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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

    Results information
    Results version number
    		 v1
    This version publication date
    01 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v2 , v3 , v4

    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, CH-4070, Basel, Switzerland,
    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
    Interim
    Date of interim/final analysis
    03 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Feb 2014
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This is 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
    04 Feb 2010
    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. All participants irrespective of the treatment period completion will commence 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
    No

    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
    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 could have been 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
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use, 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
    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 could have been 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
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use, 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
    17
    16
    0
    0
    Not completed
    47
    47
    141
    142
         Consent withdrawn by subject
    -
    2
    2
    1
         Investigator's judgement
    1
    2
    4
    5
         Disease progression
    9
    7
    8
    16
         Adverse event, non-fatal
    5
    3
    3
    2
         Protocol violation
    -
    -
    1
    -
         Death
    -
    1
    1
    4
          Protocol violation
    -
    -
    -
    4
         Treatment ongoing
    30
    32
    117
    108
         Lost to follow-up
    -
    -
    1
    -
         Lack of efficacy
    2
    -
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All participants who randomized into the study irrespective whether they received study drug or not were included.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 410 410
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ( 12.67 ) -
    Gender categorical
    Units: Subjects
        Female
    		 218 218
        Male
    		 192 192

    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 (375 mg/m^2) in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR 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 (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.

    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 1 PK Evaluable Population comprised all participants with data for Ctrough available at Cycle 7 and/or observed area under the serum concentration­time curve (AUC) available at Cycle 7. Participants were analyzed as per treatment received.
    End point type
    Primary
    End point timeframe
    Stage I: Cycle 7 Day 21 (within 2 hours pre-dose on Cycle 8) of induction treatment
    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: This endpoint was intended for Stage I only; hence, only Stage I arms are reported.
    End point values
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    48 [2]
    54 [3]
    Units: micrograms per milliliter (µg/mL)
        geometric mean (geometric coefficient of variation)
    83.1 ( 36.7 )
    134.6 ( 43.2 )
    Notes
    [2] - Number of participants = participants analyzed for this endpoint.
    [3] - Number of participants = participants analyzed for this endpoint.
    Statistical analysis title
    		 Ctrough of IV and SC Rituximab
    Statistical analysis description
    Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) v Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)
    Comparison groups
    Stage I: Rituximab SC + Chemotherapy (CHOP/CVP) v Stage I: Rituximab IV + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    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
    [4] - Non-inferior Ctrough in SC formulation was demonstrated if the lower bound of 90% confidence interval (CI) was above 0.8. Geometric mean ratio adjusted for tumor load at baseline.

    Primary: Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment

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    End point title
    		 Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment [5]
    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 Non-Hodgkin lymphoma (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 using Pearson-Clopper. Intent-to-Treat (ITT) Population = all participants who were randomized into the study irrespective whether they received study drug or not.
    End point type
    Primary
    End point timeframe
    Stage II: up to end of induction treatment Cycle 8 (24 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: This endpoint was intended for Stage II only; hence, only Stage II arms are 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
    		 Overall Response at the end of Induction Treatment
    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 [6]
    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
    Notes
    [6] - Point estimate
    Statistical analysis title
    		 Stage II: Overall Response at Induction Treatment
    Statistical analysis description
    Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment
    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 [7]
    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
    Notes
    [7] - Point estimate

    Primary: Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment
    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
    Primary
    End point timeframe
    Stage I and II: Baseline up to end of induction treatment Cycle 8 (24 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%)
    84.4 (78.7 to 89.1)
    83.4 (77.6 to 88.2)
    Statistical analysis title
    		 Stage I and II: Overall Response
    Statistical analysis description
    Stage I and II: Overall Response of CR, CRu, or PR at the End of Induction Treatment. 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 [8]
    P-value
    		 = 0.7881
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 6.4
    Notes
    [8] - Point estimate
    Statistical analysis title
    		 Stage I and II: Overall Response
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment
    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 [9]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.58
    Notes
    [9] - Point estimate

