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    Clinical Trial Results:
    Comparing two schedules of rituximab maintenance in rituximab-responding patients with untreated, chemotherapy resistant or relapsed follicular lymphoma: A randomized phase III trial

    Summary
    EudraCT number
    		 2004-002859-13
    Trial protocol
    		 IT   SK  
    Global end of trial date
    19 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK 35/03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00227695
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer, +41 31389 91 91, sakkcc@sakk.ch
    Scientific contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer, +41 31389 91 91, sakkcc@sakk.ch
    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
    10 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to investigate if maintenance with rituximab for 5 years or until relapse/progression, unacceptable toxicity or death is superior to 4 times maintenance with rituximab.
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 None
    Evidence for comparator
    		 Not applicable; no comparator was used. The study evaluated the impact of different rituximab maintenance schedules.
    Actual start date of recruitment
    05 Aug 2004
    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
    Slovakia: 2
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    North Macedonia: 10
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    Switzerland: 73
    Worldwide total number of subjects
    165
    EEA total number of subjects
    55
    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)
    119
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between August 2004 and September 2007, 270 patients were included into the trial at 19 centers in Switzerland, 2 centers in South Africa, 1 center each in Brazil, Italy, Macedonia, Serbia and Slovakia.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was enrolled. Of the 270 registered patients, 165 patients were randomized.

    Pre-assignment period milestones
    Number of subjects started
    		 270 [1]
    Number of subjects completed
    		 165

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 PD / Relapse: 17
    Reason: Number of subjects
    		 Toxicity: 2
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 SD: 75
    Reason: Number of subjects
    		 Other: 10
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: It was planned to enroll 270 patients into the induction phase and then randomize a total of about 135 patients, in order to observe the required number of 99 events.
    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    n/a

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Rituximab 375 mg/m2 | every 2 months x 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase: Rituximab 375 mg/m2 weekly x 4 || Maintenance phase: Rituximab 375 mg/m2 every 2 months x 4

    Arm title
    		 Arm B
    Arm description
    		 Rituximab 375 mg/m2 | every 2 months for 5 years or until PD, relapse or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase: Rituximab 375 mg/m2 weekly x4 || Maintenance phase: Rituximab 375 mg/m2 every 2 months for 5 years or until PD, relapse or unacceptable toxicity.

    Number of subjects in period 1
    		Arm A Arm B
    Started
    82
    83
    Completed
    82
    83
    Period 2
    Period 2 title
    Treatment phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Rituximab 375 mg/m2 | every 2 months x 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase: Rituximab 375 mg/m2 weekly x 4 || Maintenance phase: Rituximab 375 mg/m2 every 2 months x 4

    Arm title
    		 Arm B
    Arm description
    		 Rituximab 375 mg/m2 | every 2 months for 5 years or until PD, relapse or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase: Rituximab 375 mg/m2 weekly x4 || Maintenance phase: Rituximab 375 mg/m2 every 2 months for 5 years or until PD, relapse or unacceptable toxicity.

    Number of subjects in period 2
    		Arm A Arm B
    Started
    82
    83
    Completed
    80
    46
    Not completed
    2
    37
         Relapse
    -
    5
         Consent withdrawn by subject
    -
    3
         Progressive disease (PD)
    2
    21
         Death
    -
    1
         Other
    -
    2
         2nd tumour
    -
    2
         Unacceptable toxicity
    -
    3
    Period 3
    Period 3 title
    Follow-up phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Rituximab 375 mg/m2 | every 2 months x 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase: Rituximab 375 mg/m2 weekly x 4 || Maintenance phase: Rituximab 375 mg/m2 every 2 months x 4

    Arm title
    		 Arm B
    Arm description
    		 Rituximab 375 mg/m2 | every 2 months for 5 years or until PD, relapse or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase: Rituximab 375 mg/m2 weekly x4 || Maintenance phase: Rituximab 375 mg/m2 every 2 months for 5 years or until PD, relapse or unacceptable toxicity.

