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    Clinical Trial Results:
    A single-arm, multicentre, phase IIIb study to evaluate safety, efficacy and pharmacokinetic (PK) of subcutaneous (SC) rituximab administered during induction phase or maintenance in previously untreated patients with CD20+ diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL)

    Summary
    EudraCT number
    		 2013-000647-12
    Trial protocol
    		 IT  
    Global end of trial date
    28 May 2019

    Results information
    Results version number
    		 v3(current)
    This version publication date
    13 Aug 2020
    First version publication date
    14 Jun 2020
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    ML28881
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01889069
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche, Ltd.
    Sponsor organisation address
    F. Hoffmann-La Roche, Ltd., Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche, Ltd., +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche, Ltd., +41 616878333, genentech@druginfo.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the incidence of administration-associated reactions (AARs) following multiple doses of subcutaneous (SC) rituximab during Induction and/or Maintenance therapy in subjects with CD20+ follicular non-Hodgkin’s lymphoma (NHL) or CD20+ diffuse large B-cell lymphoma (DLBCL) who had previously received at least one dose of intravenous (IV) rituximab.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Sep 2013
    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?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 158
    Worldwide total number of subjects
    158
    EEA total number of subjects
    158
    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)
    107
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 37 investigational centers in Italy.

    Pre-assignment
    Screening details
    		 Adult participants with CD20+ diffuse large B-cell lymphoma or CD20+ follicular lymphoma. Total overall participants enrolled in the study was 159, however for the subject disposition and baseline characteristics the enrolled was 158 as one participant discontinued the study prior to treatment.

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

    Arms
    Arm title
    		 Subcutaneous (SC) Rituximab
    Arm description
    		 Participants will receive at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); or bendamustine as per standard local practice.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MabThera Rituxan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1400 mg of rituximab was injected subcutaneously (SC)

    Number of subjects in period 1
    		Subcutaneous (SC) Rituximab
    Started
    158
    Completed
    113
    Not completed
    45
         Consent withdrawn by subject
    3
         Progression of Disease
    14
         Death
    18
         Not Specified
    4
         Lost to follow-up
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Subcutaneous (SC) Rituximab
    Reporting group description
    		 Participants will receive at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); or bendamustine as per standard local practice.

    Reporting group values
    		 Subcutaneous (SC) Rituximab Total
    Number of subjects
    		 158 158
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 107 107
        From 65-84 years
    		 51 51
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.7 ± 11.28 -
    Sex: Female, Male
    Units: Participants
        Female
    		 72 72
        Male
    		 86 86
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 9 9
        Not Hispanic or Latino
    		 131 131
        Unknown or Not Reported
    		 18 18
    Subject analysis sets

    Subject analysis set title
    Diffuse Large B-Cell Lymphoma (DLBCL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with DLBCL, who had received at least 4 doses of rituximab 1400 mg SC once a month during the treatment phase, up to a maxium of 7 cycles, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); as per standard local practice.

    Subject analysis set title
    Follicular Lymphoma (FL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with CD20+ non-Hodgkin's (FL), who had received at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); or bendamustine as per standard local practice.

    Subject analysis set title
    Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP-14
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    DLBCL chemotherapy regimen cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 14 days (R-CHOP-14)

    Subject analysis set title
    Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP-21
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    DLBCL chemotherapy regimen cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 21 days (R-CHOP-21)

    Subject analysis sets values
    		 Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL) Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP-14 Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP-21
    Number of subjects
    72
    86
    4
    31
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    42
    65
        From 65-84 years
    30
    21
        85 years and over
    0
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    59.7 ± 12.70
    57.8 ± 9.92
    ±
    ±
    Sex: Female, Male
    Units: Participants
        Female
    28
    44
        Male
    44
    42
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    4
    5
        Not Hispanic or Latino
    59
    72
        Unknown or Not Reported
    9
    9

    End points

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    End points reporting groups
    Reporting group title
    Subcutaneous (SC) Rituximab
    Reporting group description
    		 Participants will receive at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); or bendamustine as per standard local practice.