    Secondary: Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment

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    End point title
    		 Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment [10]
    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: up to end of induction treatment Cycle 8 (24 weeks)
    Notes
    [10] - 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: This endpoint was intended for Stage I only; hence, only Stage I arms are 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
    		 Stage I: Overall Response at Induction Treatment
    Statistical analysis description
    Stage I: 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 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 [11]
    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
    Notes
    [11] - Point estimate
    Statistical analysis title
    		 Stage I: Overall Response at Induction Treatment
    Statistical analysis description
    Stage I: Percentage of Participants With Overall Response at the End 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
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    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
    Notes
    [12] - Point estimate

    Secondary: Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment

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    End point title
    		 Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment [13]
    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; 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: up to end of induction treatment Cycle 8 (24 weeks)
    Notes
    [13] - 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: This endpoint was intended for Stage I only; hence, only Stage I arms are 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 (15 to 37.1)
    42.9 (30.5 to 56)
    Statistical analysis title
    		 Stage I: Complete Response
    Statistical analysis description
    Stage I: Percentage of Participants With Complete 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 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 [14]
    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
    Notes
    [14] - Point estimate
    Statistical analysis title
    		 Stage I: Complete Response
    Statistical analysis description
    Stage I: Percentage of Participants With Complete Response at the End 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
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    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
    Notes
    [15] - Point estimate

    Secondary: Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment

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    End point title
    		 Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment [16]
    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; 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 II: up to end of induction treatment Cycle 8 (24 weeks)
    Notes
    [16] - 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: This endpoint was intended for Stage II only; hence, only Stage II arms are 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
    		 Stage II: Complete Response
    Statistical analysis description
    Stage II: Percentage of Participants With Complete 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 [17]
    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
    Notes
    [17] - Point estimate
    Statistical analysis title
    		 Stage II: Complete Response
    Statistical analysis description
    Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment
    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 [18]
    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
    Notes
    [18] - Point estimate

    Secondary: Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment

    		 Close Top of page
    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment
    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; 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 Cycle 8 (24 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%)
    32.7 (26.3 to 39.6)
    31.7 (25.4 to 38.6)
    Statistical analysis title
    		 Stage I and II (Pooled): Complete Response
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Complete 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 I and II: Rituximab SC + Chemotherapy (CHOP/CVP) v Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.8326
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 10.3
    Notes
    [19] - Point estimate
    Statistical analysis title
    		 Stage I and II (Pooled): Complete Response
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment
    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 [20]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.58
    Notes
    [20] - Point estimate

    Secondary: Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment
    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 disease­related 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. ITT population; only participants who completed all 12 cycles of rituximab maintenance or who had withdrawn during the maintenance period were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Stage I and II: up to 78 days after last maintenance dose (last maintenance dose: maintenance Cycle 12/Study Cycle 20 [30 months])
    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
    32 [21]
    36 [22]
    Units: percentage of participants
        number (confidence interval 95%)
    25 (11.5 to 43.4)
    22.2 (10.1 to 39.2)
    Notes
    [21] - Number of subjects analysed = participants evaluable for the analysis.
    [22] - Number of subjects analysed = participants evaluable for the analysis.
    Statistical analysis title
    		 Stage I and II (Pooled): Complete Response
    Statistical analysis description
    Stage 1 and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment. 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
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.7875
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    -2.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.9
         upper limit
    		 19.3
    Notes
    [23] - Point estimate
    Statistical analysis title
    		 Stage I and II (Pooled): Complete Response
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment.
    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
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 2.63
    Notes
    [24] - Point estimate

    Secondary: Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment
    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 completed all 12 cycles of rituximab maintenance or who had withdrawn during the maintenance period were included in the analysis
    End point type
    Secondary
    End point timeframe
    Stage I and II: up to 78 days after last maintenance dose (last maintenance dose: maintenance Cycle 12/Study Cycle 20 [30 months])
    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
    32 [25]
    36 [26]
    Units: percentage of participants
        number (confidence interval 95%)
    43.8 (26.4 to 62.3)
    44.4 (27.9 to 61.9)
    Notes
    [25] - Number of subjects analysed = participants evaluable for the analysis.
    [26] - Number of subjects analysed = participants evaluable for the analysis.
    Statistical analysis title
    		 Stage I and II: Overall Response
    Statistical analysis description
    Stage 1 and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment. 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
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.9541
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.9
         upper limit
    		 26.3
    Notes
    [27] - Point estimate
    Statistical analysis title
    		 Stage I and II: Overall Response
    Statistical analysis description
    Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment
    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
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 2.68
    Notes
    [28] - Point estimate