    Number of subjects in period 3
    		Arm A Arm B
    Started
    80
    46
    Completed
    42
    16
    Not completed
    38
    30
         Death
    17
    16
         Lost to follow-up
    21
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months x 4

    Reporting group title
    Arm B
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months for 5 years or until PD, relapse or unacceptable toxicity

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 82 83 165
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 59 60 119
        From 65-84 years
    		 23 23 46
    Gender categorical
    Units: Subjects
        Female
    		 44 57 101
        Male
    		 38 26 64

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months x 4

    Reporting group title
    Arm B
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months for 5 years or until PD, relapse or unacceptable toxicity
    Reporting group title
    Arm A
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months x 4

    Reporting group title
    Arm B
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months for 5 years or until PD, relapse or unacceptable toxicity
    Reporting group title
    Arm A
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months x 4

    Reporting group title
    Arm B
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months for 5 years or until PD, relapse or unacceptable toxicity

    Subject analysis set title
    Arm A - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients in Arm A (ITT population)

    Subject analysis set title
    Arm B - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients in Arm B (ITT population)

    Subject analysis set title
    Arm A - PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS is a subset of patients in the ITT population (patients who took at least one dose of the trial treatment after randomization) who comply with the requirements of the protocol: (1) patients without any major protocol violation regarding inclusion/exclusion criteria for registration and randomization, (2) patients with a CR or PR as assessed by the central re-assessment at re-staging following the induction treatment, (3) centrally reviewed PD shall be considered as PD instead of PD as recorded by the centers. Reverse cases where the center assessed the patient as being PD as supposed to CR / PR / SD by the central review will be censored at this time.

    Subject analysis set title
    Arm B - PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PPS is a subset of patients in the ITT population (patients who took at least one dose of the trial treatment after randomization) who comply with the requirements of the protocol: (1) patients without any major protocol violation regarding inclusion/exclusion criteria for registration and randomization, (2) patients with a CR or PR as assessed by the central re-assessment at re-staging following the induction treatment, (3) centrally reviewed PD shall be considered as PD instead of PD as recorded by the centers. Reverse cases where the center assessed the patient as being PD as supposed to CR / PR / SD by the central review will be censored at this time.

    Subject analysis set title
    Prognostic CRP value - short term maintenance arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with baseline CRP levels (in short term maintenance).

    Subject analysis set title
    Prognostic CRP value - long term maintenance arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with baseline CRP levels (in long term maintenance).

    Primary: Primary Endpoint | Event-free survival (EFS)

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    End point title
    		 Primary Endpoint | Event-free survival (EFS)
    End point description
    EFS was defined as the period from randomization for the maintenance until one of the following events occurred: PD or relapse, unacceptable toxicity, death from any cause, initiation of non-protocol anticancer treatment or concomitant steroids introduced because of lymphoma symptoms or concomitant radiotherapy, or secondary malignancy. NOTE: UPPER VALUES FOR 95% CONFIDENCE INTERVAL FOR ARM B (ITT AND PPS) ARE "N/A". HOWEVER, DUE TO DATABASE RESTRICTIONS VALUE = "999" WAS ENTERED.
    End point type
    Primary
    End point timeframe
    EFS was defined as the period from randomization for the maintenance until event occurence.
    End point values
    		 Arm A - ITT Arm B - ITT Arm A - PPS Arm B - PPS
    Number of subjects analysed
    82
    83
    69
    71
    Units: EFS (months)
        median (confidence interval 95%)
    3.4 (2.1 to 5.3)
    5.3 (3.5 to 999)
    3.4 (2.1 to 5.9)
    5.6 (3.4 to 999)
    Statistical analysis title
    		 KM Analysis EFS | Log rank test (ITT)
    Comparison groups
    Arm A - ITT v Arm B - ITT
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1436
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 KM Analysis EFS | Log rank test (PPS)
    Comparison groups
    Arm A - PPS v Arm B - PPS
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3041
    Method
    		 Logrank
    Confidence interval

    Secondary: Secondary Endpoint | Progression free survival (PFS)

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    End point title
    		 Secondary Endpoint | Progression free survival (PFS)
    End point description
    Patients not experiencing an event were censored at the last known time they were alive without PD or relapse (i.e. last date of tumor assessment). NOTE: UPPER VALUES FOR 95% CI ARE "N/A". HOWEVER, DUE TO DATABASE RESTRICTIONS VALUE "999" WAS ENTERED.
    End point type
    Secondary
    End point timeframe
    Time from randomization to relapse/progression or death from NHL (Non-Hodgkin’s Lymphoma).
    End point values
    		 Arm A - ITT Arm B - ITT
    Number of subjects analysed
    82
    83
    Units: PFS (months)
        median (confidence interval 95%)
    3.5 (2.1 to 5.9)
    7.4 (5.1 to 999)
    Statistical analysis title
    		 KM Analysis PFS | Log rank test (ITT)
    Comparison groups
    Arm A - ITT v Arm B - ITT
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0388
    Method
    		 Logrank
    Confidence interval

