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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Open-Label, Parallel-Group Study Of The Efficacy And Safety Of Lenalidomide (Revlimid®) Versus Chlorambucil As First-Line Therapy For Previously Untreated Elderly Patients With B-Cell Chronic Lymphocytic Leukemia

    Summary
    EudraCT number
    2008-003079-32
    Trial protocol
    ES   AT   BE   PT   CZ   GB   HU   IT   FR   NL   DK   SK   BG  
    Global end of trial date
    09 May 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    30 Jun 2019
    First version publication date
    25 May 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Updates are made to some of the secondary endpoint timeframes.

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-5013-CLL-008
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00910910
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 866-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Jeffery Jones, MD, Celgene Corporation, 01 908-673-9686, ClinicalTrialDisclosure@Celgene.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
    21 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of lenalidomide versus chlorambucil as first-line therapy in elderly patients.
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection, Archiving of Essential Documents
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Brazil: 38
    Country: Number of subjects enrolled
    Bulgaria: 19
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Croatia: 12
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Hungary: 40
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Russian Federation: 45
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Serbia: 10
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 63
    Worldwide total number of subjects
    450
    EEA total number of subjects
    212
    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)
    0
    From 65 to 84 years
    435
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    118 sites randomized participants in Austria, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Columbia, Croatia, Czech Republic, Denmark, Hungary, Israel, Italy, the Netherlands, New Zealand, Poland, Portugal, Romania, Russia, South Africa, Slovakia, Spain, Serbia, the United Kingdom, and the United States of America

    Pre-assignment
    Screening details
    Participants were randomized 1:1 to lenalidomide or chlorambucil and stratified by disease stage, presence of pre-defined co-morbidities and presence of at least one of the following poor prognostic factors: 11q deletion, 17 p deletion, unmutated IgVH and B2M>4.0 mg/dL.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lenalidomide
    Arm description
    For participants with normal renal function [defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min], 5 mg lenalidomide was administered by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to < 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    CC-5013
    Investigational medicinal product code
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg lenalidomide PO QD for participants with normal renal function [defined as CrCL ≥ 60 mL/min], on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to < 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.

    Arm title
    Chlorambucil
    Arm description
    Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
    Arm type
    Active comparator

    Investigational medicinal product name
    Chlorambucil
    Investigational medicinal product code
    Other name
    Leukeran
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Chlorambucil tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle

    Number of subjects in period 1
    Lenalidomide Chlorambucil
    Started
    225
    225
    Safety Population
    224
    223
    Completed
    0
    1
    Not completed
    225
    224
         Protocol deviation
             2
             2
         PD without histologic change
             27
             23
         PD with histologic change
             -
             2
         Adverse event, serious fatal
             9
             3
         Adverse event, non-fatal
             63
             35
         Untreated before cycle 1
             1
             2
         Unspecified
             114
             32
         Consent withdrawn by subject
             7
             5
         Completed 13 cycles of treatment
             -
             118
         Lost to follow-up
             2
             2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    For participants with normal renal function [defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min], 5 mg lenalidomide was administered by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to < 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.

    Reporting group title
    Chlorambucil
    Reporting group description
    Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).

    Reporting group values
    Lenalidomide Chlorambucil Total
    Number of subjects
    225 225 450
    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)
    0 0 0
        From 65-84 years
    215 220 435
        85 years and over
    10 5 15
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    73.0 ± 5.72 73.3 ± 5.72 -
    Sex: Female, Male
    The Intent-to-Treat (ITT) population was defined as all participants who were randomized, independent of whether they received study treatment or not.
    Units: Subjects
        Female
    93 83 176
        Male
    132 142 274

    End points

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    End points reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    For participants with normal renal function [defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min], 5 mg lenalidomide was administered by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to < 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.

    Reporting group title
    Chlorambucil
    Reporting group description
    Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).

    Primary: Kaplan-Meier Estimate of Progression Free Survival (PFS)

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    End point title
    Kaplan-Meier Estimate of Progression Free Survival (PFS)
    End point description
    Progression-free survival = the time from randomization to the first documented progression confirmed per investigator’s assessment or death due to any cause, whichever occurred first. Progressive disease included lymphadenopathy, an appearance of any new lesion such as enlarged lymph nodes (> 1.5 cm), splenomegaly, hepatomegaly or other organ infiltrates, an increase by 50% or more in greatest determined diameter of any previous site or an increase by 50% or more in the sum of the product of diameters of multiple nodes. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression. The ITT population = all subjects who were randomized, independent of whether they received study treatment or not.
    End point type
    Primary
    End point timeframe
    Data cut-off of 18 Feb 2013; up to approximately 39 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    212 [1]
    215
    Units: months
        median (confidence interval 95%)
    30.8 (18.7 to 99999)
    23.0 (19.3 to 29.2)
    Notes
    [1] - 99999 = The upper boundary of confidence interval (CI) is not estimable because of censored subjects
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratification factors: Disease stage (Binet A or Binet B or Rai I or Rai II versus (VS) Binet C or Rai III or Rai IV); Presence of at least one of the co-morbidities Asparate transaminase (AST)/Alanine transaminase (ALT) ≥ 3.0 times Upper Limits of Normal (ULN,) Creatinine clearance ≥ 30 to < 60 mL/min, Yes VS No); Presence of at least one 11q deletion, 17p deletion, unmutated Immunoglobulin Heavy-chain Variable-region (IgVH) or Beta-2 Microglobulin (ß2M )> 4.0 mg/L (Yes versus No VS Unknown)
    Comparison groups
    Lenalidomide v Chlorambucil
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.323
    Method
    stratified log rank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.21
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    1.66
    Notes
    [2] - Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