    Secondary: Stage 1 and II (Pooled): Progression-Free Survival (PFS)

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    End point title
    		 Stage 1 and II (Pooled): Progression-Free Survival (PFS)
    End point description
    PFS was defined as the time from randomization to disease progression/relapse or death due to any cause. If the specified event (disease progression/relapse, death) did not occur, PFS was censored at the last tumor assessment date showing no disease progression, either during treatment or follow-up. Disease progression was defined as progression in the participant's clinical symptoms according to the International Working Group response criteria for NHL. PFS analysis was performed using Kaplan-Meier curves. ITT Population. Data for median and corresponding 95% CI were not reached due to low number (<50%) of participants with event of interest, therefore '9999', '999', and '99999' are reported to reflect not available (NA) data for median and lower and upper range of 95% CI values, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of all cycles (Cycles 1-20), 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 3 February 2014)
    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%)
    9999 (999 to 99999)
    9999 (999 to 99999)
    Statistical analysis title
    		 Progression-Free Survival (PFS)
    Statistical analysis description
    Stage 1 and II (Pooled): Progression-Free Survival (PFS)
    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 [29]
    P-value
    		 = 0.4646
    Method
    		 Wald Test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.03
    Notes
    [29] - Point estimate

    Secondary: Percentage of Participants With Disease Progression or Death

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    End point title
    		 Percentage of Participants With Disease Progression or Death
    End point description
    Disease progression was defined as progression in the participant's clinical symptoms according to the International Working Group response criteria for NHL. ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of all cycles (Cycles 1-20), 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 3 February 2014)
    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
    16.1
    No statistical analyses for this end point

    Secondary: Stage I and II (Pooled): Event-Free Survival

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    End point title
    		 Stage I and II (Pooled): Event-Free Survival
    End point description
    Data for event-free survival will be analyzed when pooled data from both stages will be available, therefore '9999', '999', and '99999' are reported to reflect not available data for median and lower and upper range of 95% CI values, respectively. ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of all cycles (Cycles 1-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to data cutoff of 3 February 2014)
    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%)
    9999 (999 to 99999)
    9999 (999 to 99999)
    No statistical analyses for this end point

    Secondary: Stage I and II (Pooled): Median Time to Overall Survival (OS)

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    End point title
    		 Stage I and II (Pooled): Median Time to 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 (i.e., at the last time known to be alive). Data for overall survival will be analyzed when pooled data from both stages of the study will be available, therefore '9999', '999', and '99999' are reported to reflect not available data for median and lower and upper range of 95% CI values, respectively. ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of all cycles (Cycles 1-20), 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 3 February 2014)
    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%)
    9999 (999 to 99999)
    9999 (999 to 99999)
    No statistical analyses for this end point

    Secondary: Stage I: AUC of IV and SC Rituximab at Cycle 7

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    End point title
    		 Stage I: AUC of IV and SC Rituximab at Cycle 7 [30]
    End point description
    AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. The ratio of observed rituximab serum was determined as AUCSC/AUCIV during Cycle 7 of induction treatment. PK Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Stage I (Induction): pre-dose and 24 hours post-dose on Cycle 7 (Days 1, 3, 7, and 15), pre-dose on Cycle 8 Day 1; additionally within 15 minutes after end of infusion on Cycle 7 Day 1 for rituximab IV (up to data cutoff of 11 April 2012)
    Notes
    [30] - 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: This endpoint was intended for Stage I only; hence, only Stage I arms are reported.
    End point values
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    58 [31]
    59 [32]
    Units: µg.day/mL
        geometric mean (geometric coefficient of variation)
    2734.21 ( 32.51 )
    3778.93 ( 37.59 )
    Notes
    [31] - Number of participants with evaluable PK data contributing to summary statistics were included.
    [32] - Number of participants with evaluable PK data contributing to summary statistics were included.
    Statistical analysis title
    		 AUC of IV and SC Rituximab at Week 7
    Statistical analysis description
    Geometric mean ratio adjusted for tumor load at baseline.
    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 [33]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.378
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.241
         upper limit
    		 1.53
    Notes
    [33] - Point estimate