    Secondary: Secondary Endpoint | Overall survival (OS)

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    End point title
    		 Secondary Endpoint | Overall survival (OS)
    End point description
    Patients not experiencing an event were censored at the last known time they were alive. NOTE: UPPER VALUES FOR 95% CI ARE "N/A". HOWEVER, DUE TO DATABASE RESTRICTIONS VALUE "999" WAS ENTERED.
    End point type
    Secondary
    End point timeframe
    OS was calculated from randomization until death from any cause.
    End point values
    		 Arm A - ITT Arm B - ITT
    Number of subjects analysed
    82
    83
    Units: OS (months)
        median (confidence interval 95%)
    8.1 (8.1 to 999)
    7.8 (7.8 to 999)
    Statistical analysis title
    		 KM Analysis OS | Log rank test (ITT)
    Comparison groups
    Arm A - ITT v Arm B - ITT
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6336
    Method
    		 Logrank
    Confidence interval

    Secondary: Secondary Endpoint | Objective Response (OR)

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    End point title
    		 Secondary Endpoint | Objective Response (OR)
    End point description
    Objective response (OR) was defined as the observed best response (CR [complete response], CRu [complete unconfirmed response], PR [partial response], SD [stable disease], PD [progressive disease]) as assessed following the criteria of Cheson et al 1999 (1) after randomization and before switching to another treatment.
    End point type
    Secondary
    End point timeframe
    From randomization until switching to another treatment.
    End point values
    		 Arm A - ITT Arm B - ITT
    Number of subjects analysed
    82
    82 [1]
    Units: Pts with best response CR, CRu or PR (%)
        number (confidence interval 95%)
    93.9 (86.3 to 98.0)
    87.8 (78.7 to 94.0)
    Notes
    [1] - One patient did not have post-randomization tumor assessment.
    Statistical analysis title
    		 OR | Fisher's exact test (ITT)
    Comparison groups
    Arm A - ITT v Arm B - ITT
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2784
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary Endpoint | Prognostic value of baseline CRP for EFS (ITT)

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    End point title
    		 Secondary Endpoint | Prognostic value of baseline CRP for EFS (ITT)
    End point description
    Prognostic value of baseline CRP for EFS (only patients still at risk after 8 months from randomization) and PFS.
    End point type
    Secondary
    End point timeframe
    From randomization until event (see EFS and PFS for details).
    End point values
    		 Prognostic CRP value - short term maintenance arm Prognostic CRP value - long term maintenance arm
    Number of subjects analysed
    68
    62
    Units: Patients (n)
        CRP elevated
    12
    7
        CRP not elevated
    56
    55
    Statistical analysis title
    		 Hazard ratio (baseline CRP) - EFS
    Statistical analysis description
    Hazard ratio (baseline CRP elevated vs not elevated)
    Comparison groups
    Prognostic CRP value - short term maintenance arm v Prognostic CRP value - long term maintenance arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2022
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.462
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.816
         upper limit
    		 2.621
    Statistical analysis title
    		 Hazard ratio (treatment) - EFS
    Statistical analysis description
    Hazard ratio (treatment long term maintenance vs short term maintenance)
    Comparison groups
    Prognostic CRP value - short term maintenance arm v Prognostic CRP value - long term maintenance arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0665
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.658
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.029
    Statistical analysis title
    		 Hazard ratio (baseline CRP) - PFS
    Statistical analysis description
    Hazard ratio (baseline CRP elevated vs not elevated)
    Comparison groups
    Prognostic CRP value - short term maintenance arm v Prognostic CRP value - long term maintenance arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0188
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.863
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.109
         upper limit
    		 3.13
    Statistical analysis title
    		 Copy of Hazard ratio (treatment) - PFS
    Statistical analysis description
    Hazard ratio (treatment long term maintenance vs short term maintenance)
    Comparison groups
    Prognostic CRP value - short term maintenance arm v Prognostic CRP value - long term maintenance arm
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1667
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.736
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.477
         upper limit
    		 1.136

