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    Clinical Trial Results:
    A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Rituximab Plus Lenalidomide (CC-5013) Versus Rituximab Plus Placebo in Subjects With Relapsed/Refractory Indolent Lymphoma

    Summary
    EudraCT number
    		 2013-001245-14
    Trial protocol
    		 GB   BE   CZ   IT   PT   ES   PL  
    Global end of trial date
    26 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Feb 2023
    First version publication date
    11 Feb 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CC-5013-NHL-007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    11 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the efficacy and safety of rituximab plus lenalidomide (R^2) versus rituximab plus placebo in subjects with relapsed/refractory indolent lymphoma.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Brazil: 42
    Country: Number of subjects enrolled
    China: 75
    Country: Number of subjects enrolled
    Czechia: 33
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    Japan: 36
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    358
    EEA total number of subjects
    143
    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)
    203
    From 65 to 84 years
    149
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 358 randomized and 356 treated

    Period 1
    Period 1 title
    Pre-Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab + Lenalidomide (R^2)
    Arm description
    		 Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg once daily on Days 1 to 21 every 28 days up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg on days 1 to 21 every 28 days.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5

    Arm title
    		 Rituximab + Placebo
    Arm description
    		 Participants received rituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up to 12 cycles.
    Arm type
    		 Control

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    once daily on Days 1 to 21 of every 28-day cycle up to 12 cycles.

    Number of subjects in period 1
    		Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Started
    178
    180
    Completed
    176
    180
    Not completed
    2
    0
         Adverse event, serious fatal
    1
    -
         Adverse Event unrelated to Study Drug
    1
    -
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab + Lenalidomide (R^2)
    Arm description
    		 Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg once daily on Days 1 to 21 every 28 days up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg on days 1 to 21 every 28 days.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5

    Arm title
    		 Rituximab + Placebo
    Arm description
    		 Participants received rituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up to 12 cycles.
    Arm type
    		 Control

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    once daily on Days 1 to 21 of every 28-day cycle up to 12 cycles.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5

    Number of subjects in period 2
    		Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Started
    176
    180
    Completed
    124
    110
    Not completed
    52
    70
         Adverse event, serious fatal
    2
    -
         Consent withdrawn by subject
    13
    7
         Adverse event, non-fatal
    14
    8
         Progressive Disease
    21
    54
         Other reasons
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab + Lenalidomide (R^2)
    Reporting group description
    		 Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.

    Reporting group title
    Rituximab + Placebo
    Reporting group description
    		 Participants received rituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up to 12 cycles.

    Reporting group values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo Total
    Number of subjects
    		 178 180 358
    Age categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.30 ± 11.227 61.48 ± 11.160 -
    Sex: Female, Male
    Units: Participants
        Female
    		 103 83 186
        Male
    		 75 97 172
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 118 115 233
        Other Races
    		 54 64 118
        Not Collected or Reported
    		 6 1 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 24 20 44
        Not Hispanic or Latino
    		 147 158 305
        Unknown or Not Reported
    		 7 2 9

    End points

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    End points reporting groups
    Reporting group title
    Rituximab + Lenalidomide (R^2)
    Reporting group description
    		 Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.

    Reporting group title
    Rituximab + Placebo
    Reporting group description
    		 Participants received rituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up to 12 cycles.
    Reporting group title
    Rituximab + Lenalidomide (R^2)
    Reporting group description
    		 Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.

    Reporting group title
    Rituximab + Placebo
    Reporting group description
    		 Participants received rituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up to 12 cycles.

