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    Clinical Trial Results:
    A Two-Stage Phase III, International, Multi-Center, Randomized, Controlled, Open-Label Study to Investigate the Pharmacokinetics, Efficacy and Safety of Rituximab SC in Combination With CHOP or CVP Versus Rituximab IV in Combination With CHOP or CVP in Patients With Previously Untreated Follicular Lymphoma Followed by Maintenance Treatment With Either Rituximab SC or Rituximab IV

    Summary
    EudraCT number
    		 2010-021377-36
    Trial protocol
    		 ES   GB   BE   SK   IT   DK   DE   FR   FI   GR   BG  
    Global end of trial date
    31 Oct 2017

    Results information
    Results version number
    		 v4(current)
    This version publication date
    14 Nov 2018
    First version publication date
    06 Aug 2015
    Other versions
    		 v1 , v2 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    BO22334
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01200758
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.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
    31 Oct 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a two-stage, Phase III, international, multicenter, randomized, controlled, open-label study to investigate the pharmacokinetic (PK), efficacy, and safety of rituximab subcutaneous (SC) in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) or cyclophosphamide, vincristine, prednisolone (CVP) versus rituximab intravenous (IV) in combination with CHOP or CVP in participants with previously untreated follicular lymphoma (FL) followed by maintenance treatment with either rituximab SC or rituximab IV.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Feb 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    Spain: 53
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Denmark: 23
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Italy: 40
    Country: Number of subjects enrolled
    Thailand: 9
    Country: Number of subjects enrolled
    Serbia: 17
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Peru: 4
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 2
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 2
    Country: Number of subjects enrolled
    Croatia: 8
    Country: Number of subjects enrolled
    Georgia: 8
    Country: Number of subjects enrolled
    New Zealand: 9
    Worldwide total number of subjects
    410
    EEA total number of subjects
    250
    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)
    301
    From 65 to 84 years
    103
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening/baseline tests were performed within 28 days before randomization. Randomization was centralized in a 1:1 fashion using the Pocock and Simon dynamic randomization algorithm. The study was conducted in 2 stages: Stage I & II. All participants irrespective of the treatment period completion commenced follow-up period in both Stage I and II.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)
    Arm description
    		 Eight cycles of rituximab IV infusion (375 milligrams per square meter [mg/m^2]; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least partial response (PR) during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 375 mg/m^2 rituximab IV every 3 weeks for 8 cycles (the first cycle of rituximab was given on Day 0, Day 1, or Day 2, depending on institutional practice) and then maintenance therapy (375 mg/m^2) once every 8 weeks up to 24 months for participants who achieved at least PR.

    Arm title
    		 Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Arm description
    		 First cycle of rituximab IV (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 375 mg/m^2 rituximab IV for Cycle 1 followed by 1400 mg SC every 3 weeks for 7 cycles and then maintenance therapy (1400 mg SC) once every 8 weeks up to 24 months for participants who achieved at least PR.

    Arm title
    		 Stage II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Arm description
    		 Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received 375 mg/m^2 rituximab IV every 3 weeks for 8 cycles (the first cycle of rituximab was given on Day 0, Day 1, or Day 2, depending on institutional practice) and then maintenance therapy (375 mg/m^2) once every 8 weeks up to 24 months for participants who achieved at least PR.

    Arm title
    		 Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Arm description
    		 First cycle of rituximab IV (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 375 mg/m^2 rituximab IV for Cycle 1 followed by 1400 mg SC every 3 weeks for 7 cycles and then maintenance therapy (1400 mg SC) once every 8 weeks up to 24 months for participants who achieved at least PR.

    Number of subjects in period 1
    		Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) Stage II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Started
    64
    63
    141
    142
    Completed
    46
    46
    100
    92
    Not completed
    18
    17
    41
    50
         Consent withdrawn by subject
    1
    2
    4
    1
         Physician decision
    1
    1
    5
    7
         Disease progression
    9
    7
    16
    21
         Adverse event, non-fatal
    5
    5
    5
    9
         Death
    -
    1
    3
    5
         Lost to follow-up
    -
    -
    3
    1
         Lack of efficacy
    2
    1
    4
    2
         Protocol deviation
    -
    -
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 410
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ( 12.67 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 219 219
        Male
    		 191 191
    Subject analysis sets

    Subject analysis set title
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.

    Subject analysis set title
    Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    First cycle rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC 1400 mg in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.

    Subject analysis set title
    All Participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP): First cycle rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC 1400 mg in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months. Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP): Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.

    Subject analysis sets values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP) All Participants
    Number of subjects
    205
    205
    410
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    56.9 ( 12.69 )
    56.1 ( 12.66 )
    56.5 ( 12.67 )
    Gender, Male/Female
    Units: Subjects
        Female
    99
    120
    219
        Male
    106
    85
    191

    End points

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    End points reporting groups
    Reporting group title
    Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)
    Reporting group description
    		 Eight cycles of rituximab IV infusion (375 milligrams per square meter [mg/m^2]; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least partial response (PR) during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.

    Reporting group title
    Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Reporting group description
    		 First cycle of rituximab IV (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.

    Reporting group title
    Stage II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Reporting group description
    		 Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.

    Reporting group title
    Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Reporting group description
    		 First cycle of rituximab IV (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.