    Primary: Kaplan-Meier Estimate of Progression Free Survival (PFS) with a Later Cut-off Date

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    End point title
    Kaplan-Meier Estimate of Progression Free Survival (PFS) with a Later Cut-off Date
    End point description
    Progression-free survival = the time from randomization to the first documented progression confirmed per investigator’s assessment or death due to any cause, whichever occurred first. Progressive disease included lymphadenopathy, an appearance of any new lesion such as enlarged lymph nodes (> 1.5 cm), splenomegaly, hepatomegaly or other organ infiltrates, an increase by 50% or more in greatest determined diameter of any previous site or an increase by 50% or more in the sum of the product of diameters of multiple nodes. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression. The Intent-to-Treat (ITT) population = all subjects who were randomized, independent of whether they received study treatment or not.
    End point type
    Primary
    End point timeframe
    From randomization to data cut off date of 26 April 2013; median follow up time for all participants was 12.6 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    225 [3]
    225
    Units: months
        median (confidence interval 95%)
    30.8 (18.7 to 99999)
    21.4 (19.3 to 25.1)
    Notes
    [3] - 99999= The upper boundary of CI is not estimable because of censored subjects.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratification factors: Disease stage (Binet A or Binet B or Rai I or Rai II versus (VS) Binet C or Rai III or Rai IV); Presence of at least one of the co-morbidities Asparate transaminase (AST)/Alanine transaminase (ALT) ≥ 3.0 times Upper Limits of Normal (ULN,) Creatinine clearance ≥ 30 to < 60 mL/min, Yes VS No); Presence of at least one 11q deletion, 17p deletion, unmutated Immunoglobulin Heavy-chain Variable-region (IgVH) or Beta-2 Microglobulin (ß2M )> 4.0 mg/L (Yes versus No VS Unknown)
    Comparison groups
    Lenalidomide v Chlorambucil
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.967 [5]
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.99
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.29
    Notes
    [4] - Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    [5] - The p-value is based on a stratified log-rank test

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    Number of Participants with Adverse Events (AEs)
    End point description
    AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment, regardless of cause. Serious AE (SAE) = an AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on the subjects symptoms according to the Common Terminology Criteria for Adverse Events (Version 4.0) and were evaluated based on following scale -Grade (GR) 1 = Mild - transient or mild discomfort; no medical intervention required; GR 2 - Moderate- mild to moderate limitation in activity; GR 3 = Severe; GR 4 = Life threatening; GR 5 = Death; Safety population = subjects who received at least 1 dose of study drug
    End point type
    Secondary
    End point timeframe
    From randomization up to data cut-off of 18 Feb 2013; Up to approximately 39 months; maximum duration of exposure for Lenalidomide was 1086 days and 406 days for Chlorambucil
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    211
    213
    Units: participants
        ≥ 1 TEAE
    202
    186
        ≥ 1 TEAE related to study drug
    183
    139
        ≥ 1 NCI CTC Grade 3-4 TEAE
    173
    117
        Grade 3-4 adverse event related to any study drug
    143
    82
        ≥ 1 NCI CTC Grade 5 TEAE
    21
    9
        ≥ Grade 5 adverse event related to any study drug
    6
    1
        ≥ 1 Serious TEAE
    129
    76
        ≥ 1 Serious TEAE related to any study drug
    95
    46
        ≥1 TEAE leading to stopping either study drug
    61
    34
        ≥1 Related TEAE leading to stopping either drug
    39
    19
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events with a Later Cut-off Date of 31 March 2014

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    End point title
    Number of Participants With Adverse Events with a Later Cut-off Date of 31 March 2014
    End point description
    AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment, regardless of cause. Serious AE (SAE) = an AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on the subjects symptoms according to the Common Terminology Criteria for Adverse Events (Version 4.0) and were evaluated based on following scale -Grade (GR) 1 = Mild - transient or mild discomfort; no medical intervention required; GR 2 - Moderate- mild to moderate limitation in activity; GR 3 = Severe; GR 4 = Life threatening; GR 5 = Death; Safety population = subjects who received at least 1 dose of study drug
    End point type
    Secondary
    End point timeframe
    From randomization to the data cut-off of 31 March 2014; Up to 53 months; maximum duration of exposure for Lenalidomide was 1140 days and 406 days for Chlorambucil
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    224
    223
    Units: participants
        ≥ 1 TEAE
    216
    202
        ≥ 1 TEAE related to study drug
    194
    155
        ≥ 1 NCI CTC Grade 3-4 TEAE
    188
    131
        Grade 3-4 adverse event related to any study drug
    157
    90
        ≥ 1 NCI CTC Grade 5 TEAE
    21
    11
        ≥ Grade 5 adverse event related to any study drug
    6
    1
        ≥ 1 Serious TEAE
    148
    90
        ≥ 1 Serious TEAE related to any study drug
    107
    53
        ≥1 TEAE leading to stopping either study drug
    70
    42
        ≥1 Related TEAE leading to stopping either drug
    46
    23
    No statistical analyses for this end point