    Primary: Kaplan Meier Estimate of Progression Free Survival Assessed by the Independent Review Committee (IRC) According to the 2007 International Working Group Response Criteria (IWGRC)

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    End point title
    		 Kaplan Meier Estimate of Progression Free Survival Assessed by the Independent Review Committee (IRC) According to the 2007 International Working Group Response Criteria (IWGRC)
    End point description
    Progression-free survival (PFS) was defined as the time from date of randomization into the study to the first observation of documented disease progression or death due to any cause, whichever occurred first. PFS was based on the data from the IRC review using the modified 2007 International Working Group Response Criteria (IWGRC) using FDA censoring rules. 99999=NA; not enough events had occurred at the time of the data cut-off date
    End point type
    Primary
    End point timeframe
    From randomization of study drug up to disease progression or death, which occurred first; up to the data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    178
    180
    Units: months
        median (confidence interval 95%)
    39.4 (22.9 to 99999)
    14.1 (11.4 to 16.7)
    Statistical analysis title
    		 Hazard Ratio
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.62

    Secondary: Durable Complete Response Rate (DCCR) as Assessed by the IRC According to the 2007 IWGRC

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    End point title
    		 Durable Complete Response Rate (DCCR) as Assessed by the IRC According to the 2007 IWGRC
    End point description
    DCCR was defined as the percentage of participants with a best response of complete response (CR) that lasted no less than one year (≥ 48 weeks) during the study prior to administration of new anti-lymphoma therapy. A CR is defined as a complete disappearance of any disease-related symptoms and normalization of biochemical abnormalities.
    End point type
    Secondary
    End point timeframe
    From first dose of investigational product (IP) to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomiade arm and 11.04 months in the rituximab/placebo arm
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    178
    180
    Units: Percentage of Participants
        number (confidence interval 95%)
    25.3 (19.1 to 32.3)
    11.1 (6.9 to 16.6)
    Statistical analysis title
    		 P-Value
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0006
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Kaplan-Meier Estimate of Overall Survival (OS)

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    End point title
    		 Kaplan-Meier Estimate of Overall Survival (OS)
    End point description
    Overall survival was defined as the time from randomization to death from any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented. 99999=NA; insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From date of randomization to death due to any cause (Average of 55.71 months and a maximum up to 95.2 months)
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    178
    180
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Stratified by 3 factors: previous rituximab treatment, time since last antilymphoma therapy (≤ 2, > 2 years), and disease histology (FL, MZL).
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.95

    Secondary: Percentage of Participants with an Objective Response as Assessed by the IRC According to the 2007 IWGRC

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    End point title
    		 Percentage of Participants with an Objective Response as Assessed by the IRC According to the 2007 IWGRC
    End point description
    Percentage of participants with an objective response is defined as having a response of at least a PR during the study without administration of new anti-lymphoma therapy. A complete response = a complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of any disease-related symptoms, and normalization of biochemical abnormalities; a partial response (PR) = 50% decrease in SPD of the 6 largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD.
    End point type
    Secondary
    End point timeframe
    From date of first dose to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    178
    180
    Units: Percentage of Participants
        number (confidence interval 95%)
    77.5 (70.7 to 83.4)
    53.3 (45.8 to 60.8)
    Statistical analysis title
    		 P-value
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of Participants with a Best Response of Complete Response as Assessed by the IRC According to the 2007 IWGRC

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    End point title
    		 Percentage of Participants with a Best Response of Complete Response as Assessed by the IRC According to the 2007 IWGRC
    End point description
    Percentage of participants with a best response of at CR during the study without administration of new anti-lymphoma therapy. A CR = Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of any disease-related symptoms, and normalization of biochemical abnormalities.
    End point type
    Secondary
    End point timeframe
    From date of first dose up to data cut-off date of 22 June 2018; the median treatment duration was 11.19 months in the rituximab/lenalidomide arm and 11.04 months in the rituximab/placebo arm
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    178
    180
    Units: Percentage of Participants
        number (confidence interval 95%)
    33.7 (26.8 to 41.2)
    18.3 (13.0 to 24.8)
    Statistical analysis title
    		 P-value
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Kaplan-Meier Estimate of Duration of Objective Response as Assessed by the IRC According to the 2007 IWGRC