    Subject analysis set title
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.

    Subject analysis set title
    Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    First cycle rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC 1400 mg in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.

    Subject analysis set title
    All Participants
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP): First cycle rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC 1400 mg in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months. Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP): Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.

    Primary: Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab

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    End point title
    		 Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab [1]
    End point description
    Stage I PK Evaluable Population comprised all participants with data for Ctrough available at Cycle 7 and/or observed area under the serum concentration-time curve (AUC) available at Cycle 7. Participants were analyzed as per treatment received. Number of participants analyzed = participants analyzed for this outcome measure.
    End point type
    Primary
    End point timeframe
    Stage I: Cycle (Cy) 7 Day (D) 21 (within 2 hours predose on Cy8) of induction treatment (1 Cy=3 weeks)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported
    End point values
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    48
    54
    Units: micrograms per milliliter (mcg/mL)
        geometric mean (geometric coefficient of variation)
    83.1 ( 36.7 )
    134.6 ( 43.2 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) vs Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)
    Comparison groups
    Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.62
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.36
         upper limit
    		 1.94
    Notes
    [2] - Non-inferior Ctrough in SC formulation was demonstrated, if the lower bound of 90% confidence interval (CI) was above 0.8.

    Primary: Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for Non-Hodgkin lymphoma (NHL)

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    End point title
    		 Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for Non-Hodgkin lymphoma (NHL) [3]
    End point description
    Overall Response comprised complete response (CR), CR unconfirmed (CRu), or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and computed tomography (CT) scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by more than (>) 75% in the sum of the products of greatest diameters (SPD); PR: Greater than or equal to (≥) 50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper. Stage II ITT population included all participants who were randomized in Stage II irrespective whether they received study drug or not.
    End point type
    Primary
    End point timeframe
    Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported
    End point values
    		 Stage II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    141
    142
    Units: percentage of participants
        number (confidence interval 95%)
    85.1 (78.1 to 90.5)
    80.3 (72.8 to 86.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment. The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.
    Comparison groups
    Stage II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2835
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    -4.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 4.4
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.33

    Secondary: Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL [4]
    End point description
    Overall Response comprised CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in the SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper. Stage I ITT Population included all participants who were randomized in Stage I irrespective whether they received study drug or not.
    End point type
    Secondary
    End point timeframe
    Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported
    End point values
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    64
    63
    Units: percentage of participants
        number (confidence interval 95%)
    82.8 (71.3 to 91.1)
    90.5 (80.4 to 96.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL. The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.
    Comparison groups
    Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2047
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    7.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 20.3
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 5.71

    Secondary: Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
    End point description
    Overall Response comprised of CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumour response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper. ITT population.
    End point type
    Secondary
    End point timeframe
    Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    205
    205
    Units: percentage of participants
        number (confidence interval 95%)
    84.9 (79.2 to 89.5)
    84.4 (78.7 to 89.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage I and II: Overall Response of CR, CRu, or PR at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL. The 95% CI for the difference in response rates was estimated using the Hauck-Anderson.
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8911
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.7
         upper limit
    		 6.8
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.65

    Secondary: Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL [5]
    End point description
    Complete Response was comprised CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI was estimated for one sample binomial using Pearson-Clopper. Stage I ITT population.
    End point type
    Secondary
    End point timeframe
    Stage I: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported
    End point values
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    64
    63
    Units: percentage of participants
        number (confidence interval 95%)
    25.0 (15.0 to 37.4)
    42.9 (30.5 to 56.0)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 4.78
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL. The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.
    Comparison groups
    Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0335
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    17.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 35

    Secondary: Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL [6]
    End point description
    Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper. Stage II ITT population.
    End point type
    Secondary
    End point timeframe
    Stage II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported
    End point values
    		 Stage II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    141
    142
    Units: percentage of participants
        number (confidence interval 95%)
    34.8 (26.9 to 43.2)
    28.2 (20.9 to 36.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL. The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.
    Comparison groups
    Stage II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2331
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    -6.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.8
         upper limit
    		 4.6
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    283
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.22

    Secondary: Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
    End point description
    Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper. ITT population.
    End point type
    Secondary
    End point timeframe
    Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    205
    205
    Units: percentage of participants
        number (confidence interval 95%)
    31.7 (25.4 to 38.6)
    32.2 (25.9 to 39.1)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.51
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment Assessed Using International Working Group Response Criteria for NHL. The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9157
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 9.8

    Secondary: Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL
    End point description
    Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD. ITT population; only participants who entered the maintenance phase and received at least 1 cycle of rituximab maintenance treatment from Cycle 9 to Cycle 20 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Stage I and II: Baseline up to 57 days after last maintenance dose (last maintenance dose: maintenance Cy12/Study Cy20 [30 months]) (up to data cutoff of 31 Oct 2017 [up to 6 years]) (1 Cy=8 weeks)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    178
    172
    Units: percentage of participants
        number (confidence interval 95%)
    57.9 (50.4 to 65.2)
    50.6 (42.9 to 58.3)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL.
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.22
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL. The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1715
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    -7.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18
         upper limit
    		 3.5