    Secondary: Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab at Cycle 7

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    End point title
    		 Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab at Cycle 7 [34]
    End point description
    Stage 1 PK Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Stage I (Induction): pre-dose and 24 hours post-dose on Cycle 7 (Days 1, 3, 7, and 15), pre-dose on Cycle 8 Day 1; additionally within 15 minutes after end of infusion on Cycle 7 Day 1 (up to cutoff date of 11 April 2012)
    Notes
    [34] - 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: This endpoint was intended for Stage I only; hence, only Stage I arms are reported.
    End point values
    		 Stage I: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I: Rituximab SC + Chemotherapy (CHOP/CVP)
    Number of subjects analysed
    58 [35]
    59 [36]
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    250.63 ( 19.66 )
    236.82 ( 31.45 )
    Notes
    [35] - Number of participants with evaluable PK data contributing to summary statistics were included.
    [36] - Number of participants with evaluable PK data contributing to summary statistics were included.
    No statistical analyses for this end point

    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
    ITT Population.
    End point type
    Secondary
    End point timeframe
    C-trough values are based upon samples scheduled 21 days after study drug administration (before the next scheduled cycle), except for Cycle 8 which were scheduled 28 days after drug administration (up to data cutoff of 3 February 2014).
    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
    198 [37]
    193 [38]
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (n = 198, 193)
    14 ( 157.53 )
    12.88 ( 189.7 )
        Cycle 2 (n = 197, 190)
    30.13 ( 145.36 )
    40 ( 124.5 )
        Cycle 3 (n = 192, 190)
    45.25 ( 110.35 )
    63.83 ( 101.83 )
        Cycle 4 (n = 186, 185)
    54.06 ( 108.9 )
    81.71 ( 92.28 )
        Cycle 5 (n = 185, 185)
    64.68 ( 89.9 )
    98 ( 71.91 )
        Cycle 6 (n = 187, 180)
    71.02 ( 87.6 )
    109.56 ( 58.74 )
        Cycle 7 (n = 183, 172)
    78.31 ( 77.76 )
    120.75 ( 55.6 )
        Cycle 8 (n = 52, 54)
    77.6 ( 70.53 )
    131.48 ( 50.2 )
    Notes
    [37] - n = number of participants analyzed for the endpoint at the specified timepoint.
    [38] - n = number of participants analyzed for the endpoint at the specified timepoint.
    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
    ITT Population. The data was provided up to data cutoff of 3 February 2014.
    End point type
    Secondary
    End point timeframe
    C-trough values are based upon samples scheduled before each maintenance Cycle 9 to 20 (maintenance Cycle 1 to 12). i.e. 'Cycle 8' and ‘Cycle 19’ are before the first and last maintenance administration at ‘Cycle 9’ and 'Cycle 20’, respectively.
    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
    156 [39]
    158 [40]
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        Cycle 8 (n = 156, 158)
    36.54 ( 97.1 )
    62.08 ( 67 )
        Cycle 9 (n = 142, 140)
    29.27 ( 73.85 )
    48.26 ( 83.74 )
        Cycle 10 (n = 105, 109)
    27.66 ( 78.63 )
    44.65 ( 78.57 )
        Cycle 11 (n = 78, 83)
    27.15 ( 71.27 )
    44.65 ( 66.62 )
        Cycle 12 (n = 61, 58)
    27.12 ( 59.19 )
    45.7 ( 67.32 )
        Cycle 13 (n = 49, 52)
    28.33 ( 52.03 )
    45.52 ( 67.02 )
        Cycle 14 (n = 47, 52)
    28.18 ( 44.8 )
    45.54 ( 65.44 )
        Cycle 15 (n = 43, 49)
    28.45 ( 35.36 )
    45.16 ( 69.99 )
        Cycle 16 (n = 45, 51)
    29.36 ( 44 )
    44.09 ( 65.08 )
        Cycle 17 (n = 42, 46)
    31.5 ( 43.97 )
    42.96 ( 63.89 )
        Cycle 18 (n = 29, 26)
    31.29 ( 39.15 )
    49.11 ( 56.03 )
        Cycle 19 (n = 17, 16)
    31.1 ( 36.91 )
    44.99 ( 61.55 )
    Notes