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    End point title
    		 Kaplan-Meier Estimate of Duration of Objective Response as Assessed by the IRC According to the 2007 IWGRC
    End point description
    Duration of response (DOR) was defined as the time from initial response (at least PR) until documented progressive disease (PD) or death. Participants who had not progressed at the time of analysis were censored at the last assessment date that the participant was known to be progression free. Participants who received a new treatment without documented progression were censored at the last assessment date that the participants was known to be progression free. 99999=NA; Not estimable as not enough events had occurred at the time of the data cut-off date
    End point type
    Secondary
    End point timeframe
    From randomization up to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    138
    96
    Units: months
        median (confidence interval 95%)
    36.6 (22.9 to 99999)
    21.7 (12.8 to 27.6)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0015
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.79

    Secondary: Kaplan-Meier Estimate of Duration of Complete Response (DOCR) as Assessed by the IRC According to the 2007 IWGRC

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    End point title
    		 Kaplan-Meier Estimate of Duration of Complete Response (DOCR) as Assessed by the IRC According to the 2007 IWGRC
    End point description
    DOCR was defined as the time from initial CR until documented PD or death. Participants who had not progressed at the time of analysis were censored at the last assessment date that the participant was known to be progression free. Participants who received a new treatment without documented progression were censored at the last assessment date that the participants was known to be progression free. 99999=NA; Not enough events had occurred at the time of the data cut-off date
    End point type
    Secondary
    End point timeframe
    From randomization up to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    60
    33
    Units: months
        median (confidence interval 95%)
    99999 (25.3 to 99999)
    99999 (13.8 to 99999)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2993
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.43

    Secondary: Kaplan Meier Estimate of Event Free Survival as Assessed by the IRC According to the 2007 IWGRC

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    End point title
    		 Kaplan Meier Estimate of Event Free Survival as Assessed by the IRC According to the 2007 IWGRC
    End point description
    Event-free survival (EFS) was defined as the time from date of randomization to date of first documented progression, relapse, institution of new anti-lymphoma treatment (chemotherapy, radiotherapy or immunotherapy) or death from any cause. Responding participants and those who were lost to follow up were censored at their last tumor assessment date. 99999=NA; Not enough events had occurred at the time of the data cut-off date
    End point type
    Secondary
    End point timeframe
    From date of randomization to data cut-off date of 22 June 2018; overall median follow-up time for all participants was 28.30 months (range: 0.1 to 51.3 months).
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    178
    180
    Units: months
        median (confidence interval 95%)
    27.6 (22.1 to 99999)
    13.9 (11.4 to 16.7)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log-Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.67

    Secondary: Kaplan Meier Estimate of Time to Next Anti-Lymphoma Treatment (TTNLT)

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    End point title
    		 Kaplan Meier Estimate of Time to Next Anti-Lymphoma Treatment (TTNLT)
    End point description
    Time to next anti-lymphoma treatment (TTNLT) was defined as the time from date of randomization to date of first documented administration of a new anti-lymphoma treatment (including chemotherapy, radiotherapy, radioimmunotherapy or immunotherapy). The time to the next anti-lymphoma treatment was of special interest to the study. 99999=NA; upper limit not available due to insufficient number of participants with events
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of first documented administration of a new anti-lymphoma treatment (Average of 55.71 months and a maximum up to 95.2 months)
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    178
    180
    Units: Months
        median (confidence interval 95%)
    73.1 (43.0 to 99999)
    31.8 (22.2 to 39.4)
    Statistical analysis title
    		 Hazard Ratio (HR)
    Comparison groups
    Rituximab + Lenalidomide (R^2) v Rituximab + Placebo
    Number of subjects included in analysis
    358
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Stratified Log Rank Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.71