    Secondary: Percentage of Participants with the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines

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    End point title
    Percentage of Participants with the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines
    End point description
    A best overall response rate is a CR, CRi, nPR or PR and is defined as: Complete Remission (CR): • No lymphadenopathy • No hepatomegaly or splenomegaly • Absence of constitutional symptoms • Polymorphonuclear leukocytes ≥ 1500/ul • No circulating clonal B-lymphocytes • Platelets > 100,000/ul • Hemoglobin >11.0 g/dl • Normocellular <30% lymphocytes, no B-lymphoid nodules; Incomplete Clinical Response (CRi): • CR without bone marrow biopsy confirmation. Nodular Partial Response (nPR): • CR with the presence of residual clonal nodules. Partial Response (PR) requires: • ≥ 50% decrease in peripheral blood lymphocyte count • ≥ 50% reduction in lymphadenopathy • ≥ 50% reduction in size of liver and/or spleen • 1 or more of the following:• Polymorphonuclear leukocytes ≥ 1500/ul • Platelets >100,000/ul. A smaller population was used (earlier cut-off date) prior to the last subject enrolled. The ITT population = all subjects who were randomized, independent of whether they received study drug
    End point type
    Secondary
    End point timeframe
    Up to data cut-off of 18 Feb 2013; approximately 39 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    212
    215
    Units: percentage of participants
        number (not applicable)
    51.9
    62.3
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide v Chlorambucil
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.032
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    0.96

    Secondary: Percentage of Participants with a Best Overall Response based on IWCLL Guidelines with a Later Cut-off Date of 31 March 2014

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    End point title
    Percentage of Participants with a Best Overall Response based on IWCLL Guidelines with a Later Cut-off Date of 31 March 2014
    End point description
    A best overall response rate is a CR, CRi, nPR or PR and is defined as: Complete Remission (CR): • No lymphadenopathy • No hepatomegaly or splenomegaly • Absence of constitutional symptoms • Polymorphonuclear leukocytes ≥ 1500/ul • No circulating clonal B-lymphocytes • Platelets > 100,000/ul • Hemoglobin > 11.0 g/dl • Normocellular <30% lymphocytes, no B-lymphoid nodules; Incomplete Clinical Response (CRi): • CR without bone marrow biopsy confirmation. Nodular Partial Response: • CR with the presence of residual clonal nodules. Partial Response requires: • ≥ 50% decrease in peripheral blood lymphocyte count • ≥ 50% reduction in lymphadenopathy • ≥ 50% reduction in size of liver and/or spleen • 1 or more of the following: • Polymorphonuclear leukocytes ≥ 1500/ul • Platelets >100,000/ul. The Intent-to-Treat population was defined as all participants who were randomized, independent of whether they received study treatment or not.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off of 31 March 2014; approximately 53 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    225
    225
    Units: percentage of participants
        number (not applicable)
    60.9
    70.2
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide v Chlorambucil
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.047
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    0.98

    Secondary: Kaplan-Meier Estimate for Duration of Response

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    End point title
    Kaplan-Meier Estimate for Duration of Response
    End point description
    Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) patients who had not progressed at the time of analysis; 2) patients who had withdrawn consent or were lost to follow-up prior to documentation of progression. Intent to Treat population with an objective response as of 18 Feb 2013; includes responders.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off of 18 Feb 2013; up to approximately 39 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    110 [6]
    134
    Units: weeks
        median (confidence interval 95%)
    99999 (131.1 to 99999)
    105.3 (77.4 to 123.7)
    Notes
    [6] - 99999 = median & upper limit of CI not estimable due to insufficient number of subjects with events
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide v Chlorambucil
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.826
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    1.52
    Notes
    [7] - Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

    Secondary: Kaplan-Meier Estimate for Duration of Response with a Later Cut-off Date of 31 March 2014

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    End point title
    Kaplan-Meier Estimate for Duration of Response with a Later Cut-off Date of 31 March 2014
    End point description
    Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) participants who had not progressed at the time of analysis; 2) participants who had withdrawn consent or were lost to follow-up prior to documentation of progression. Intent to Treat population with an objective response as of 31 March 2014; includes responders.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off of 31 March 2014; up to approximately 53 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    137 [8]
    158
    Units: weeks
        median (confidence interval 95%)
    99999 (149.4 to 99999)
    87.1 (77.1 to 108.7)
    Notes
    [8] - 99999 = The median and upper boundary of CI is not estimable because of censored subjects.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide v Chlorambucil
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.149
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.71
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.05
    Notes
    [9] - Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