    Subject analysis set title
    Diffuse Large B-Cell Lymphoma (DLBCL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with DLBCL, who had received at least 4 doses of rituximab 1400 mg SC once a month during the treatment phase, up to a maxium of 7 cycles, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); as per standard local practice.

    Subject analysis set title
    Follicular Lymphoma (FL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with CD20+ non-Hodgkin's (FL), who had received at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); or bendamustine as per standard local practice.

    Subject analysis set title
    Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP-14
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    DLBCL chemotherapy regimen cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 14 days (R-CHOP-14)

    Subject analysis set title
    Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP-21
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    DLBCL chemotherapy regimen cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 21 days (R-CHOP-21)

    Primary: Percentage of Participants with Administration-Associated Reactions (AAR)

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    End point title
    		 Percentage of Participants with Administration-Associated Reactions (AAR) [1]
    End point description
    AARs were defined as all adverse events (AEs) occurring within 24 hours of rituximab administration and which were considered related to study drug. AARs included infusion/injection-related reactions (IIRRs), injection-site reactions, administration site conditions and all symptoms thereof. Grading was completed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
    End point type
    Primary
    End point timeframe
    Baseline up to 54 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed. Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    158
    72
    86
    Units: Percentage of Participants
    number (not applicable)
        At least One AAR
    6.3
    4.2
    8.1
        At Least One AAR Grade ≥3
    0
    0
    0
        Cutaneous and Soft Tissue AARs (Localized)
    5.1
    1.4
    8.1
        Cutaneous and Soft Tissue AARs (Non-Localized)
    1.3
    2.8
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with At Least One Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Participants with At Least One Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the treatment. An adverse event was therefore any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsened during the study were also considered as adverse events. Grading was completed according to the CTCAE, version 4.0.
    End point type
    Secondary
    End point timeframe
    Baseline up to 54 months
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    158
    72
    86
    Units: Percentage of Participants
        number (not applicable)
    46.8
    51.4
    43.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with At Least One Grade ≥ 3 Infusion/ Injection Related Reactions (IIRRs)

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    End point title
    		 Percentage of Participants with At Least One Grade ≥ 3 Infusion/ Injection Related Reactions (IIRRs)
    End point description
    Grading of IIRRs was completed according to the CTCAE, version 4.0.
    End point type
    Secondary
    End point timeframe
    Baseline up to 54 months
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    158
    72
    86
    Units: Percentage of Participants
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with At Least One Treatment-Emergent Serious Adverse Events

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    End point title
    		 Percentage of Participants with At Least One Treatment-Emergent Serious Adverse Events
    End point description
    SAE was defined as any experience that suggested a significant hazard, contraindication, side effect, or precaution, and fulfilled any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here.
    End point type
    Secondary
    End point timeframe
    Baseline up to 54 months
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    158
    72
    86
    Units: Percentage of Participants
        number (not applicable)
    31.0
    36.1
    26.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Event-Free Survival (EFS) According to IWG Response Criteria

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    End point title
    		 Percentage of Participants with Event-Free Survival (EFS) According to IWG Response Criteria
    End point description
    EFS was defined as the time from first dose of rituximab to first occurrence of progression or relapse, according to the International Working Group (IWG) response criteria or other country standards, or initiation of a non–protocol-specified anti-lymphoma therapy or death, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    Day 1 up to first occurrence of progression or relapse, or initiation of a non-protocol-specified anti-lymphoma therapy or death, whichever occurs first (up to maximum 54 months)
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    40
    21
    19
    Units: Percentage of Participants
        number (not applicable)
    25.3
    29.2
    22.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Progression-Free Survival (PFS) According to IWG Response Criteria