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    TEAEs include AEs that started or worsened between the date of the first dose and 28 days after the date of the last dose. A serious adverse event (SAE) is any: • Death; • Life-threatening event; • Any inpatient hospitalization or prolongation of existing hospitalization; • Persistent or significant disability or incapacity; • Congenital anomaly or birth defect; • Any other important medical event. The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.03) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death
    End point type
    Secondary
    End point timeframe
    From first dose to 28 days post last dose (Average of 55.71 months and a maximum up to 95.2 months)
    End point values
    		 Rituximab + Lenalidomide (R^2) Rituximab + Placebo
    Number of subjects analysed
    176
    180
    Units: Participants
        Any TEAE
    174
    173
        Any TEAE Related to Lenalidomide/Placebo (LEN/PBO)
    159
    118
        Any TEAE Related to Rituximab (RIT)
    134
    105
        Any Serious TEAE
    45
    25
        Any Serious TEAE Related to LEN/PBO
    23
    8
        Any Serious TEAE Related to RIT
    13
    4
        Any CTCAE Grade (GR) 3/4 TEAE
    121
    58
        Any CTCAE GR 3/4 TEAE Related to LEN/PBO
    101
    38
        Any CTCAE GR 3/4 TEAE Related to RIT
    57
    20
        Any GR 5 TEAE
    2
    2
        Any TEAE Leading to Dose Reduction LEN/PBO
    46
    6
        Any TEAE Leading to Dose Interruption LEN/PBO
    113
    47
        Any TEAE Leading to Dose Interruption RIT
    59
    38
        Any TEAE Leading to Discontinuation of LEN/PBO
    15
    9
        Any TEAE Leading to Discontinuation of RIT
    6
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and NSAEs are collected from first dose to 28 days post last dose (Average of 55.71 months and a maximum of 95.2 months). Deaths (All-causes) was assessed from date of randomization to study completion (Up to approximately 100 months).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Rituximab + Placebo
    Reporting group description
    		 Participants received rituximab 375 mg/m^2 IV every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from cycle 2 to 5 plus placebo (identically matched capsule) once daily on Days 1 to 21 of every 28-day cycle up to 12 cycles.

    Reporting group title
    Rituximab + Lenalidomide (R^2)
    Reporting group description
    		 Participants received rituximab 375 mg/m^2 intravenously (IV) every week in Cycle 1 (Days 1, 8, 15 and 22) and on Day 1 of every 28-day cycle from Cycles 2 to 5 plus lenalidomide 20 mg by mouth (PO) once daily on Days 1 to 21 every 28 days up to 12 cycles (21-day treatment and 7-day rest period); if creatinine clearance (CrCl) was ≥ 30 mL/min but < 60 mL/min, participants received lenalidomide 10 mg capsules on days 1 to 21 every 28 days.