    Secondary: Time to Response

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    End point title
    Time to Response
    End point description
    Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines. The Intent to Treat participants with an objective response as of 18 February 2013.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off of 18 Feb 2013; up to approximately 39 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    110
    134
    Units: weeks
        median (full range (min-max))
    8.6 (3.7 to 104.3)
    8.1 (3.7 to 52.7)
    No statistical analyses for this end point

    Secondary: Time to Response for a Later Cut-off Date of 31 March 2014

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    End point title
    Time to Response for a Later Cut-off Date of 31 March 2014
    End point description
    Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines. ITT participants who had not progressed at the time of analysis; or those who had withdrawn consent or were lost to follow-up prior to documentation of progression.
    End point type
    Secondary
    End point timeframe
    Up to data cut-off of 31 March 2014; up to approximately 53 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    137
    158
    Units: weeks
        median (full range (min-max))
    10.4 (3.7 to 136.1)
    8.1 (3.7 to 68.7)
    No statistical analyses for this end point

    Secondary: Kaplan Meier Estimate of Overall Survival

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    End point title
    Kaplan Meier Estimate of Overall Survival
    End point description
    Overall Survival is defined as the time between randomization and death from any cause. 99999 = the median OS was not reached due to the long survival of the subjects relative to the study duration. The Intent-to-Treat population was defined as all participants who were randomized, independent of whether they received study treatment or not.
    End point type
    Secondary
    End point timeframe
    Up to data cut off of 31 March 2014; median follow-up for all participants was 18.8 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    225 [10]
    225 [11]
    Units: Months
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    44.0 (37.3 to 99999)
    Notes
    [10] - 99999 = The median has not been reached and CI not estimable because of small number of events.
    [11] - 99999 = median OS was not reached due to the long survival relative to the study duration
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide v Chlorambucil
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.883
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    1.46
    Notes
    [12] - Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

    Secondary: Kaplan Meier Estimate for Overall Survival at the Final Analysis

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    End point title
    Kaplan Meier Estimate for Overall Survival at the Final Analysis
    End point description
    Overall Survival (OS) is defined as the time between randomization and death from any cause. 99999 = the median OS was not reached due to the long survival of the subjects relative to the study duration. The ITT population was defined as all participants who were randomized, independent of whether they received study treatment.
    End point type
    Secondary
    End point timeframe
    Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    225
    225 [13]
    Units: Months
        median (confidence interval 95%)
    74.3 (58.5 to 84.4)
    70.5 (57.1 to 99999)
    Notes
    [13] - 99999 = Upper CI not estimable because of censored observations.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide v Chlorambucil
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    = 0.709
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.34
    Notes
    [14] - Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups

    Secondary: Functional Assessment of Cancer Therapy-General to Create the FACT-Leukemia (FACT-Leu) Quality of Life Instrument

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    End point title
    Functional Assessment of Cancer Therapy-General to Create the FACT-Leukemia (FACT-Leu) Quality of Life Instrument
    End point description
    The FACT-Leu scale is a valid, reliable, and efficient measure of leukemia-specific health-related quality of life for acute and chronic disease. The FACT-Leu is described as including 27 items that assess 17 physical symptoms (fevers, bleeding, general pain, stomach pain, chills, night sweats, bruising, lymph node swelling, weakness, tiredness, weight loss, appetite, shortness of breath, functional ability, diarrhea, concentration, and mouth sores) and 10 emotional/social concerns (frustration with activity limitation, discouraged by illness, future planning, uncertainty, worry about illness, emotional lability, isolation, infertility concern, family worry, and worry about infections). No data were collected for the FACT-Leu QOL assessment. Analysis was not conducted due to the discontinuation of the lenalidomide arm.
    End point type
    Secondary
    End point timeframe
    Day 1 and once every 8 weeks
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: participants
        number (not applicable)
    Notes
    [15] - Analysis not conducted due to the discontinuation of the lenalidomide arm.
    [16] - Analysis not conducted due to the discontinuation of the lenalidomide arm.
    No statistical analyses for this end point

    Secondary: Euro Quality of Life Five Dimension (EQ-5D) Questionnaire

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    End point title
    Euro Quality of Life Five Dimension (EQ-5D) Questionnaire
    End point description
    The standardized extended version of EQ-5D was designed for the collection of health state values using a visual analogue scale (VAS) rating scale - a vertical 20 cm visual analogue scale with the end points labeled best imaginable health state at the top and worst imaginable health state at the bottom having numeric values of 100 and 0 respectively. The participant is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. No data were collected for the EQ-5D QOL assessment. The EQ-5D analysis was not conducted due to the discontinuation of the lenalidomide arm.
    End point type
    Secondary
    End point timeframe
    Day 1 and once every 8 weeks
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: participants
        number (not applicable)
    Notes
    [17] - Analysis not conducted due to the discontinuation of the lenalidomide arm
    [18] - Analysis not conducted due to the discontinuation of the lenalidomide arm.
    No statistical analyses for this end point