    [39] - n = number of participants analyzed for the endpoint at the specified timepoint. 
    [40] - n = number of participants analyzed for the endpoint at the specified timepoint. 
    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.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks, and 36 weeks after the last rituximab administration (median treatment duration: 383.5 days for IV dose and 406 days for SC dose; up to data cutoff of 3 February 2014)
    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
    5 [41]
    6 [42]
    Units: µg/mL
    median (full range (min-max))
        Week 12: Follow-up Visit 1 (n = 5, 6)
    21 (4.76 to 80.4)
    29.35 (24.1 to 50.5)
        Week 24: Follow-up Visit 2 (n = 2, 5)
    5.03 (1.25 to 8.81)
    10.4 (3.31 to 62.1)
        Week 36: Follow-up Visit 3 (n = 2, 1)
    26.22 (1.03 to 51.4)
    8.93 (8.93 to 8.93)
    Notes
    [41] - n = number of participants analyzed for the endpoint at the specified timepoint.
    [42] - n = number of participants analyzed for the endpoint at the specified timepoint.
    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
    ITT Population. The data was presented up to data cutoff of 3 February 2014.
    End point type
    Secondary
    End point timeframe
    Stage I and II (induction): for rituximab IV - Day 1 of Cycle 1 to 8; for rituximab SC - Day 1 of Cycle 1 and Cycle 3 to 8, Day 0 of Cycle 2, thereafter at follow-up visits every 12 weeks after the last rituximab administration until 72 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
    188 [43]
    168 [44]
    Units: percentage of participants
    number (not applicable)
        Cycle 1 Day 1 - Baseline (n=188, 168)
    51.6
    54.8
        Cycle 2 Day 0/1 (n=183, 180)
    95.1
    95
        Cycle 3 Day 1 (n=175, 175)
    99.4
    99.4
        Cycle 4 Day 1 (n=178, 179)
    99.4
    100
        Cycle 5 Day 1 (n=179, 176)
    100
    100
        Cycle 6 Day 1 (n=173, 175)
    100
    100
        Cycle 7 Day 1 (n=178, 173)
    100
    100
        Cycle 8 Day 1 (n=175, 174)
    100
    100
        Cycle 8 Day 19 Final Assessment (n=151, 145)
    100
    100
        Week 12: Follow-up Visit 1 (n=20, 17)
    90
    100
        Week 24: Follow-up Visit 2 (n=10, 10)
    100
    100
        Week 36: Follow-up Visit 3 (n=3, 3)
    100
    100
        Week 48: Follow-up Visit 4 (n=3, 1)
    66.7
    100
        Week 60: Follow-up Visit 5 (n=1, 0)
    100
    0
        Week 72: Follow-up Visit 6 (n=1, 0)
    100
    0
    Notes
    [43] - n = number of participants analyzed for the endpoint at the specified timepoint.
    [44] - n = number of participants analyzed for the endpoint at the specified timepoint.
    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
    ITT Population.
    End point type
    Secondary
    End point timeframe
    Stage I and II (maintenance): Day 1 of Cycle 9 to 20 (up to data cutoff of 3 February 2014)
    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
    169 [45]
    160 [46]
    Units: percentage of participants
    number (not applicable)
        Cycle 9 Day 1 (n=169, 160)
    99.4
    100
        Cycle 10 Day 1 (n=158, 159)
    99.4
    100
        Cycle 11 Day 1 (n=130, 139)
    92.2
    100
        Cycle 12 Day 1 (n=106, 110)
    100
    100
        Cycle 13 Day 1 (n=79, 81)
    100
    100
        Cycle 14 Day 1 (n=62, 62)
    100
    100
        Cycle 15 Day 1 (n=47, 48)
    100
    100
        Cycle 16 Day 1 (n=45, 49)
    100
    100
        Cycle 17 Day 1 (n=45, 50)
    100
    100
        Cycle 18 Day 1 (n=43, 49)
    100
    100
        Cycle 19 Day 1 (n=45, 43)
    100
    100
        Cycle 20 Day 1 (n=31, 35)
    100
    100
    Notes
    [45] - n = number of participants analyzed for the endpoint at the specified timepoint.
    [46] - n = number of participants analyzed for the endpoint at the specified timepoint.
    No statistical analyses for this end point