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    End point title
    		 Percentage of Participants with Progression-Free Survival (PFS) According to IWG Response Criteria
    End point description
    PFS was defined as the time from first dose of rituximab to the first occurrence of disease progression or relapse, according to the International Working Group (IWG) response criteria or other country standards, or death from any cause, whichever occurred first.
    End point type
    Secondary
    End point timeframe
    Day 1 up to first occurrence of progression or relapse, or death, whichever occurs first (up to maximum 54 months)
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    40
    21
    19
    Units: Percentage of Participants
        number (not applicable)
    25.3
    29.2
    22.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Overall Survival (OS)

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    End point title
    		 Percentage of Participants with Overall Survival (OS)
    End point description
    OS was defined as the time from first dose of rituximab to death from any cause.
    End point type
    Secondary
    End point timeframe
    Day 1 until death (up to maximum 54 months)
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    18
    14
    4
    Units: Percentage of Participants
        number (not applicable)
    11.4
    19.4
    4.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Disease-Free Survival (DFS) According to IWG Response Criteria

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    End point title
    		 Percentage of Participants with Disease-Free Survival (DFS) According to IWG Response Criteria
    End point description
    DFS assessed in participants achieving complete response (CR) including complete response unconfirmed (Cru) and was defined as the period from 4 to 8 weeks after end of Induction period up to relapse or death from any cause, whichever occured first.
    End point type
    Secondary
    End point timeframe
    From 4 to 8 weeks after end of Induction period up to relapse or death from any cause, whichever occurs first (up to maximum 54 months) (end of Induction period = up to 8 months)
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    20
    10
    10
    Units: Percentage of Participants
        number (not applicable)
    23.5
    21.7
    25.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Complete Response (CR) According to IWG Response Criteria

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    End point title
    		 Percentage of Participants with Complete Response (CR) According to IWG Response Criteria
    End point description
    Complete response required: 1) the complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities, 2) all lymph nodes and nodal masses had regressed to normal size, 3) the spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and not be palpable on physical examination and 4) if the bone marrow was involved by lymphoma before treatment, the infiltrate was cleared on repeat bone marrow aspirate and biopsy of the same site. CR/unconfirmed (CRu) included those patients who fulfilled criteria 1 and 3 above as well as 1) a residual lymph node mass greater than 1.5 cm in greatest transverse diameter that regressed by more than 75% in the SPD and 2) indeterminate bone marrow. Response was assessed according to the IWG response criteria.
    End point type
    Secondary
    End point timeframe
    At 4 to 8 weeks after end of Induction period (end of Induction period = up to 8 months)
    End point values
    		 Subcutaneous (SC) Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    158
    72
    86
    Units: Percentage of Participants
        number (confidence interval 95%)
    66.4 (57.2 to 74.8)
    65.2 (52.4 to 76.5)
    67.9 (53.7 to 80.1)
    No statistical analyses for this end point

    Secondary: FL: Plasma Trough Concentrations of Rituximab

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    End point title
    		 FL: Plasma Trough Concentrations of Rituximab
    End point description
    FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. Pharmacokinetic (PK) data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days.
    End point type
    Secondary
    End point timeframe
    Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1
    End point values
    		 Follicular Lymphoma (FL)
    Number of subjects analysed
    31
    Units: micrograms per millilitre (ug/mL)
    arithmetic mean (standard deviation)
        Cycle 2 Predose (n=10)
    55.49 ± 64.275
        Cycle 3 Predose (n=6)
    119.50 ± 139.606
        Cycle 4 Predose (n=4)
    157.25 ± 132.583
        Cycle 5 Predose (n=1)
    7.60 ± 9999999
        Baseline (n=21)
    90.88 ± 107.089
        Cycle 8 Predose (n=23)
    201.56 ± 372.609
    No statistical analyses for this end point

    Secondary: FL: Overall Geometric Least Square (LS) Mean Plasma Trough Concentrations of Rituximab