    Secondary: Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL
    End point description
    Overall Response comprised of CR, CRu, or PR . A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumour response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper. ITT population; only participants who entered the maintenance phase and received at least 1 cycle of rituximab maintenance treatment from Cycle 9 to Cycle 20 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Stage I and II: Baseline up to 57 days after last maintenance dose (last maintenance dose: maintenance Cy12/Study Cy20 [30 months]) (1 Cy=8 weeks)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    178
    172
    Units: percentage of participants
        number (confidence interval 95%)
    78.1 (71.3 to 83.9)
    77.9 (71.0 to 83.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL. The 95% CI for the difference in response rates was estimated using the Hauck-Anderson method.
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9671
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 8.8
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.64

    Secondary: Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL
    End point description
    PFS: time from randomization to PD/relapse or death due to any cause, analyzed using Kaplan-Meier curves. If the specified event (PD/relapse, death) did not occur, PFS was censored at the last tumor assessment date showing no PD, either during treatment or follow-up. Disease progression: Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node >1 cm in its short axis or in the SPD of more than one node. Data for median and corresponding 95% CI were not reached due to <50% of participants with event of interest, therefore '99999' are reported. Baseline, D1 of Cy 1-20 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented PD/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])
    End point type
    Secondary
    End point timeframe
    Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    205
    205
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Progression-Free Survival (PFS)
    Statistical analysis description
    Stage 1 and II (Pooled): Progression-Free Survival (PFS) Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5526
    Method
    		 Wald test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.26

    Secondary: Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse or Death Assessed Using International Working Group Response Criteria for NHL
    End point description
    Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node >1 cm in its short axis or in the SPD of more than one node. Here, number of participants analyzed = participants who were evaluable for this outcome measure. ITT population. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])
    End point type
    Secondary
    End point timeframe
    Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    205
    205
    Units: percentage of participants
        number (not applicable)
    34.6
    31.7
    No statistical analyses for this end point

    Secondary: Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL
    End point description
    Event-free survival was defined as the time from randomization to disease progression/relapse, death or initiation of new NHL therapy treatment. If the specified event (progression/relapse, death or new NHL treatment) did not occur, event-free survival was censored at the last tumor assessment date either during treatment or follow up. Event-free survival analysis was performed using Kaplan-Meier curves. ITT population. Data for median and upper limit of 95% CI were not reached due to low number (<50%) of participants with event of interest, therefore '99999' are reported to reflect not available (NA) data for median and upper range of 95% CI values. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])
    End point type
    Secondary
    End point timeframe
    Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    205
    205
    Units: days
        median (confidence interval 95%)
    99999 (2126 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Stage I and II (Pooled): Event-Free Survival
    Statistical analysis description
    Stage I and II (Pooled): Event-Free Survival Assessed Using International Working Group Response Criteria for NHL
    Comparison groups
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9115
    Method
    		 Wald test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.36

    Secondary: Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse, New Anti-Lymphoma Treatment or Death Assessed Using International Working Group Response Criteria for NHL

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Disease Progression/Relapse, New Anti-Lymphoma Treatment or Death Assessed Using International Working Group Response Criteria for NHL
    End point description
    Disease progression: ≥50% increase from nadir in the SPD of any previously identified abnormal node or appearance of any new lesion during or at the end of therapy or ≥50% increase in the greatest diameter of any previously identified node >1 cm in its short axis or in the SPD of more than one node. Here, number of participants analyzed = participants who were evaluable for this outcome measure. ITT population. Baseline, D1 of all cycles (Cy 1-20) (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 31 Oct 2017 [up to 6 years])
    End point type
    Secondary
    End point timeframe
    Baseline up to disease progression or death up to data cutoff of 31 Oct 2017 (up to 6 years) (See detailed timeframe in Outcome Measure description)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    205
    205
    Units: percentage of participants
        number (not applicable)
    36.1
    35.1
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without event were censored at the time of last follow-up information for survival, ie, at the last time known to be alive. ITT population. Data for median and corresponding 95% CI were not reached due to low number (<10%) of participants with event of interest, therefore '99999' are reported to reflect not available (NA) data for median and corresponding 95% CI values.
    End point type
    Secondary
    End point timeframe
    Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    205
    205
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Stage 1: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab

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    End point title
    		 Stage 1: Observed Area Under the Serum Concentration-Time Curve (AUC) of Rituximab [7]
    End point description
    AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. PK evaluable population. Here, number of participants analyzed = participants evaluable for this outcome measure. Predose (within 2 hr) and 24 hrs postdose on Cy 7 (D1,3,7,15), predose (within 2 hr) on Cy 8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy 7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 [up to 26 months])
    End point type
    Secondary
    End point timeframe
    Stage I (Induction): Predose (within 2hr) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported
    End point values
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    58
    55
    Units: mcg*day/mL
        geometric mean (geometric coefficient of variation)
    2734.21 ( 32.51 )
    3778.93 ( 37.59 )
    Statistical analysis title
    		 Stage 1: AUC of Rituximab
    Statistical analysis description
    The ratio of observed rituximab serum was determined as AUC SC/AUC IV during Cycle 7 of induction treatment.
    Comparison groups
    Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.38
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.24
         upper limit
    		 1.53