    Secondary: Secondary Endpoint | Molecular remission (Swiss centers only)

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    End point title
    		 Secondary Endpoint | Molecular remission (Swiss centers only)
    End point description
    Blood (PB): The absence of t(14;18) positive cells in blood, in patients with a positive result before registration, after induction treatment with rituximab, at 6 and 12 months since randomization during maintenance treatment and every 12 months after the end of the treatment until relapse/progression. Bone marrow (BM): The absence of t(14;18) positive cells in bone marrow, in patients with a positive result before registration, after induction treatment with rituximab, at 12 months since randomization during maintenance treatment and every 12 months after the end of the treatment until relapse/progression. Duration of molecular remission was calculated from the first demonstration of t(14;18) negativity in bone marrow and peripheral blood until the demonstration of t(14;18) positivity for patients who were positive prior to registration.
    End point type
    Secondary
    End point timeframe
    After induction of treatment until relapse/progression.
    End point values
    		 Arm A - ITT Arm B - ITT
    Number of subjects analysed
    37 [2]
    36 [3]
    Units: patients || days
    number (not applicable)
        PB: t(14;18) positive cells at BSL (pts.)
    17
    19
        PB: t(14;18) negativity (pts.)
    16
    19
        PB: Median time to MR (days)
    85.5
    91
        PB: Molecular relapse (pts.)
    1
    2
        BM: t(14;18) positive cells at BSL (pts.)
    10
    9
        BM: t(14;18) negativity (pts.)
    8
    7
        BM: Median time to MR (days)
    456
    433
        BM: Molecular relapse (pts.)
    1
    0
    Notes
    [2] - Only patiens at swiss centers.
    [3] - Only patients at swiss centers.
    No statistical analyses for this end point

    Secondary: Secondary Endpoint |Immunophenotyping analysis (Swiss centers only)

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    End point title
    		 Secondary Endpoint |Immunophenotyping analysis (Swiss centers only)
    End point description
    The evolution over time of the concentration of CD19+ B-lymphocytes in the peripheral blood.
    End point type
    Secondary
    End point timeframe
    From randomization at various time points.
    End point values
    		 Arm A - ITT Arm B - ITT
    Number of subjects analysed
    37 [4]
    36 [5]
    Units: Samples, n
    37
    36
    Attachments
    		 CD19+ B lymphocytes (cells/μl)
    Notes
    [4] - Patients from swiss centers only.
    [5] - Patients from swiss centers only.
    No statistical analyses for this end point

    Other pre-specified: Primary Endpoint | Event-free survival (EFS) at 3 and 5 years

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    End point title
    		 Primary Endpoint | Event-free survival (EFS) at 3 and 5 years
    End point description
    End point type
    Other pre-specified
    End point timeframe
    EFS probability at 3 years and 5 years.
    End point values
    		 Arm A - ITT Arm B - ITT
    Number of subjects analysed
    82
    83
    Units: EFS probability (%)
    number (confidence interval 95%)
        3-year EFS probability
    54.5 (42.9 to 64.8)
    62.7 (51.3 to 72.1)
        5-year EFS probability
    41.8 (30.5 to 52.6)
    52.8 (41.5 to 62.9)
    Statistical analysis title
    		 3-year EFS probability
    Comparison groups
    Arm A - ITT v Arm B - ITT
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.2958
    Method
    		 cloglog
    Confidence interval
    Notes
    [6] - cloglog-Test
    Statistical analysis title
    		 5-year EFS probability
    Comparison groups
    Arm A - ITT v Arm B - ITT
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.1657
    Method
    		 cloglog
    Confidence interval
    Notes
    [7] - cloglog-Test

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Events are reported from time of randomization until end of study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months x4

    Reporting group title
    Arm B
    Reporting group description
    		 Rituximab 375 mg/m2 | every 2 months for 5 years or until PD, relapse or unacceptable toxicity