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

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    End point title
    		 Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs)
    End point description
    Levels of HACA in serum were collected at Day of each cycle up to Cycle 8 and at follow-up visit. Safety Analysis Population.
    End point type
    Secondary
    End point timeframe
    Baseline, Post-Baseline (Cycle 1 Day 1 [induction] up to follow-up) (a median of 27 months; up to data cutoff of 3 February 2014)
    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
    207 [47]
    197 [48]
    Units: percentage of participants
    number (not applicable)
        Baseline (n=207, 189)
    6
    3
        Post-Baseline (n=206, 197)
    1
    2
    Notes
    [47] - n = number of participants analyzed for the endpoint at the specified timepoint.
    [48] - n = number of participants analyzed for the endpoint at the specified timepoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Other adverse event (AE): up to 28 days after last treatment (up to 31 months) Treatment-emergent serious AEs (SAEs): up to 1 year after last treatment of study drug (up to 42 months) Treatment-related SAEs: up to the end of the study (up to 91 months).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
    Reporting group description
    		 Eight cycles of rituximab IV (375 mg/m^2) in combination with up to 8 cycles of CHOP or CVP chemotherapy administered every 3 weeks. Participants achieving at least PR entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.

    Reporting group title
    Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Reporting group description
    		 First cycle rituximab IV (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.