    Secondary: Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment

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    End point title
    Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment
    End point description
    Subsequent anti-cancer therapies administered to participants following the discontinuation of study drug (either Lenalidomide or Chlorambucil). ITT population includes all participants who were randomized, independent of whether they received study treatment or not.
    End point type
    Secondary
    End point timeframe
    Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    224
    223
    Units: participants
        Participants Receiving Additional CLL Therapy
    125
    120
        Participants Receiving Alkylating Agents
    107
    106
        Participants Receiving Antineoplastic Agents
    93
    86
        Participants Receiving Antimetabolites
    34
    24
        Participants Receiving Corticosteroids
    27
    16
        Participants Receiving Plant Alkaloids
    22
    11
        Participants Receiving Cytotoxic Antibiotic
    10
    3
        Participants Receiving Immunosuppressants
    3
    2
        Participants Receiving Therapeutic Products
    4
    3
        Participants Receiving Other Unspecified Products
    0
    2
        Antihistamine For Systemic Use
    1
    1
        Drugs for Peptic Ulcer and Gastric Reflex
    1
    0
        Immunoglobulins
    1
    2
        Other Analgesics and Antipyretics
    1
    1
        Specific Antirheumatic Agents
    1
    0
        Antiemetics and Antinauseants
    0
    1
        Corticosteriods for Systemic Use
    0
    1
        Immunostimulants
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Number of Participants Deaths During the Treatment and Survival Follow-Up Phase

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    End point title
    Number of Participants Deaths During the Treatment and Survival Follow-Up Phase
    End point description
    The number of study participants deaths during the treatment and follow-up phase
    End point type
    Other pre-specified
    End point timeframe
    Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months
    End point values
    Lenalidomide Chlorambucil
    Number of subjects analysed
    225
    225
    Units: Participants
    101
    95
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were recorded by the Investigator(s) from first dose of study drug to 30 days after the treatment discontinuation visit. The median treatment duration was 263 days for lenalidomide and 362 days for chlorambucil.
    Adverse event reporting additional description
    Secondary Primary Malignancies (SPMs) were monitored and are reported as SAEs regardless of the arm the participant was is in. These are reported from the time of signing the informed consent up to and including the survival follow-up period. Participants were followed for at least 5 years from the date the last patient was randomized.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Chlorambucil
    Reporting group description
    Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months

    Reporting group title
    Lenalidomide
    Reporting group description
    For participants with normal renal function [defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min], 5 mg lenalidomide was administered by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to < 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.