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 82 (13.41%)
    20 / 83 (24.10%)
         number of deaths (all causes)
    17
    16
         number of deaths resulting from adverse events
    3
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    2 / 82 (2.44%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Basal cell carcinoma
    Additional description: One of these events (Arm B): Cutaneous basal cell carcinoma (face) with curative complete resection
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease stage IV
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive breast carcinoma
    Additional description: One of these events (Arm B): Invasive breast carcinoma and mastectomy
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
    Additional description: One of these events (Arm B): Hormone receptor positive invasive ductal breast cancer
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         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
    1 / 82 (1.22%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sarcoma
    Additional description: Sarcoma and sarcoma excision
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
    Additional description: Inguinal pain, deep vein thrombosis (v. femoris profunda) and local infection with normal absolute neutrophil count
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Meniscus removal
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
    Additional description: Headache, migraine
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
    Additional description: Cystitis, epididymitis, prostatitis
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
    Additional description: Ileus, acute abdomen and peritonitis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Abdominal pain upper
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (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 distress syndrome
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Non-cirrhotic portal hypertension
    Additional description: Idiopathic portal hypertension (IPH) and hepatopathy
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin infection
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: One of these events (Arm B): Pneumonia with fever
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 83 (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
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 82 (50.00%)
    63 / 83 (75.90%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 82 (0.00%)
    8 / 83 (9.64%)
         occurrences all number
    0
    9
    Hot flush
         subjects affected / exposed
    2 / 82 (2.44%)
    8 / 83 (9.64%)
         occurrences all number
    2
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 82 (1.22%)
    7 / 83 (8.43%)
         occurrences all number
    1
    7
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 82 (0.00%)
    7 / 83 (8.43%)
         occurrences all number
    0
    7
    Headache
         subjects affected / exposed
    2 / 82 (2.44%)
    6 / 83 (7.23%)
         occurrences all number
    2
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 82 (8.54%)
    20 / 83 (24.10%)
         occurrences all number
    8
    28
    Pyrexia
         subjects affected / exposed
    3 / 82 (3.66%)
    8 / 83 (9.64%)
         occurrences all number
    3
    10
    Oedema peripheral
         subjects affected / exposed
    3 / 82 (3.66%)
    6 / 83 (7.23%)
         occurrences all number
    3
    8
    Influenza like illness
         subjects affected / exposed
    1 / 82 (1.22%)
    14 / 83 (16.87%)
         occurrences all number
    1
    16
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 82 (2.44%)
    13 / 83 (15.66%)
         occurrences all number
    2
    19
    Nausea
         subjects affected / exposed
    5 / 82 (6.10%)
    6 / 83 (7.23%)
         occurrences all number
    5
    8
    Abdominal pain
         subjects affected / exposed
    2 / 82 (2.44%)
    10 / 83 (12.05%)
         occurrences all number
    2
    14
    Respiratory, thoracic and mediastinal disorders
    Laryngeal pain
         subjects affected / exposed
    1 / 82 (1.22%)
    6 / 83 (7.23%)
         occurrences all number
    1
    8
    Cough
         subjects affected / exposed
    6 / 82 (7.32%)
    24 / 83 (28.92%)
         occurrences all number
    6
    34
    Dyspnoea
         subjects affected / exposed
    2 / 82 (2.44%)
    5 / 83 (6.02%)
         occurrences all number
    2
    7
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 82 (3.66%)
    9 / 83 (10.84%)
         occurrences all number
    3
    10
    Rash
         subjects affected / exposed
    2 / 82 (2.44%)
    7 / 83 (8.43%)
         occurrences all number
    2
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 82 (2.44%)
    6 / 83 (7.23%)
         occurrences all number
    2
    6
    Depression
         subjects affected / exposed
    2 / 82 (2.44%)
    5 / 83 (6.02%)
         occurrences all number
    2
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 82 (2.44%)
    9 / 83 (10.84%)
         occurrences all number
    2
    10
    Pain in extremity
         subjects affected / exposed
    3 / 82 (3.66%)
    9 / 83 (10.84%)
         occurrences all number
    3
    11
    Arthralgia
         subjects affected / exposed
    5 / 82 (6.10%)
    12 / 83 (14.46%)
         occurrences all number
    5
    13
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 82 (0.00%)
    8 / 83 (9.64%)
         occurrences all number
    0
    9
    Influenza
         subjects affected / exposed
    2 / 82 (2.44%)
    6 / 83 (7.23%)
         occurrences all number
    2
    8
    Sinusitis
         subjects affected / exposed
    0 / 82 (0.00%)
    5 / 83 (6.02%)
         occurrences all number
    0
    5
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 82 (2.44%)
    8 / 83 (9.64%)
         occurrences all number
    2
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26712227
    http://www.ncbi.nlm.nih.gov/pubmed/33275769
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