    Serious adverse events
    		 Rituximab + Placebo Rituximab + Lenalidomide (R^2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 180 (13.89%)
    45 / 176 (25.57%)
         number of deaths (all causes)
    47
    26
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (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
    0 / 180 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell cancer of the renal pelvis and ureter localised
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour flare
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 180 (0.56%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 180 (0.00%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related hypersensitivity reaction
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adnexal torsion
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (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
    Asthmatic crisis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 180 (1.67%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 180 (0.56%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 180 (0.00%)
    2 / 176 (1.14%)
         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
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Atrial fibrillation
         subjects affected / exposed
    2 / 180 (1.11%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 180 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 180 (0.00%)
    5 / 176 (2.84%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 180 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 180 (0.00%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         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
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 180 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seronegative arthritis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurosyphilis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         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 / 180 (3.33%)
    6 / 176 (3.41%)
         occurrences causally related to treatment / all
    2 / 7
    5 / 8
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 180 (1.11%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 180 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Rituximab + Placebo Rituximab + Lenalidomide (R^2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    158 / 180 (87.78%)
    170 / 176 (96.59%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour flare
         subjects affected / exposed
    1 / 180 (0.56%)
    18 / 176 (10.23%)
         occurrences all number
    1
    18
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 180 (6.11%)
    6 / 176 (3.41%)
         occurrences all number
    14
    7
    Hypotension
         subjects affected / exposed
    1 / 180 (0.56%)
    9 / 176 (5.11%)
         occurrences all number
    4
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    18 / 180 (10.00%)
    24 / 176 (13.64%)
         occurrences all number
    22
    28
    Chills
         subjects affected / exposed
    8 / 180 (4.44%)
    14 / 176 (7.95%)
         occurrences all number
    8
    19
    Fatigue
         subjects affected / exposed
    33 / 180 (18.33%)
    38 / 176 (21.59%)
         occurrences all number
    42
    46
    Influenza like illness
         subjects affected / exposed
    7 / 180 (3.89%)
    9 / 176 (5.11%)
         occurrences all number
    7
    10
    Malaise
         subjects affected / exposed
    10 / 180 (5.56%)
    13 / 176 (7.39%)
         occurrences all number
    10
    14
    Oedema peripheral
         subjects affected / exposed
    15 / 180 (8.33%)
    24 / 176 (13.64%)
         occurrences all number
    20
    28
    Pyrexia
         subjects affected / exposed
    27 / 180 (15.00%)
    35 / 176 (19.89%)
         occurrences all number
    35
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 180 (17.22%)
    40 / 176 (22.73%)
         occurrences all number
    43
    54
    Dyspnoea
         subjects affected / exposed
    7 / 180 (3.89%)
    18 / 176 (10.23%)
         occurrences all number
    7
    24
    Oropharyngeal pain
         subjects affected / exposed
    9 / 180 (5.00%)
    10 / 176 (5.68%)
         occurrences all number
    11
    14
    Productive cough
         subjects affected / exposed
    8 / 180 (4.44%)
    12 / 176 (6.82%)
         occurrences all number
    9
    17
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 180 (6.11%)
    14 / 176 (7.95%)
         occurrences all number
    11
    22
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 180 (8.33%)
    18 / 176 (10.23%)
         occurrences all number
    23
    31
    Lymphocyte count decreased
         subjects affected / exposed
    13 / 180 (7.22%)
    12 / 176 (6.82%)
         occurrences all number
    25
    29
    Blood bilirubin increased
         subjects affected / exposed
    0 / 180 (0.00%)
    11 / 176 (6.25%)
         occurrences all number
    0
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 180 (5.00%)
    10 / 176 (5.68%)
         occurrences all number
    14
    18
    White blood cell count decreased
         subjects affected / exposed
    14 / 180 (7.78%)
    17 / 176 (9.66%)
         occurrences all number
    34
    52
    Weight decreased
         subjects affected / exposed
    2 / 180 (1.11%)