    Secondary: Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab

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    End point title
    		 Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab [8]
    End point description
    Predose (within 2 hr) and 24 hrs postdose on Cy 7 (D1,3,7,15), predose (within 2 hr) on Cy 8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion (infusion duration=30 minutes) on Cy 7 D1 for rituximab IV (up to data cutoff of 11 Apr 2012 [up to 26 months])
    End point type
    Secondary
    End point timeframe
    Stage I (Induction): Predose (within 2hr) up to data cutoff of 11 Apr 2012 [up to 26 months]) (See detailed timeframe in Outcome Measure description)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported
    End point values
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    58
    59
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    250.63 ( 19.66 )
    236.82 ( 31.45 )
    Statistical analysis title
    		 Stage I: Cmax of IV and SC Rituximab
    Comparison groups
    Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) v Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.941
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.872
         upper limit
    		 1.015

    Secondary: Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle

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    End point title
    		 Stage I and II (Pooled): Ctrough of Rituximab at Each Induction Treatment Cycle
    End point description
    Stage I and II (Induction): Rituximab IV: Predose (within 2 hr) on D1 of Cy1-8 (1 Cy=3 weeks & 4 weeks for Cy8); Rituximab SC: Predose (within 2 hr) on D1 of Cy1 & Cy3-8 (1 Cy=3 weeks and 4 weeks for Cy8), predose (within 2 hr) on D0 of Cy2 (up to data cutoff of 31 Oct 2013 [up to 32 months])
    End point type
    Secondary
    End point timeframe
    Stage I and II (induction): Predose (within 2hr) up to data cutoff of 31 Oct 2013 [up to 32 months]) (See detailed timeframe in Outcome Measure description)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    155
    154
    Units: mcg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n = 198, 193)
    14.00 ( 157.53 )
    12.88 ( 189.70 )
        Cycle 2 (n = 197, 190)
    30.13 ( 145.36 )
    40.00 ( 124.50 )
        Cycle 3 (n = 192, 190)
    45.25 ( 110.35 )
    63.83 ( 101.83 )
        Cycle 4 (n = 186, 185)
    54.06 ( 108.90 )
    81.71 ( 92.28 )
        Cycle 5 (n = 185, 185)
    64.68 ( 89.90 )
    98.00 ( 71.91 )
        Cycle 6 (n = 187, 180)
    71.02 ( 87.60 )
    109.56 ( 58.74 )
        Cycle 7 (n = 183, 172)
    80.7 ( 40.7 )
    122.2 ( 43.8 )
        Cycle 8 (n = 52, 54)
    77.60 ( 70.53 )
    131.48 ( 50.20 )
    No statistical analyses for this end point

    Secondary: Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle

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    End point title
    		 Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle
    End point description
    Stage I and II (maintenance): D29 of Cy8 (induction; 1 Cy=4 weeks), predose (within 2 hr) on D1 of Cy 9 to 19 (maintenance Cycle 1 to 12 [1 Cy=8 weeks]; up to data cutoff of 11 Jan 2016 [up to 6 years]). ITT Population. Here, number of participants analyzed = participants evaluable for the outcome measure. Here "n" = number of participants evaluable for this outcome measure at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Stage I and II (maintenance): Predose (within 2hr) up to data cutoff of 11 Jan 2016 [up to 6 years]) (See detailed timeframe in Outcome Measure description)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    174
    170
    Units: mcg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 8 (n = 174, 170)
    37.69 ( 94.30 )
    61.31 ( 65.52 )
        Cycle 9 (n = 171, 168)
    30.35 ( 75.03 )
    49.47 ( 81.23 )
        Cycle 10 (n = 164, 160)
    28.44 ( 84.64 )
    47.27 ( 73.03 )
        Cycle 11 (n = 164, 157)
    28.77 ( 65.28 )
    46.70 ( 66.80 )
        Cycle 12 (n = 160, 150)
    28.80 ( 56.97 )
    44.72 ( 68.74 )
        Cycle 13 (n = 157, 150)
    28.84 ( 54.04 )
    44.32 ( 67.67 )
        Cycle 14 (n = 153, 147)
    28.09 ( 55.61 )
    43.32 ( 67.97 )
        Cycle 15 (n = 148, 143)
    28.19 ( 52.69 )
    44.11 ( 67.92 )
        Cycle 16 (n = 150, 145)
    28.05 ( 57.19 )
    42.96 ( 64.32 )
        Cycle 17 (n = 149, 143)
    28.24 ( 57.51 )
    42.82 ( 65.67 )
        Cycle 18 (n = 143, 132)
    28.59 ( 62.06 )
    44.79 ( 68.56 )
        Cycle 19 (n = 138, 131)
    27.75 ( 78.26 )
    43.69 ( 69.02 )
    No statistical analyses for this end point

    Secondary: Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration

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    End point title
    		 Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration
    End point description
    Safety Analysis Population included all participants who received at least one dose of rituximab, either IV or SC. Participants were analyzed as treated. Here, number of participants analyzed = participants evaluable for the outcome measure. Here “n”= participants who were evaluable for each category, for respective arm groups.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks, and 36 weeks after the last rituximab administration (up to data cutoff of 11 Jan 2016 [up to 6 years])
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    117
    118
    Units: mcg/mL
    median (full range (min-max))
        Week 12: Follow-up Visit 1 (n = 117, 118)
    15.60 (0.70 to 80.40)
    22.35 (0.65 to 107.00)
        Week 24: Follow-up Visit 2 (n = 88, 96)
    2.89 (0.58 to 17.40)
    5.19 (0.69 to 62.10)
        Week 36: Follow-up Visit 3 (n = 38, 53)
    1.08 (0.52 to 51.40)
    2.02 (0.53 to 33.90)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase