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    End point title
    		 FL: Overall Geometric Least Square (LS) Mean Plasma Trough Concentrations of Rituximab
    End point description
    Measure type reported is geometric least square mean. FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. PK data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days.
    End point type
    Secondary
    End point timeframe
    Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1.
    End point values
    		 Follicular Lymphoma (FL)
    Number of subjects analysed
    31
    Units: micrograms per millilitre (ug/mL)
        least squares mean (confidence interval 90%)
    61.01 (42.49 to 87.61)
    No statistical analyses for this end point

    Secondary: FL: Plasma Trough Concentrations of Rituximab in Participants with Complete Response/Complete Response Unconfirmed (CR/CRu)

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    End point title
    		 FL: Plasma Trough Concentrations of Rituximab in Participants with Complete Response/Complete Response Unconfirmed (CR/CRu)
    End point description
    FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. PK data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days. The value '9999999' in the results table indicates that the standard deviation could not be calculated using data from a single participant.
    End point type
    Secondary
    End point timeframe
    Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1.
    End point values
    		 Follicular Lymphoma (FL)
    Number of subjects analysed
    20
    Units: micrograms per millilitre (ug/mL)
    arithmetic mean (standard deviation)
        Cycle 2 Predose (n=8)
    48.86 ± 57.640
        Cycle 3 Predose (n=3)
    156.33 ± 193.753
        Cycle 4 Predose (n=3)
    200.33 ± 123.411
        Cycle 5 Predose (n=1)
    7.60 ± 9999999
        Baseline (n=15)
    97.90 ± 118.897
        Cycle 8 Predose (n=12)
    284.08 ± 504.113
    No statistical analyses for this end point

    Secondary: DLBCL: Plasma Concentrations of Rituximab

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    End point title
    		 DLBCL: Plasma Concentrations of Rituximab
    End point description
    DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL)
    Number of subjects analysed
    36
    Units: micrograms per millilitre (ug/mL)
    arithmetic mean (standard deviation)
        Cycle 2 Predose (n=10)
    42.53 ± 49.637
        Cycle 3 Predose (n=9)
    88.92 ± 92.790
        Cycle 4 Predose (n=2)
    110.50 ± 101.116
        Cycle 5 Predose (n=5)
    100.20 ± 44.483
        Baseline (n=30)
    92.92 ± 114.466
        Cycle 7 Predose (n=26)
    141.44 ± 122.314
        Cycle 7 Day 7 (n=20)
    348.81 ± 490.785
        Cycle 7 Day 14 (n=5)
    226.40 ± 136.729
        Cycle 8 Predose (n=28)
    117.61 ± 89.394
    No statistical analyses for this end point

    Secondary: DLBCL: Plasma Trough Concentrations of Rituximab

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    End point title
    		 DLBCL: Plasma Trough Concentrations of Rituximab
    End point description
    DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 pre-dose on Day 1
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL)
    Number of subjects analysed
    36
    Units: micrograms per millilitre (ug/mL)
    arithmetic mean (standard deviation)
        Cycle 2 Predose (n=10)
    42.53 ± 49.637
        Cycle 3 Predose (n=9)
    88.92 ± 92.790
        Cycle 4 Predose (n=2)
    110.50 ± 101.116
        Cycle 5 Predose (n=5)
    100.20 ± 44.483
        Baseline (n=30)
    92.92 ± 114.466
        Cycle 7 Predose (n=26)
    141.44 ± 122.314
        Cycle 8 Predose (n=21)
    117.61 ± 89.394
    No statistical analyses for this end point

    Secondary: DLBCL: Area Under the Plasma Concentration-Time Curve (AUC) of Rituximab

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    End point title
    		 DLBCL: Area Under the Plasma Concentration-Time Curve (AUC) of Rituximab
    End point description
    DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. The value '9999' indicates AUC was not estimable for available PK concentrations in DLBCL participants.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL)
    Number of subjects analysed
    36 [2]
    Units: mcg*hr/mL
        arithmetic mean (standard deviation)
    9999 ± 9999
    Notes
    [2] - AUC was not estimable for available PK concentrations in DLBCL participants
    No statistical analyses for this end point