    Serious adverse events
    Chlorambucil Lenalidomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 223 (40.36%)
    148 / 224 (66.07%)
         number of deaths (all causes)
    11
    21
         number of deaths resulting from adverse events
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 223 (0.45%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LERICHE SYNDROME
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERY ANEURYSM
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SHOCK
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    THROMBOPHLEBITIS SUPERFICIAL
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENOUS THROMBOSIS LIMB
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA PANCREAS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    8 / 223 (3.59%)
    5 / 224 (2.23%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASOSQUAMOUS CARCINOMA OF SKIN
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BOWEN'S DISEASE
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC LYMPHOCYTIC LEUKAEMIA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COLON ADENOMA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CANCER
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HODGKIN'S DISEASE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG SQUAMOUS CELL CARCINOMA STAGE II
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTASES TO LIVER
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTATIC MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RICHTER'S SYNDROME
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN CANCER
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    7 / 223 (3.14%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    5 / 21
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR FLARE
         subjects affected / exposed
    0 / 223 (0.00%)
    8 / 224 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    2 / 223 (0.90%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTI-ORGAN FAILURE
         subjects affected / exposed
    0 / 223 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    2 / 3
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    6 / 223 (2.69%)
    10 / 224 (4.46%)
         occurrences causally related to treatment / all
    1 / 7
    2 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUDDEN CARDIAC DEATH
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKULL FRACTURE
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR PSEUDOANEURYSM
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD UREA INCREASED
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERNATIONAL NORMALISED RATIO INCREASED
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 223 (0.45%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK FIRST DEGREE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    0 / 223 (0.00%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 223 (0.00%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    CARDIOPULMONARY FAILURE
         subjects affected / exposed
    0 / 223 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    CARDIOGENIC SHOCK
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONGESTIVE CARDIOMYOPATHY
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY DISEASE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 223 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SICK SINUS SYNDROME
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    ACUTE PULMONARY OEDEMA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHIECTASIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1 / 223 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    1 / 223 (0.45%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFILTRATION
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY ALVEOLAR HAEMORRHAGE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    PULMONARY HYPERTENSION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 223 (0.45%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SINUS CONGESTION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    AGRANULOCYTOSIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    10 / 223 (4.48%)
    18 / 224 (8.04%)
         occurrences causally related to treatment / all
    8 / 18
    16 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AUTOIMMUNE HAEMOLYTIC ANAEMIA
         subjects affected / exposed
    4 / 223 (1.79%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 223 (1.35%)
    7 / 224 (3.13%)
         occurrences causally related to treatment / all
    2 / 3
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOLYTIC ANAEMIA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IDIOPATHIC THROMBOCYTOPENIC PURPURA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHOPENIA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    33 / 223 (14.80%)
    54 / 224 (24.11%)
         occurrences causally related to treatment / all
    48 / 54
    108 / 117
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPLENIC HAEMORRHAGE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    13 / 223 (5.83%)
    19 / 224 (8.48%)
         occurrences causally related to treatment / all
    13 / 18
    32 / 35
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    CEREBRAL INFARCTION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONVULSION
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HEMIPARESIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCIATICA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SIMPLE PARTIAL SEIZURES
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 223 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 223 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    DIPLOPIA
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MACULOPATHY
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 223 (0.90%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN LOWER
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL HERNIA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    2 / 223 (0.90%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL COLIC
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    RENAL FAILURE ACUTE
         subjects affected / exposed
    0 / 223 (0.00%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS CHRONIC
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS TOXIC
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    BLISTER
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG ERUPTION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EXFOLIATIVE RASH
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    1 / 223 (0.45%)
    4 / 224 (1.79%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH GENERALISED
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STEVENS-JOHNSON SYNDROME
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URTICARIA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHROPATHY
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLANK PAIN
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL OSTEOARTHRITIS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    3 / 223 (1.35%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GOUT
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOCALCAEMIA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    3 / 223 (1.35%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR LYSIS SYNDROME