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    End point title
    		 Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase
    End point description
    Depletion is defined as a cluster of differentiation (CD) 19 value <80 cells per cubic millimeter (cells/mm^3). ITT Population. Here, number of participants analyzed = participants evaluable for the outcome measure. Here "n" = number of participants evaluable for this outcome measure at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Time Frame: Stage I and II (induction): for rituximab IV - D1 of Cy 1 to 8 (1 Cy=3 weeks); for rituximab SC - D1 of Cy 1 and Cy 3 to 8, D0 of Cy2
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    188
    180
    Units: percentage of participants
    number (not applicable)
        Cycle 1 Day 1 - Baseline (n=188, 168)
    51.6
    54.8
        Cycle 2 Day 0 (n=183, 180)
    95.1
    95.0
        Cycle 3 Day 1 (n=175, 175)
    99.4
    99.4
        Cycle 4 Day 1 (n=178, 180)
    99.4
    100.0
        Cycle 5 Day 1 (n=179, 176)
    100.0
    100.0
        Cycle 6 Day 1 (n=173, 175)
    100.0
    100.0
        Cycle 7 Day 1 (n=178, 173)
    100.0
    100.0
        Cycle 8 Day 1 (n=175, 174)
    100.0
    100.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase

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    End point title
    		 Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase
    End point description
    Depletion is defined as a CD19 value <80 cells/mm^3. ITT Population. Here, number of participants analyzed = participants evaluable for the outcome measure. Here "n" = number of participants evaluable for this outcome measure at specified timepoint.
    End point type
    Secondary
    End point timeframe
    Stage I and II (maintenance): D1 of Cy 9 to 20 (1 Cy=8 weeks) (up to data cutoff of 11 Jan 2016 [up to 6 years])
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    170
    164
    Units: percentage of participants
    number (not applicable)
        Cycle 9 Day 1 (n=170, 161)
    99.4
    100.0
        Cycle 10 Day 1 (n=165, 164)
    99.4
    100.0
        Cycle 11 Day 1 (n=158, 158)
    99.4
    100.0
        Cycle 12 Day 1 (n=151, 146)
    100.0
    100.0
        Cycle 13 Day 1 (n=149, 141)
    100.0
    100.0
        Cycle 14 Day 1 (n=152, 143)
    100.0
    100.0
        Cycle 15 Day 1 (n=149, 140)
    100.0
    100.0
        Cycle 16 Day 1 (n=142, 141)
    100.0
    100.0
        Cycle 17 Day 1 (n=145, 142)
    100.0
    100.0
        Cycle 18 Day 1 (n=141, 140)
    100.0
    100.0
        Cycle 19 Day 1 (n=140, 138)
    100.0
    100.0
        Cycle 20 Day 1 (n=139, 134)
    100.0
    100.0
    No statistical analyses for this end point

    Secondary: Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) to Rituximab
    End point description
    Levels of HACA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Safety Analysis Population: included 6 participants who were randomized under Rituximab SC arm but withdrew after Cy1 and then analyzed under Rituximab IV arm. Here, number of participants analyzed = participants evaluable for the outcome measure. Here "n" = number of participants evaluable for this outcome measure at specified timepoint. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 [up to 6 years])
    End point type
    Secondary
    End point timeframe
    Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    208
    197
    Units: percentage of participants
    number (not applicable)
        Baseline (n=208, 191)
    5.8
    2.6
        Post-Baseline (n=206, 197)
    1.5
    2.0
    No statistical analyses for this end point

    Secondary: Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Human Antibodies (HAHAs) to Rituximab
    End point description
    Levels of HAHA in serum were detected at Day 1 of each cycle up to Cycle 8 and at follow-up visit. Safety Analysis Population. Here, number of participants analyzed = participants evaluable for the outcome measure. Here "n" = number of participants evaluable for this outcome measure at specified timepoint. Stage I and II: Baseline: pre-dose (72 hours prior) D1 of Cy1, Cy 3-20, D0 of Cy2 (1 Cy=3 weeks for Cy1-8 & 8 weeks for Cy9-20), post-baseline: every 12 weeks after last rituximab administration until 96 weeks (a median of 27 months; up to data cutoff of 11 Jan 2016 [up to 6 years])
    End point type
    Secondary
    End point timeframe
    Stage I and II: Baseline, post-baseline (See detailed timeframe in Outcome Measure description)
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    68
    197
    Units: percentage of participants
    number (not applicable)
        Baseline (n=68, 188)
    10.3
    11.2
        Post-Baseline (n=66, 197)
    7.6
    13.2
    No statistical analyses for this end point