    Secondary: DLBCL: Maximum Plasma Concentration (Cmax) of Rituximab

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    End point title
    		 DLBCL: Maximum Plasma Concentration (Cmax) of Rituximab
    End point description
    DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. The value '9999' indicates Cmax was not estimable for available PK concentrations in DLBCL participants.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL)
    Number of subjects analysed
    36 [3]
    Units: micrograms per millilitre (ug/mL)
        arithmetic mean (standard deviation)
    9999 ± 9999
    Notes
    [3] - Cmax was not estimable for available PK concentrations in DLBCL participants.
    No statistical analyses for this end point

    Secondary: DLBCL: Apparent Total Clearance (CL/F) of Rituximab

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    End point title
    		 DLBCL: Apparent Total Clearance (CL/F) of Rituximab
    End point description
    DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. The value '9999' indicates that CL/F was not estimable for available PK concentrations in DLBCL participants.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL)
    Number of subjects analysed
    36 [4]
    Units: liter per hour (L/h)
        arithmetic mean (standard deviation)
    9999 ± 9999
    Notes
    [4] - AUC was not estimable for available PK concentrations in DLBCL participants
    No statistical analyses for this end point

    Secondary: DLBCL: Plasma Trough Concentrations of Rituximab in Participants with Complete Response/Complete Response Unconfirmed (CR/CRu)

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    End point title
    		 DLBCL: Plasma Trough Concentrations of Rituximab in Participants with Complete Response/Complete Response Unconfirmed (CR/CRu)
    End point description
    DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL)
    Number of subjects analysed
    28
    Units: micrograms per millilitre (ug/mL)
    arithmetic mean (standard deviation)
        Cycle 2 Predose (n=7)
    53.97 ± 56.169
        Cycle 3 Predose (n=7)
    101.79 ± 101.223
        Cycle 4 Predose (n=2)
    110.50 ± 101.116
        Cycle 5 Predose (n=3)
    121.67 ± 45.092
        Baseline (n=23)
    109.40 ± 125.603
        Cycle 7 Predose (n=21)
    157.93 ± 131.178
        Cycle 8 Predose (n=21)
    132.57 ± 95.447
    No statistical analyses for this end point

    Secondary: DLBCL: Overall Geometric Least Square (LS) Mean Plasma Trough Concentrations of Rituximab

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    End point title
    		 DLBCL: Overall Geometric Least Square (LS) Mean Plasma Trough Concentrations of Rituximab
    End point description
    Measure type reported is geometric least square mean DDLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL)
    Number of subjects analysed
    36
    Units: micrograms per millilitre (ug/mL)
        least squares mean (confidence interval 90%)
    70.50 (57.60 to 86.28)
    No statistical analyses for this end point

    Secondary: DLBCL: Plasma Concentrations During Different Scheduling of Rituximab SC R-CHOP-14 or R-CHOP-21

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    End point title
    		 DLBCL: Plasma Concentrations During Different Scheduling of Rituximab SC R-CHOP-14 or R-CHOP-21
    End point description
    Plasma concentrations of rituximab in participants with DLBCL by chemotherapy regimen cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 14 days (R-CHOP-14) or cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 21 days (R-CHOP-21) in the pharmacokinetic (PK) population. The value '99999' in the results table indicates that the standard deviation could not be calculated using data from a single participant. The Value '9999' in the results table indicates data is not reportable as no participants analyzed. DLBCL participants have received at least 1 infusion of rituximab and must be able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline pk sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each cycle is 21 days.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP-14 Diffuse Large B-Cell Lymphoma (DLBCL) R-CHOP-21
    Number of subjects analysed
    4
    31
    Units: micrograms per millilitre (ug/mL)
    arithmetic mean (standard deviation)
        Cycle 2 Predose (n=1,9)
    170.00 ± 99999
    28.37 ± 22.695
        Cycle 3 Predose (n=0,9)
    9999 ± 9999
    88.92 ± 92.790
        Cycle 4 Predose (n=0,2)
    9999 ± 9999
    110.50 ± 101.116
        Cycle 5 Predose (n=1,4)
    125.00 ± 99999
    94.00 ± 48.806
        Baseline (n=4,26)
    214.25 ± 233.493
    74.25 ± 77.064
        Cycle 7 Predose (n=2,23)
    93.50 ± 79.903
    150.13 ± 126.221
        Cycle 7 Day 7 (n=2,17)
    71.55 ± 26.092
    398.76 ± 517.974
        Cycle 7 Day 14 (n=1,4)
    42.00 ± 99999
    272.50 ± 103.722
        Cycle 8 Predose (n=2,25)
    78.50 ± 14.849
    123.76 ± 92.606
    No statistical analyses for this end point