    Serious adverse events
    		 Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 210 (26.19%)
    57 / 197 (28.93%)
         number of deaths (all causes)
    5
    8
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (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
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         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 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 210 (2.38%)
    6 / 197 (3.05%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Pelvic cyst
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 210 (1.90%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 197 (0.51%)
         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 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hydropneumothorax
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 210 (1.43%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site pain
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         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
    1 / 210 (0.48%)
    0 / 197 (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
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         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
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 197 (0.51%)
         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
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma hepatic
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    9 / 210 (4.29%)
    11 / 197 (5.58%)
         occurrences causally related to treatment / all
    5 / 12
    6 / 13
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Anaemia
         subjects affected / exposed
    1 / 210 (0.48%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 210 (1.90%)
    5 / 197 (2.54%)
         occurrences causally related to treatment / all
    2 / 5
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 210 (0.95%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral lichen planus
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctocolitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lichen planus
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 210 (0.48%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 210 (0.95%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 210 (0.48%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 210 (1.90%)
    7 / 197 (3.55%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    4 / 210 (1.90%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 210 (0.95%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 210 (0.48%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 210 (0.95%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial prostatitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         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
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Giardiasis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 210 (0.48%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 210 (1.43%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Pathological fracture
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 210 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 210 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         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 IV + Chemotherapy (CHOP/CVP) Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    171 / 210 (81.43%)
    169 / 197 (85.79%)
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    30 / 210 (14.29%)
    20 / 197 (10.15%)
         occurrences all number
    36
    31
    Headache
         subjects affected / exposed
    12 / 210 (5.71%)
    23 / 197 (11.68%)
         occurrences all number
    21
    31
    Dizziness
         subjects affected / exposed
    13 / 210 (6.19%)
    11 / 197 (5.58%)
         occurrences all number
    15
    42
    Paraesthesia
         subjects affected / exposed
    25 / 210 (11.90%)
    28 / 197 (14.21%)
         occurrences all number
    29
    41
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 210 (0.00%)
    26 / 197 (13.20%)
         occurrences all number
    0
    104
    Chills
         subjects affected / exposed
    17 / 210 (8.10%)
    13 / 197 (6.60%)
         occurrences all number
    20
    13
    Fatigue
         subjects affected / exposed
    32 / 210 (15.24%)
    36 / 197 (18.27%)
         occurrences all number
    40
    51
    Pyrexia
         subjects affected / exposed
    24 / 210 (11.43%)
    26 / 197 (13.20%)
         occurrences all number
    33
    35
    Chest pain
         subjects affected / exposed
    6 / 210 (2.86%)
    13 / 197 (6.60%)
         occurrences all number
    8
    14
    Injection site pain
         subjects affected / exposed
    0 / 210 (0.00%)
    14 / 197 (7.11%)
         occurrences all number
    0
    14
    Asthenia
         subjects affected / exposed
    22 / 210 (10.48%)
    29 / 197 (14.72%)
         occurrences all number
    37
    43
    Mucosal inflammation
         subjects affected / exposed
    14 / 210 (6.67%)
    10 / 197 (5.08%)
         occurrences all number
    16
    15
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    53 / 210 (25.24%)
    60 / 197 (30.46%)
         occurrences all number
    135
    151
    Anaemia
         subjects affected / exposed
    24 / 210 (11.43%)
    28 / 197 (14.21%)
         occurrences all number
    30
    59
    Leukopenia
         subjects affected / exposed
    22 / 210 (10.48%)
    12 / 197 (6.09%)
         occurrences all number
    41
    20
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    52 / 210 (24.76%)
    46 / 197 (23.35%)
         occurrences all number
    78
    58
    Diarrhoea
         subjects affected / exposed
    28 / 210 (13.33%)
    29 / 197 (14.72%)
         occurrences all number
    41
    40
    Nausea
         subjects affected / exposed
    45 / 210 (21.43%)
    59 / 197 (29.95%)
         occurrences all number
    85
    99
    Abdominal pain
         subjects affected / exposed
    19 / 210 (9.05%)
    24 / 197 (12.18%)
         occurrences all number
    25
    35
    Dyspepsia
         subjects affected / exposed
    10 / 210 (4.76%)
    16 / 197 (8.12%)
         occurrences all number
    15
    19
    Vomiting
         subjects affected / exposed
    25 / 210 (11.90%)
    26 / 197 (13.20%)
         occurrences all number
    28
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 210 (10.00%)
    35 / 197 (17.77%)
         occurrences all number
    28
    44
    Oropharyngeal pain
         subjects affected / exposed
    10 / 210 (4.76%)
    16 / 197 (8.12%)
         occurrences all number
    11
    25
    Dyspnoea
         subjects affected / exposed
    12 / 210 (5.71%)
    19 / 197 (9.64%)
         occurrences all number
    12
    22
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    11 / 210 (5.24%)
    16 / 197 (8.12%)
         occurrences all number
    13
    24
    Pruritus
         subjects affected / exposed
    19 / 210 (9.05%)
    19 / 197 (9.64%)
         occurrences all number
    20
    20
    Erythema
         subjects affected / exposed
    11 / 210 (5.24%)
    16 / 197 (8.12%)
         occurrences all number
    12
    32
    Alopecia
         subjects affected / exposed
    22 / 210 (10.48%)
    28 / 197 (14.21%)
         occurrences all number
    23
    29
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 210 (7.14%)
    18 / 197 (9.14%)
         occurrences all number
    17
    21
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    4 / 210 (1.90%)
    10 / 197 (5.08%)
         occurrences all number
    4
    14
    Pain in extremity
         subjects affected / exposed
    8 / 210 (3.81%)
    16 / 197 (8.12%)
         occurrences all number
    8
    19
    Arthralgia
         subjects affected / exposed
    14 / 210 (6.67%)
    13 / 197 (6.60%)
         occurrences all number
    18
    14
    Back pain
         subjects affected / exposed
    18 / 210 (8.57%)
    15 / 197 (7.61%)
         occurrences all number
    20
    16
    Myalgia
         subjects affected / exposed
    9 / 210 (4.29%)
    12 / 197 (6.09%)
         occurrences all number
    17
    16
    Bone pain
         subjects affected / exposed
    16 / 210 (7.62%)
    19 / 197 (9.64%)
         occurrences all number
    21
    24
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    18 / 210 (8.57%)
    11 / 197 (5.58%)
         occurrences all number
    31
    13
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 210 (6.19%)
    18 / 197 (9.14%)
         occurrences all number
    20
    27
    Nasopharyngitis
         subjects affected / exposed
    14 / 210 (6.67%)
    15 / 197 (7.61%)
         occurrences all number
    14
    19
    Bronchitis
         subjects affected / exposed
    11 / 210 (5.24%)
    10 / 197 (5.08%)
         occurrences all number
    14
    12
    Sinusitis
         subjects affected / exposed
    6 / 210 (2.86%)
    10 / 197 (5.08%)
         occurrences all number
    7
    11

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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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