    Secondary: Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20

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    End point title
    		 Stage I and II (Pooled): Percentage of Responses Showing Time Saved of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20
    End point description
    All investigator physicians and nurses involved in this study were asked to provide the staff time that could be saved with each administration of rituximab SC as compared with rituximab IV to participants in routine practice afetr Cy 8, 15, 20 and categorized as less than (<) 1 hr, at least 1 hr but <2 hrs, at least 2 hrs but <3 hrs, at least 3 hrs but <4 hrs, >/=4 hrs. Staff were asked not to consider the time needed for the first IV administration. ITT Population. Here, number of participants analyzed = participants evaluable for the outcome measure. Here "n" = number of participants evaluable for this outcome measure at specified timepoint. Analysis was done in all participants to show a comparison on the time saved by staffs when administered via SC and IV.
    End point type
    Secondary
    End point timeframe
    After Cycle 8 of induction treatment (24 weeks) and during the maintenance part of the study after 12 months (i.e., Cycle 15), and after the end of the maintenance treatment, (i.e., Cycle 20) (1 Cycle=4 weeks for Cycle 8 and 8 weeks for Cycles 15 and 20)
    End point values
    		 All Participants
    Number of subjects analysed
    166
    Units: percentage of responses
        Cycle 8: <1 hour (n=166)
    11
        Cycle 8: ≥1 to <2 hours (n=166)
    20
        Cycle 8: ≥2 to <3 hours (n=166)
    35
        Cycle 8: ≥3 to <4 hours (n=166)
    18
        Cycle 8: ≥4 hours (n=166)
    16
        Cycle 15: <1 hour (n=130)
    13
        Cycle 15: ≥1 to <2 hours (n=130)
    17
        Cycle 15: ≥2 to <3 hours (n=130)
    34
        Cycle 15: ≥3 to <4 hours (n=130)
    14
        Cycle 15: ≥4 hours (n=130)
    22
        Cycle 20: <1 hour (n=126)
    14
        Cycle 20: ≥1 to <2 hours (n=126)
    32
        Cycle 20: ≥2 to <3 hours (n=126)
    21
        Cycle 20: ≥3 to <4 hours (n=126)
    13
        Cycle 20: ≥4 hours (n=126)
    19
    No statistical analyses for this end point

    Secondary: Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion

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    End point title
    		 Percentage of Responses Who Showed Rituximab SC Formulation Convenient as Compared to Rituximab IV Formulation as Assessed by Physician/Nurse Opinion
    End point description
    All investigator physicians and nurses involved in this study were asked to complete question i.e. "Which formulation of rituximab (SC or IV) do you think is more convenient?" based on their experience with the rituximab SC and IV formulations across all participants and presented as rituximab SC is much more convenient; rituximab SC is a little more convenient; both formulations are equally convenient; rituximab IV is a little more convenient; and rituximab IV is much more convenient. ITT Population. Here, number of participants analyzed = participants evaluable for the outcome measure. Here "n" = number of participants evaluable for this outcome measure at specified timepoint.
    End point type
    Secondary
    End point timeframe
    After Cycle 8 of induction treatment (24 weeks) and during the maintenance part of the study after 12 months (i.e., Cycle 15), and after the end of the maintenance treatment, (i.e., Cycle 20) (1 Cycle=4 weeks for Cycle 8 and 8 weeks for Cycles 15 and 20)
    End point values
    		 All Participants
    Number of subjects analysed
    166
    Units: percentage of responses
        Cy8: Rituximab SC much more convenient (n=166)
    81
        Cy8: Rituximab SC little more convenient (n=166)
    13
        Cy8: Both formulations equally convenient (n=166)
    2
        Cy8: Rituximab IV little more convenient (n=166)
    4
        Cy8: Rituximab IV much more convenient (n=166)
    0
        Cy15: Rituximab SC much more convenient (n=130)
    88
        Cy15: Rituximab SC little more convenient (n=130)
    7
        Cy15: Both formulations equally convenient (n=130)
    5
        Cy15: Rituximab IV little more convenient (n=130)
    0
        Cy15: Rituximab IV much more convenient (n=130)
    0
        Cy20: Rituximab SC much more convenient (n=126)
    88
        Cy20: Rituximab SC little more convenient (n=126)
    9
        Cy20: Both formulations equally convenient (n=126)
    2
        Cy20: Rituximab IV little more convenient (n=126)
    1
        Cy20: Rituximab IV much more convenient (n=126)
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died

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    End point title
    		 Percentage of Participants Who Died
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to death (up to data cutoff of 31 Oct 2017 [up to 6 years])
    End point values
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    205
    205
    Units: percentage of participants
        number (not applicable)
    12.7
    8.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to data cutoff date of 31 Oct 2017 (up to 6 years)
    Adverse event reporting additional description
    Safety Analysis Population included all participants who received at least one dose of rituximab, either IV or SC. Safety Analysis Population included 6 participants who were randomized under Rituximab SC arm but withdrew after Cy1 and then analyzed under Rituximab IV arm.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Reporting group description
    		 First cycle of rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.

    Reporting group title
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Reporting group description
    		 Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.