    Secondary: Rituximab Administration Satisfaction Questionnaire (RASQ) Convenience and Satisfaction Domain Scores

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    End point title
    		 Rituximab Administration Satisfaction Questionnaire (RASQ) Convenience and Satisfaction Domain Scores
    End point description
    Patient-assessed satisfaction was evaluated using RASQ. Participants were asked questions regarding convenience and satisfaction for rituximab SC. Each domain is scored on a scale of 0 to 100, with higher scores indicative of more positive feelings toward therapy. The score for each domain was averaged among all participants. The value '99999' in the results table indicates that the standard deviation could not be calculated using data from a single participant. The value '9999' in the results table indicates DLBCL participants or FL participants did not complete the RASQ at the time point.
    End point type
    Secondary
    End point timeframe
    DLBCL: Cycle (C) 2, C3, C4, C5, C6, End of C8; FL: Induction: C3, C4, C5, C6, C8, Maintenance: C2, C3, C4, C5, C6, C7, C8, C10, C12, End of treatment (4-8 weeks after last dose)
    End point values
    		 Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    72
    86
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Convenience domain Cycle 3 Induction (n=0,27)
    9999 ± 9999
    81.8 ± 8.66
        Convenience domain Cycle 4 Induction (n=0,11)
    9999 ± 9999
    76.5 ± 6.26
        Convenience domain Cycle 5 Induction (n=0,9)
    9999 ± 9999
    79.6 ± 10.30
        Convenience domain Cycle 6 Induction (n=0,2)
    9999 ± 9999
    95.8 ± 5.89
        Convenience domain Cycle 8 Induction (n=0,43)
    9999 ± 9999
    83.1 ± 9.18
        Convenience domain Cycle 2 Treatment (n=1,0)
    75.0 ± 99999
    9999 ± 9999
        Convenience domain Cycle 3 Treatment (n=30,0)
    81.9 ± 10.28
    9999 ± 9999
        Convenience domain Cycle 4 Treatment (n=20,0)
    82.1 ± 12.17
    9999 ± 9999
        Convenience domain Cycle 5 Treatment (n=8,0)
    83.3 ± 9.96
    9999 ± 9999
        Convenience domain Cycle 6 Treatment (n=13,0)
    80.8 ± 9.85
    9999 ± 9999
        Convenience domain Cycle 8 Treatment (n=53,0)
    83.8 ± 11.60
    9999 ± 9999
        Convenience domain Cycle 2 Maintenance (n=0,33)
    9999 ± 9999
    83.6 ± 8.71
        Convenience domain Cycle 3 Maintenance (n=0,6)
    9999 ± 9999
    87.5 ± 19.54
        Convenience domain Cycle 4 Maintenance (n=0,2)
    9999 ± 9999
    100.0 ± 0.00
        Convenience domain Cycle 5 Maintenance (n=0,8)
    9999 ± 9999
    80.2 ± 12.55
        Convenience domain Cycle 6 Maintenance (n=0,3)
    9999 ± 9999
    83.3 ± 16.67
        Convenience domain Cycle 7 Maintenance (n=0,39)
    9999 ± 9999
    82.7 ± 12.59
        Convenience domain Cycle 8 Maintenance (n=0,4)
    9999 ± 9999
    93.8 ± 12.50
        Convenience domain Cycle 10 Maintenance (n=0,1)
    9999 ± 9999
