 4
    7 / 7
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 227 (1.32%)
    1 / 217 (0.46%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebellar ischaemia
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 217 (0.46%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 217 (0.92%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial haematoma
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 217 (0.92%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 217 (0.46%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Aphthous ulcer
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 217 (0.92%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 227 (0.88%)
    1 / 217 (0.46%)
    3 / 444 (0.68%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 217 (0.92%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 217 (0.46%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 227 (0.44%)
    3 / 217 (1.38%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 227 (1.32%)
    2 / 217 (0.92%)
    5 / 444 (1.13%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    Oral herpes
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 217 (0.46%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis bacterial
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Pneumonia
         subjects affected / exposed
    11 / 227 (4.85%)
    8 / 217 (3.69%)
    19 / 444 (4.28%)
         occurrences causally related to treatment / all
    12 / 12
    8 / 8
    20 / 20
         deaths causally related to treatment / all
    1 / 2
    1 / 1
    2 / 3
    Pneumonia legionella
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 217 (0.46%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 217 (0.92%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 217 (0.46%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 217 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Chlorambucil Ofatumumab 1000 mg + Chlorambucil Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    175 / 227 (77.09%)
    183 / 217 (84.33%)
    358 / 444 (80.63%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 227 (0.44%)
    11 / 217 (5.07%)
    12 / 444 (2.70%)
         occurrences all number
    1
    11
    2
    Hypertension
         subjects affected / exposed
    1 / 227 (0.44%)
    11 / 217 (5.07%)
    12 / 444 (2.70%)
         occurrences all number
    1
    12
    6
    Hypotension
         subjects affected / exposed
    2 / 227 (0.88%)
    12 / 217 (5.53%)
    14 / 444 (3.15%)
         occurrences all number
    3
    16
    3
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 227 (0.00%)
    17 / 217 (7.83%)
    17 / 444 (3.83%)
         occurrences all number
    0
    29
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 227 (11.01%)
    33 / 217 (15.21%)
    58 / 444 (13.06%)
         occurrences all number
    29
    38
    65
    Dyspnoea
         subjects affected / exposed
    10 / 227 (4.41%)
    25 / 217 (11.52%)
    35 / 444 (7.88%)
         occurrences all number
    10
    32
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 227 (11.89%)
    16 / 217 (7.37%)
    43 / 444 (9.68%)
         occurrences all number
    31
    25
    58
    Leukopenia
         subjects affected / exposed
    4 / 227 (1.76%)
    14 / 217 (6.45%)
    18 / 444 (4.05%)
         occurrences all number
    4
    22
    27
    Neutropenia
         subjects affected / exposed
    36 / 227 (15.86%)
    57 / 217 (26.27%)
    93 / 444 (20.95%)
         occurrences all number
    55
    103
    161
    Thrombocytopenia
         subjects affected / exposed
    56 / 227 (24.67%)
    30 / 217 (13.82%)
    86 / 444 (19.37%)
         occurrences all number
    69
    41
    114
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 227 (6.61%)
    10 / 217 (4.61%)
    25 / 444 (5.63%)
         occurrences all number
    21
    13
    29
    Headache
         subjects affected / exposed
    7 / 227 (3.08%)
    18 / 217 (8.29%)
    25 / 444 (5.63%)
         occurrences all number
    7
    30
    26
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 227 (4.85%)
    18 / 217 (8.29%)
    29 / 444 (6.53%)
         occurrences all number
    11
    19
    28
    Chills
         subjects affected / exposed
    1 / 227 (0.44%)
    18 / 217 (8.29%)
    19 / 444 (4.28%)
         occurrences all number
    1
    20
    3
    Fatigue
         subjects affected / exposed
    40 / 227 (17.62%)
    35 / 217 (16.13%)
    75 / 444 (16.89%)
         occurrences all number
    46
    36
    85
    Oedema peripheral
         subjects affected / exposed
    12 / 227 (5.29%)
    15 / 217 (6.91%)
    27 / 444 (6.08%)
         occurrences all number
    13
    17
    30
    Pyrexia
         subjects affected / exposed
    18 / 227 (7.93%)
    36 / 217 (16.59%)
    54 / 444 (12.16%)
         occurrences all number
    26
    45
    41
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    17 / 227 (7.49%)
    12 / 217 (5.53%)
    29 / 444 (6.53%)