    Serious adverse events
    		 Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 197 (37.56%)
    76 / 210 (36.19%)
         number of deaths (all causes)
    16
    28
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma stage 0
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kaposi’s sarcoma
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (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 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinom
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (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
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian artery occlusion
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bladder calculus removal
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (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
    Pyrexia
         subjects affected / exposed
    6 / 197 (3.05%)
    5 / 210 (2.38%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    0 / 197 (0.00%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Reproductive system and breast disorders
    Pelvic cyst
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (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
    Dyspnoea
         subjects affected / exposed
    2 / 197 (1.02%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 197 (0.51%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Stress fracture
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Procedural pain
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 197 (1.02%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Coma hepatic
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Migraine
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 197 (0.00%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    12 / 197 (6.09%)
    10 / 210 (4.76%)
         occurrences causally related to treatment / all
    7 / 14
    5 / 13
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Neutropenia
         subjects affected / exposed
    6 / 197 (3.05%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    8 / 9
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 197 (1.02%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         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
    2 / 197 (1.02%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 197 (1.02%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 197 (0.00%)
    3 / 210 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral lichen planus
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (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
    Hyperhidrosis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichen planus
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    2 / 197 (1.02%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 197 (1.02%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 197 (0.00%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    2 / 197 (1.02%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    11 / 197 (5.58%)
    7 / 210 (3.33%)
         occurrences causally related to treatment / all
    1 / 13
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenic sepsis
         subjects affected / exposed
    1 / 197 (0.51%)
    4 / 210 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    2 / 197 (1.02%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 197 (1.02%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    2 / 197 (1.02%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    1 / 197 (0.51%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 197 (0.00%)
    2 / 210 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    3 / 197 (1.52%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bacterial prostatitis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Giardiasis
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    2 / 197 (1.02%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 197 (1.02%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis B
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection fungal
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creutzfeldt−Jakob disease
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cellulitis gangrenous
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 210 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 197 (1.02%)
    0 / 210 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    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
    		 Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    186 / 197 (94.42%)
    187 / 210 (89.05%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 197 (6.09%)
    13 / 210 (6.19%)
         occurrences all number
    15
    13
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    30 / 197 (15.23%)
    27 / 210 (12.86%)
         occurrences all number
    43
    32
    Dizziness
         subjects affected / exposed
    16 / 197 (8.12%)
    15 / 210 (7.14%)
         occurrences all number
    47
    17
    Neuropathy peripheral
         subjects affected / exposed
    24 / 197 (12.18%)
    30 / 210 (14.29%)
         occurrences all number
    34
    39
    Headache
         subjects affected / exposed
    27 / 197 (13.71%)
    20 / 210 (9.52%)
         occurrences all number
    35
    31
    Hypoaesthesia
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    10 / 197 (5.08%)
    7 / 210 (3.33%)
         occurrences all number
    13
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    42 / 197 (21.32%)
    38 / 210 (18.10%)
         occurrences all number
    58
    48
    Injection site erythema
         subjects affected / exposed
    27 / 197 (13.71%)
    0 / 210 (0.00%)
         occurrences all number
    125
    0
    Pyrexia
         subjects affected / exposed
    29 / 197 (14.72%)
    29 / 210 (13.81%)
         occurrences all number
    38
    41
    Asthenia
         subjects affected / exposed
    35 / 197 (17.77%)
    27 / 210 (12.86%)
         occurrences all number
    53
    44
    Chills
         subjects affected / exposed
    16 / 197 (8.12%)
    18 / 210 (8.57%)
         occurrences all number
    17
    21
    Mucosal inflammation
         subjects affected / exposed
    9 / 197 (4.57%)
    12 / 210 (5.71%)
         occurrences all number
    14
    14
    Injection site pain
         subjects affected / exposed
    16 / 197 (8.12%)
    0 / 210 (0.00%)
         occurrences all number
    16
    0
    Chest pain
         subjects affected / exposed
    14 / 197 (7.11%)
    7 / 210 (3.33%)
         occurrences all number
    16
    9
    Oedema peripheral
         subjects affected / exposed
    10 / 197 (5.08%)
    13 / 210 (6.19%)
         occurrences all number
    13
    17
    Influenza like illness
         subjects affected / exposed
    5 / 197 (2.54%)
    12 / 210 (5.71%)
         occurrences all number