    91.7 ± 99999
        Convenience domain Cycle 12 Maintenance (n=0,48)
    9999 ± 9999
    86.3 ± 12.69
        Convenience domain End of Treatment (n=0,3)
    9999 ± 9999
    75.0 ± 16.67
        Satisfaction domain Cycle 3 Induction (n=0,27)
    9999 ± 9999
    89.4 ± 10.23
        Satisfaction domain Cycle 4 Induction (n=0,11)
    9999 ± 9999
    84.1 ± 13.80
        Satisfaction domain Cycle 5 Induction (n=0,9)
    9999 ± 9999
    91.7 ± 8.84
        Satisfaction domain Cycle 6 Induction (n=0,2)
    9999 ± 9999
    93.8 ± 8.84
        Satisfaction domain Cycle 8 Induction (n=0,40)
    9999 ± 9999
    91.3 ± 9.47
        Satisfaction domain Cycle 2 Treatment (n=1,0)
    87.5 ± 99999
    9999 ± 9999
        Satisfaction domain Cycle 3 Treatment (n=30,0)
    83.3 ± 11.53
    9999 ± 9999
        Satisfaction domain Cycle 4 Treatment (n=20,0)
    85.6 ± 13.62
    9999 ± 9999
        Satisfaction domain Cycle 5 Treatment (n=9,0)
    83.3 ± 8.84
    9999 ± 9999
        Satisfaction domain Cycle 6 Treatment (n=13,0)
    84.6 ± 14.57
    9999 ± 9999
        Satisfaction domain Cycle 8 Treatment (n=54,0)
    91.2 ± 12.76
    9999 ± 9999
        Satisfaction domain Cycle 2 Maintenance (n=0,33)
    9999 ± 9999
    92.0 ± 9.28
        Satisfaction domain Cycle 3 Maintenance (n=0,6)
    9999 ± 9999
    79.2 ± 20.41
        Satisfaction domain Cycle 4 Maintenance (n=0,1)
    9999 ± 9999
    100.0 ± 99999
        Satisfaction domain Cycle 5 Maintenance (n=0,8)
    9999 ± 9999
    79.7 ± 16.28
        Satisfaction domain Cycle 6 Maintenance (n=0,2)
    9999 ± 9999
    87.5 ± 17.68
        Satisfaction domain Cycle 7 Maintenance (n=0,39)
    9999 ± 9999
    94.2 ± 9.00
        Satisfaction domain Cycle 8 Maintenance (n=0,4)
    9999 ± 9999
    93.8 ± 7.22
        Satisfaction domain Cycle 10 Maintenance (n=0,1)
    9999 ± 9999
    50.0 ± 99999
        Satisfaction domain Cycle 12 Maintenance (n=0,47)
    9999 ± 9999
    91.0 ± 13.21
        Satisfaction domain End of treatment (n=0,3)
    9999 ± 9999
    75.0 ± 21.65
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 54 months
    Adverse event reporting additional description
    Post study start AEs (AEs occurring on the day of or after the first administration of study drug and up to 28 days after the last dose) and is defined as treatment-emergent adverse event (TEAE). All-Cause Mortality is reported for the ITT population
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Diffuse Large B-Cell Lymphoma (DLBCL)
    Reporting group description
    		 Participants with DLBCL, who had received at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); or bendamustine as per standard local practice.

    Reporting group title
    Follicular Lymphoma (FL)
    Reporting group description
    		 Participants with CD20+ non-Hodgkin's (FL), who had received at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); or bendamustine as per standard local practice.