         occurrences all number
    17
    13
    27
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 227 (2.20%)
    11 / 217 (5.07%)
    16 / 444 (3.60%)
         occurrences all number
    5
    12
    10
    Constipation
         subjects affected / exposed
    13 / 227 (5.73%)
    10 / 217 (4.61%)
    23 / 444 (5.18%)
         occurrences all number
    14
    11
    25
    Diarrhoea
         subjects affected / exposed
    31 / 227 (13.66%)
    38 / 217 (17.51%)
    69 / 444 (15.54%)
         occurrences all number
    37
    44
    70
    Nausea
         subjects affected / exposed
    57 / 227 (25.11%)
    43 / 217 (19.82%)
    100 / 444 (22.52%)
         occurrences all number
    72
    66
    105
    Vomiting
         subjects affected / exposed
    24 / 227 (10.57%)
    23 / 217 (10.60%)
    47 / 444 (10.59%)
         occurrences all number
    30
    26
    25
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 227 (0.88%)
    11 / 217 (5.07%)
    13 / 444 (2.93%)
         occurrences all number
    2
    14
    5
    Hyperhidrosis
         subjects affected / exposed
    5 / 227 (2.20%)
    12 / 217 (5.53%)
    17 / 444 (3.83%)
         occurrences all number
    6
    13
    14
    Pruritus
         subjects affected / exposed
    11 / 227 (4.85%)
    26 / 217 (11.98%)
    37 / 444 (8.33%)
         occurrences all number
    11
    33
    28
    Rash
         subjects affected / exposed
    21 / 227 (9.25%)
    53 / 217 (24.42%)
    74 / 444 (16.67%)
         occurrences all number
    25
    67
    44
    Urticaria
         subjects affected / exposed
    2 / 227 (0.88%)
    22 / 217 (10.14%)
    24 / 444 (5.41%)
         occurrences all number
    2
    30
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 227 (3.52%)
    11 / 217 (5.07%)
    19 / 444 (4.28%)
         occurrences all number
    8
    11
    18
    Back pain
         subjects affected / exposed
    12 / 227 (5.29%)
    11 / 217 (5.07%)
    23 / 444 (5.18%)
         occurrences all number
    13
    13
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    20 / 227 (8.81%)
    13 / 217 (5.99%)
    33 / 444 (7.43%)
         occurrences all number
    20
    15
    34
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 227 (4.41%)
    11 / 217 (5.07%)
    21 / 444 (4.73%)
         occurrences all number
    11
    11
    22
    Nasopharyngitis
         subjects affected / exposed
    19 / 227 (8.37%)
    9 / 217 (4.15%)
    28 / 444 (6.31%)
         occurrences all number
    21
    9
    30
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 227 (7.05%)
    12 / 217 (5.53%)
    28 / 444 (6.31%)
         occurrences all number
    17
    13
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2008
    1) Clarification of translational research and consent language to comply with local Institutional Review Board / Ethics Committee requirements. 2) The steroid pre-infusion schedule was modified to allow dose reduction for patients where steroid administration was not medically indicated (U.S. FDA request). 3) DoR and PROs were removed as inferential secondary endpoints because a formal comparison of these endpoints was not considered feasible with the proposed study design. Instead, OS was added as an inferential secondary endpoint (U.S. FDA/EMA request).
    10 Aug 2009
    1) Addition of inclusion criterion, ‘considered inappropriate for fludarabine-based therapy, for reasons that include, but not limited to, advanced age or presence of comorbidities’ to further define patient population (U.S. FDA request). 2) Addition of a CT scan at time of progression to provide the IRC a means of objective assessment of progressive disease by lymphadenopathy, for sensitivity analysis (U.S. FDA request). 3) Update of CLL diagnosis definition and response assessment criteria in alignment with the IWCLL updated (NCI-WG) guidelines.
    25 Nov 2009
    1) Implementation of Hepatitis B virus DNA monitoring for HBcAb-positive patients to monitor for potential hepatitis reactivation. 2) Addition of a drug-drug interaction and ECG substudy to evaluate potential ofatumumab/chlorambucil interaction and any effect of ofatumumab on QTc intervals (FDA request).
    23 May 2014
    1) Change of Medical Monitor. 2) Removal of CT scan at time of progression 3) Extension of follow-up period from 5 to up to 10 years 4) Clarification of data collection period for concomitant medication in follow-up 5) Update Data Disclosure information
    24 Sep 2015
    1) Delete or replace references to GSK or its staff with that of Novartis/Novartis and its authorized agents. 2) 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.
    The study was terminated early because the majority of patients (62%) had been treated with next line therapies, including new highly effective therapies confounding the interpretation of the OS results.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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