    14 / 176 (7.95%)
         occurrences all number
    2
    15
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    24 / 180 (13.33%)
    24 / 176 (13.64%)
         occurrences all number
    36
    28
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 180 (9.44%)
    26 / 176 (14.77%)
         occurrences all number
    29
    38
    Dizziness
         subjects affected / exposed
    9 / 180 (5.00%)
    15 / 176 (8.52%)
         occurrences all number
    11
    18
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 180 (4.44%)
    28 / 176 (15.91%)
         occurrences all number
    12
    48
    Lymphopenia
         subjects affected / exposed
    14 / 180 (7.78%)
    8 / 176 (4.55%)
         occurrences all number
    21
    26
    Leukopenia
         subjects affected / exposed
    18 / 180 (10.00%)
    37 / 176 (21.02%)
         occurrences all number
    25
    140
    Neutropenia
         subjects affected / exposed
    40 / 180 (22.22%)
    103 / 176 (58.52%)
         occurrences all number
    81
    355
    Thrombocytopenia
         subjects affected / exposed
    9 / 180 (5.00%)
    26 / 176 (14.77%)
         occurrences all number
    23
    75
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    25 / 180 (13.89%)
    46 / 176 (26.14%)
         occurrences all number
    34
    71
    Abdominal pain
         subjects affected / exposed
    16 / 180 (8.89%)
    22 / 176 (12.50%)
         occurrences all number
    19
    28
    Abdominal pain upper
         subjects affected / exposed
    7 / 180 (3.89%)
    11 / 176 (6.25%)
         occurrences all number
    7
    14
    Diarrhoea
         subjects affected / exposed
    42 / 180 (23.33%)
    55 / 176 (31.25%)
         occurrences all number
    52
    111
    Dyspepsia
         subjects affected / exposed
    5 / 180 (2.78%)
    16 / 176 (9.09%)
         occurrences all number
    5
    20
    Nausea
         subjects affected / exposed
    23 / 180 (12.78%)
    21 / 176 (11.93%)
         occurrences all number
    28
    33
    Stomatitis
         subjects affected / exposed
    7 / 180 (3.89%)
    9 / 176 (5.11%)
         occurrences all number
    10
    11
    Vomiting
         subjects affected / exposed
    13 / 180 (7.22%)
    18 / 176 (10.23%)
         occurrences all number
    16
    20
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    6 / 180 (3.33%)
    9 / 176 (5.11%)
         occurrences all number
    6
    9
    Pruritus
         subjects affected / exposed
    8 / 180 (4.44%)
    33 / 176 (18.75%)
         occurrences all number
    12
    44
    Rash
         subjects affected / exposed
    9 / 180 (5.00%)
    20 / 176 (11.36%)
         occurrences all number
    10
    28
    Rash maculo-papular
         subjects affected / exposed
    4 / 180 (2.22%)
    14 / 176 (7.95%)
         occurrences all number
    4
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 180 (9.44%)
    19 / 176 (10.80%)
         occurrences all number
    23
    25
    Back pain
         subjects affected / exposed
    18 / 180 (10.00%)
    14 / 176 (7.95%)
         occurrences all number
    24
    17
    Muscle spasms
         subjects affected / exposed
    9 / 180 (5.00%)
    23 / 176 (13.07%)
         occurrences all number
    15
    28
    Myalgia
         subjects affected / exposed
    12 / 180 (6.67%)
    10 / 176 (5.68%)
         occurrences all number
    12
    14
    Infections and infestations
    Influenza
         subjects affected / exposed
    8 / 180 (4.44%)
    17 / 176 (9.66%)
         occurrences all number
    10
    17
    Pneumonia
         subjects affected / exposed
    7 / 180 (3.89%)
    14 / 176 (7.95%)
         occurrences all number
    8
    16
    Nasopharyngitis
         subjects affected / exposed
    18 / 180 (10.00%)
    13 / 176 (7.39%)
         occurrences all number
    24
    22
    Sinusitis
         subjects affected / exposed
    5 / 180 (2.78%)
    13 / 176 (7.39%)
         occurrences all number
    5
    13
    Urinary tract infection
         subjects affected / exposed
    7 / 180 (3.89%)
    12 / 176 (6.82%)
         occurrences all number
    9
    16
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 180 (12.78%)
    33 / 176 (18.75%)
         occurrences all number
    28
    48
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 180 (6.11%)
    23 / 176 (13.07%)
         occurrences all number
    12
    27
    Hyperglycaemia
         subjects affected / exposed
    11 / 180 (6.11%)
    12 / 176 (6.82%)
         occurrences all number
    16
    20
    Hyperuricaemia
         subjects affected / exposed
    8 / 180 (4.44%)
    10 / 176 (5.68%)
         occurrences all number
    15
    13
    Hypokalaemia
         subjects affected / exposed
    5 / 180 (2.78%)
    15 / 176 (8.52%)
         occurrences all number
    5
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jul 2013
    Update inclusion criteria and exploratory endpoints
    22 May 2014
    Update exclusion and inclusion criteria. Clarify treatment continuation rules and other minor clarifications/corrections.
    21 Oct 2015
    Modified inclusion criteria and revised exclusion criteria.
    13 Dec 2018
    Updated contact information. Updated follow-up frequency.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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