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infections and infestations
    ANAL ABSCESS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRITIS BACTERIAL
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    1 / 223 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHOPNEUMONIA
         subjects affected / exposed
    1 / 223 (0.45%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS BACTERIAL
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    3 / 223 (1.35%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS STAPHYLOCOCCAL
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA INFECTIOUS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROBACTER SEPSIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ESCHERICHIA SEPSIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOBAR PNEUMONIA
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 223 (0.45%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOCALISED INFECTION
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 224 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC INFECTION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCOCCAL SEPSIS
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    6 / 223 (2.69%)
    24 / 224 (10.71%)
         occurrences causally related to treatment / all
    3 / 9
    15 / 34
         deaths causally related to treatment / all
    1 / 3
    3 / 5
    PNEUMONIA PNEUMOCOCCAL
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    4 / 223 (1.79%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SEPSIS SYNDROME
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TONSILLITIS
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 224 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 223 (0.45%)
    3 / 224 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRITIS INFECTIVE
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 224 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Chlorambucil Lenalidomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    184 / 223 (82.51%)
    204 / 224 (91.07%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    7 / 223 (3.14%)
    14 / 224 (6.25%)
         occurrences all number
    14
    23
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    7 / 223 (3.14%)
    14 / 224 (6.25%)
         occurrences all number
    10
    18
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    7 / 223 (3.14%)
    22 / 224 (9.82%)
         occurrences all number
    11
    60
    WEIGHT DECREASED
         subjects affected / exposed
    23 / 223 (10.31%)
    34 / 224 (15.18%)
         occurrences all number
    26
    47
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR FLARE
         subjects affected / exposed
    11 / 223 (4.93%)
    85 / 224 (37.95%)
         occurrences all number
    11
    166
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    21 / 223 (9.42%)
    38 / 224 (16.96%)
         occurrences all number
    25
    48
    DYSPNOEA
         subjects affected / exposed
    12 / 223 (5.38%)
    21 / 224 (9.38%)
         occurrences all number
    16
    28
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    46 / 223 (20.63%)
    69 / 224 (30.80%)
         occurrences all number
    102
    133
    NEUTROPENIA
         subjects affected / exposed
    74 / 223 (33.18%)
    126 / 224 (56.25%)
         occurrences all number
    195
    576
    THROMBOCYTOPENIA
         subjects affected / exposed
    50 / 223 (22.42%)
    72 / 224 (32.14%)
         occurrences all number
    114
    228
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    12 / 223 (5.38%)
    16 / 224 (7.14%)
         occurrences all number
    12
    19
    HEADACHE
         subjects affected / exposed
    11 / 223 (4.93%)
    16 / 224 (7.14%)
         occurrences all number
    23
    24
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    10 / 223 (4.48%)
    19 / 224 (8.48%)
         occurrences all number
    11
    31
    FATIGUE
         subjects affected / exposed
    53 / 223 (23.77%)
    66 / 224 (29.46%)
         occurrences all number
    86
    109
    OEDEMA PERIPHERAL
         subjects affected / exposed
    16 / 223 (7.17%)
    43 / 224 (19.20%)
         occurrences all number
    23
    65
    PYREXIA
         subjects affected / exposed
    18 / 223 (8.07%)
    37 / 224 (16.52%)
         occurrences all number
    25
    61
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    11 / 223 (4.93%)
    14 / 224 (6.25%)
         occurrences all number
    15
    17
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    10 / 223 (4.48%)
    30 / 224 (13.39%)
         occurrences all number
    15
    36
    CONSTIPATION
         subjects affected / exposed
    17 / 223 (7.62%)
    28 / 224 (12.50%)
         occurrences all number
    23
    39
    DIARRHOEA
         subjects affected / exposed
    32 / 223 (14.35%)
    66 / 224 (29.46%)
         occurrences all number
    45
    117
    NAUSEA
         subjects affected / exposed
    63 / 223 (28.25%)
    33 / 224 (14.73%)
         occurrences all number
    100
    47
    VOMITING
         subjects affected / exposed
    28 / 223 (12.56%)
    11 / 224 (4.91%)
         occurrences all number
    48
    15
    Skin and subcutaneous tissue disorders
    NIGHT SWEATS
         subjects affected / exposed
    14 / 223 (6.28%)
    24 / 224 (10.71%)
         occurrences all number
    15
    34
    PRURITUS
         subjects affected / exposed
    7 / 223 (3.14%)
    18 / 224 (8.04%)
         occurrences all number
    11
    24
    RASH
         subjects affected / exposed
    19 / 223 (8.52%)
    41 / 224 (18.30%)
         occurrences all number
    23
    76
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    12 / 223 (5.38%)
    15 / 224 (6.70%)
         occurrences all number
    16
    27
    BACK PAIN
         subjects affected / exposed
    18 / 223 (8.07%)
    28 / 224 (12.50%)
         occurrences all number
    21
    37
    MUSCLE SPASMS
         subjects affected / exposed
    5 / 223 (2.24%)
    15 / 224 (6.70%)
         occurrences all number
    5
    20
    PAIN IN EXTREMITY
         subjects affected / exposed
    4 / 223 (1.79%)
    16 / 224 (7.14%)
         occurrences all number
    5
    23
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    13 / 223 (5.83%)
    30 / 224 (13.39%)
         occurrences all number
    18
    42
    HYPERKALAEMIA
         subjects affected / exposed
    4 / 223 (1.79%)
    12 / 224 (5.36%)
         occurrences all number
    4
    13
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    4 / 223 (1.79%)
    16 / 224 (7.14%)
         occurrences all number
    4
    20
    INFLUENZA
         subjects affected / exposed
    2 / 223 (0.90%)
    13 / 224 (5.80%)
         occurrences all number
    2
    14
    NASOPHARYNGITIS
         subjects affected / exposed
    3 / 223 (1.35%)
    12 / 224 (5.36%)
         occurrences all number
    4
    14
    PNEUMONIA
         subjects affected / exposed
    1 / 223 (0.45%)
    13 / 224 (5.80%)
         occurrences all number
    2
    15
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    11 / 223 (4.93%)
    16 / 224 (7.14%)
         occurrences all number
    12
    22