    6
    15
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    65 / 197 (32.99%)
    57 / 210 (27.14%)
         occurrences all number
    165
    159
    Anaemia
         subjects affected / exposed
    30 / 197 (15.23%)
    26 / 210 (12.38%)
         occurrences all number
    66
    34
    Leukopenia
         subjects affected / exposed
    13 / 197 (6.60%)
    23 / 210 (10.95%)
         occurrences all number
    21
    44
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    65 / 197 (32.99%)
    47 / 210 (22.38%)
         occurrences all number
    113
    89
    Vomiting
         subjects affected / exposed
    29 / 197 (14.72%)
    27 / 210 (12.86%)
         occurrences all number
    52
    31
    Diarrhoea
         subjects affected / exposed
    34 / 197 (17.26%)
    35 / 210 (16.67%)
         occurrences all number
    47
    49
    Constipation
         subjects affected / exposed
    50 / 197 (25.38%)
    55 / 210 (26.19%)
         occurrences all number
    66
    87
    Abdominal pain
         subjects affected / exposed
    29 / 197 (14.72%)
    25 / 210 (11.90%)
         occurrences all number
    43
    32
    Dyspepsia
         subjects affected / exposed
    16 / 197 (8.12%)
    14 / 210 (6.67%)
         occurrences all number
    19
    22
    Abdominal pain upper
         subjects affected / exposed
    11 / 197 (5.58%)
    11 / 210 (5.24%)
         occurrences all number
    14
    16
    Stomatitis
         subjects affected / exposed
    12 / 197 (6.09%)
    11 / 210 (5.24%)
         occurrences all number
    15
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    49 / 197 (24.87%)
    32 / 210 (15.24%)
         occurrences all number
    60
    47
    Oropharyngeal pain
         subjects affected / exposed
    17 / 197 (8.63%)
    17 / 210 (8.10%)
         occurrences all number
    29
    18
    Dyspnoea
         subjects affected / exposed
    21 / 197 (10.66%)
    13 / 210 (6.19%)
         occurrences all number
    24
    16
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    20 / 197 (10.15%)
    25 / 210 (11.90%)
         occurrences all number
    22
    26
    Erythema
         subjects affected / exposed
    19 / 197 (9.64%)
    11 / 210 (5.24%)
         occurrences all number
    34
    13
    Alopecia
         subjects affected / exposed
    28 / 197 (14.21%)
    23 / 210 (10.95%)
         occurrences all number
    29
    25
    Rash
         subjects affected / exposed
    20 / 197 (10.15%)
    14 / 210 (6.67%)
         occurrences all number
    28
    18
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    19 / 197 (9.64%)
    19 / 210 (9.05%)
         occurrences all number
    22
    21
    Anxiety
    alternative dictionary used: MedDRA 20.1
         subjects affected / exposed
    11 / 197 (5.58%)
    7 / 210 (3.33%)
         occurrences all number
    13
    8
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    20 / 197 (10.15%)
    16 / 210 (7.62%)
         occurrences all number
    26
    22
    Back pain
         subjects affected / exposed
    18 / 197 (9.14%)
    25 / 210 (11.90%)
         occurrences all number
    19
    29
    Myalgia
         subjects affected / exposed
    16 / 197 (8.12%)
    10 / 210 (4.76%)
         occurrences all number
    20
    17
    Muscle spasms
         subjects affected / exposed
    17 / 197 (8.63%)
    7 / 210 (3.33%)
         occurrences all number
    21
    7
    Pain in extremity
         subjects affected / exposed
    22 / 197 (11.17%)
    11 / 210 (5.24%)
         occurrences all number
    25
    13
    Arthralgia
         subjects affected / exposed
    26 / 197 (13.20%)
    22 / 210 (10.48%)
         occurrences all number
    27
    35
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    30 / 197 (15.23%)
    26 / 210 (12.38%)
         occurrences all number
    51
    39
    Urinary tract infection
         subjects affected / exposed
    16 / 197 (8.12%)
    28 / 210 (13.33%)
         occurrences all number
    23
    49
    Nasopharyngitis
         subjects affected / exposed
    22 / 197 (11.17%)
    25 / 210 (11.90%)
         occurrences all number
    29
    31
    Bronchitis
         subjects affected / exposed
    15 / 197 (7.61%)
    15 / 210 (7.14%)
         occurrences all number
    18
    23
    Sinusitis
         subjects affected / exposed
    14 / 197 (7.11%)
    10 / 210 (4.76%)
         occurrences all number
    16
    15
    Conjunctivitis
         subjects affected / exposed
    9 / 197 (4.57%)
    12 / 210 (5.71%)
         occurrences all number
    10
    15
    Pneumonia
         subjects affected / exposed
    12 / 197 (6.09%)
    4 / 210 (1.90%)
         occurrences all number
    12
    5
    Influenza
         subjects affected / exposed
    9 / 197 (4.57%)
    14 / 210 (6.67%)
         occurrences all number
    10
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2012
    - Added additional flexibility in the protocol for the number of cycles of CHOP chemotherapy to reflect institutional practice based on the PRIMA study. ­- Added guidance to clarify acceptable timeframe for dose delays during maintenance treatment. ­- Provided clarification on acceptable malignancy types and remission time periods that render a participant eligible. - Removed past hepatitis C virus (HCV) exposure from the exclusion criteria because only anecdotal reports in the literature of HCV reactivation and no clear links established that rituximab is involved in HCV reactivation in previously infected HCV participant. Thus, exclusion of participants with a history of HCV infection was, on balance, not considered necessary. ­- Removed bone marrow aspirate and biopsy at unscheduled visit for ethical reasons. ­- Added that following drug administration, any participant experiencing a severe or serious adverse event, which is considered immunogenic and possibly related to rituximab administration, serum samples for rituximab PK, anti­rituximab, (and following Cycle 2 for participants randomized in the SC arm anti­rHuPH20) were to be collected within 7 days of the event becoming known to the investigator to ensure participant safety was monitored thoroughly. - Clarified that anti­rHuPH20 sampling should only be performed in participants receiving rituximab SC formulation, as only this formulation includes rHuPH20 excipient.
    15 Oct 2012
    Added possibility of performing safety snapshot(s) during the study to address potential health authority or regulatory questions.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    21 Oct 2011
    Temporary stop on recruitment occurred between Stage 1 and Stage 2 whilst PK non-inferiority was confirmed by the 1400 mg Stage 1 dose.
    16 Jul 2012

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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