    Serious adverse events
    		 Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 72 (36.11%)
    23 / 86 (26.74%)
         number of deaths (all causes)
    14
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostatic Adenoma
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 86 (1.16%)
         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
    Chylothorax
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    5 / 72 (6.94%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Meniscus Injury
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 86 (1.16%)
         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 / 72 (1.39%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Tachycardia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Monoparesis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    15 / 72 (20.83%)
    13 / 86 (15.12%)
         occurrences causally related to treatment / all
    3 / 23
    5 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    4 / 72 (5.56%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Subileus
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (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
    0 / 72 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder Diverticulum
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella Infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Micrococcus Infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 72 (69.44%)
    56 / 86 (65.12%)
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    9 / 72 (12.50%)
    1 / 86 (1.16%)
         occurrences all number
    13
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    5 / 72 (6.94%)
    0 / 86 (0.00%)
         occurrences all number
    6
    0
    Headache
         subjects affected / exposed
    3 / 72 (4.17%)
    7 / 86 (8.14%)
         occurrences all number
    4
    8
    Paraesthesia
         subjects affected / exposed
    9 / 72 (12.50%)
    7 / 86 (8.14%)
         occurrences all number
    11
    7
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    21 / 72 (29.17%)
    20 / 86 (23.26%)
         occurrences all number
    32
    46
    Anaemia
         subjects affected / exposed
    11 / 72 (15.28%)
    6 / 86 (6.98%)
         occurrences all number
    15
    10
    Leukopenia
         subjects affected / exposed
    2 / 72 (2.78%)
    7 / 86 (8.14%)
         occurrences all number
    3
    20
    Thrombocytopenia
         subjects affected / exposed
    4 / 72 (5.56%)
    3 / 86 (3.49%)
         occurrences all number
    8
    14
    Lymphopenia
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 86 (5.81%)
         occurrences all number
    1
    19
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    11 / 72 (15.28%)
    15 / 86 (17.44%)
         occurrences all number
    15
    23
    Asthenia
         subjects affected / exposed
    14 / 72 (19.44%)
    3 / 86 (3.49%)
         occurrences all number
    14
    3
    Influenza Like Illness
         subjects affected / exposed
    2 / 72 (2.78%)
    9 / 86 (10.47%)
         occurrences all number
    2
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 72 (9.72%)
    7 / 86 (8.14%)
         occurrences all number
    8
    11
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal Pain
         subjects affected / exposed
    5 / 72 (6.94%)
    0 / 86 (0.00%)
         occurrences all number
    5
    0
    Cough
         subjects affected / exposed
    6 / 72 (8.33%)
    15 / 86 (17.44%)
         occurrences all number
    7
    19
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 72 (0.00%)
    6 / 86 (6.98%)
         occurrences all number
    0
    7
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    4 / 72 (5.56%)
    4 / 86 (4.65%)
         occurrences all number
    4
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 86 (5.81%)
         occurrences all number
    1
    6
    Herpes Zoster
         subjects affected / exposed
    0 / 72 (0.00%)
    5 / 86 (5.81%)
         occurrences all number
    0
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2014
    The first protocol amendment led to protocol version 3, dated 04 Mar 2014, and was implemented for the following reasons: The CT scan timelines were modified from 35 to 45 days prior the first IV administration of rituximab; The meaning of the previous statement on first dosing was clarified;The procedures for enrollment in this study, in particular in the Maintenance period, were clarified; Changes in some inclusion/exclusion criteria were made for better clarity; Guidelines reference for the management of HBV patients was provided; Details for PRO data collection were provided; Details on the actual SAE reporting process were provided; Details on patient discontinuation procedures were given.
    05 Jul 2016
    The second protocol amendment led to protocol version 4, dated 05 July 2016, and was implemented for the following reasons: An intermediate analysis was considered necessary to analyse all patients who concluded the Induction phase regarding the safety and PK endpoints (i.e. the analysis performed for the interim Clinical Study Report); Due to inconsistencies between the core text and schedule of assessments, the “Early termination/End of Treatment visit” was added in the Protocol Appendix 11.1 and 11.1.1; Changes in protocol Section 4.3.4 regarding post-study access to Rituximab SC were made in agreement with new requirements.

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

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