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Mar 2009
    1. Modified language about anti-thrombotic therapy to be consistent with other CLL protocols. 2. Deleted inclusion criterion (must not have received a prior treatment for B-cell CLL) as this was listed as an exclusion criterion (Prior treatment for B-cell CLL). 3. Deleted exclusion criterion (uncontrolled hyperthyroidism or hypothyroidism) 4. Added the exclusion criterion (serum total bilirubin > 1.5 x ULN, except in case of hemolytic anemia or Gilbert’s syndrome) and deleted co-morbidity of bilirubin ≥ 2.0 times ULN, with the exception of Gilbert’s syndrome. 5. Added nPR as a response and changed the CR/CRi confirmation visit to ≥ 8 weeks after all clinical and laboratory response criteria had been met to be consistent with December 2008 Hallek criteria. 6. Changed the time for retesting peripheral blood and bone marrow for MRD status from 16 weeks to 8 weeks for subjects who reached CR/CRi with blood negativity achieved within the 6 months after the CR/CRi confirmation visit and the bone marrow was still MRD positive. 7. Added that if bone marrow was hypocellular at the CR/CRi confirmation visit, a repeat specimen (including adequate biopsy sample) was to be obtained 4 weeks later provided that blood counts had recovered. 8. Clarified that allopurinol therapy was to be started only after confirmation of the subject’s eligibility in the study. 9. Removed ibuprofen as a suggested treatment for ≥ Grade 2 tumor flare because of the potential impact of ibuprofen on renal function. 10. Added a pregnancy test assessment at Study Day 1 for subjects in the chlorambucil arm. 11. Changed the Broca’s index to formula referenced in the Robinson, 1983 article. 12. Added dose reduction and modification guidelines for changes in liver function. 13. Clarified that thyroid function tests were required for all subjects at screening and for subjects in the lenalidomide arm at additional specified intervals during the study.
    23 Oct 2009
    1. Corrected the disease stage stratification to include Binet Stage B with the Rai Stage I and II category instead of the Rai Stage III and IV category. 2. Allowed the splitting of the chlorambucil dose over 2 days for subjects who could not swallow a full dose in 1 day and allowed the used of systemic anti-emetics prior to chlorambucil treatment. 3. Clarified that the MRD analysis was to be repeated each time a CR/CRi confirmation was performed. For this analysis, an additional peripheral blood sample was to be collected. 4. Limited allopurinol use for TLS prophylaxis to allopurinol 300 mg/day for 3 days prior to starting study treatment and for the first cycle of treatment for subjects in the chlorambucil arm, and added guidance that all subjects entering the study on allopurinol for an indication other than TLS were to continue on their prescribed dose according to the stipulated guidance. 5. Modified the required prophylaxis regimen for thromboembolic events; additional guidance was added to allow investigators to choose the most appropriate anti-thrombotic therapy based on subject’s thrombotic and bleeding risks. 6. Allowed the investigators more flexibility for the treatment of ≥ Grade 1 TLS. 7. Add an exclusion criterion for subjects with a known allergy to allopurinol.
    15 Jan 2010
    1. Added guidance to investigators to interrupt, adjust, or discontinue anti-thrombotic treatment for subjects with platelet counts < 50,000/μL and for subjects with platelet count < 20,000/μL. 2. Added guidance to investigators that Study Day 1 laboratory values were to be carefully reviewed within the first few days of study therapy initiation and appropriate dose reductions/interruptions made based on these results and that clinical assessments (physical examination and vital signs) were to be carefully assessed on Study Day 1 prior to subjects entering the study. 3. Corrected the formula used to determine Broca’s ideal weight for women.
    11 Apr 2011
    1. Deleted the exclusion criterion for subjects with uncontrolled hyperthyroidism or hypothyroidism. 2. Changed the visit schedule to reduce the number of visits in Cycle 1 and Cycle 2 and the first and second cycle of each dose escalation. 3. Defined the end of study as the time when all subjects had been followed for at least 5 years following randomization and when at least 284 deaths had occurred. 4. Allowed the use of historic/archived bone marrow core or 10-cut, unstained biopsy slides that had been collected within 60 days of screening for the purposes of the screening histology review. 5. Allowed the use of peripheral blood for FISH, ZAP-70, IgVH mutational status analyses and storage obtained within 84 days of Study Day 1 as the screening sample for subjects who were re-screened. 6. Required that all subjects who discontinued treatment or the progression-free follow up phase for reasons other than PD be followed until PD and/or death. 7. Added quality of life assessments during the Survival Follow-Up Phase. 8. Required that subjects with decreased renal function (CrCL ≥ 30 to < 60 mL/min) take a reduced dose of 100 mg of allopurinol. 9. Modified the allopurinol treatment schedule for subjects on lenalidomide to the first cycle of treatment and the first cycle of each dose escalation. 10. Allowed subjects with carcinoma in situ of the bladder to enroll in the study. 11. Corrected the timing of the first ECG from Cycle 4, Day 1 to Cycle 5, Day 1. 12. Deleted the requirement for a bone marrow aspirate and biopsy to be collected for molecular CR determination. 13. Required SMPs to be treated as SAEs and reported throughout study.
    10 Nov 2011
    1. Changed the exclusion criteria for subjects with a history of prior malignancies from 3 years to ≥ 5 years. 2. Added exploratory analyses of biomarkers of study drug activity (DNA, RNA, protein). 3. Clarified that the thyroid function tests for subjects on lenalidomide, and the ECG and Quality-of-Life questionnaires for subjects in both arms were not required during drug holds. 4. Required all Grade 3 hematologic laboratory abnormalities to be reported as AEs on the AE page of the eCRF.
    06 May 2013
    1. Required the immediate discontinuation of study drug, regardless of treatment assignment, for all subjects 81 years of age or older at the time of signing the informed consent, and provided guidance for subsequent follow-up for these subjects and for subjects 70 to 80 years of age at the time of signing the informed consent who continued in the study.
    02 Aug 2013
    1. Required the immediate discontinuation of lenalidomide treatment for all subjects randomized to the lenalidomide arm and provided guidance for subsequent follow-up for these subjects. 2. Allowed subjects in the chlorambucil arm to continue to receive study drug at the discretion of the investigator for a total duration of 13 cycles (approximately 12 months) or until PD or unacceptable toxicity developed, whichever occurred first. 3. Deleted all efficacy assessments. 4. Deleted the 28-day progression-free follow-up period and required that all subjects enter the survival follow-up period and were contacted every 4 months to collect information on SPMs, OS, and other anti cancer CLL therapies for at least 5 years after the last subject was randomized.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Jul 2012
    The FDA placed the study on partial clinical hold due to the greater number of deaths reported in the lenalidomide arm compared with the chlorambucil arm, and a trend in overall survival in favor of chlorambucil.
    02 Aug 2013

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    After notification by the US Food and Drug Administration on 12Jul2013, Celgene agreed to stop lenalidomide due to an imbalance in the number of deaths on the lenalidomide arm versus the chlorambucil arm; no causality for the imbalance was identified
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