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    Clinical Trial Results:
    Open-Label, Single-arm, Phase IIIb Clinical Trial to Evaluate the Safety of Switching from Intravenous Rituximab to Subcutaneous Rituximab During First-Line Treatment for CD20+ Non-Hodgkin's Follicular Lymphoma and Diffuse Large B-cell Lymphoma

    Summary
    EudraCT number
    		 2013-001118-14
    Trial protocol
    		 ES  
    Global end of trial date
    11 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Apr 2018
    First version publication date
    20 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML28943
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01987505
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, + 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Apr 2017
    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 Nov 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
    Spain: 140
    Worldwide total number of subjects
    140
    EEA total number of subjects
    140
    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)
    80
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 140 subjects were enrolled across 39 sites in Spain.

    Pre-assignment
    Screening details
    		 This study included adult subjects with CD20+ diffuse large B-cell lymphoma or CD20+ follicular lymphoma, who had already received at least one complete dose of rituximab IV during induction or maintenance.

    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 Rituximab
    Arm description
    		 Subjects with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab were treated with subcutaneous (SC) rituximab during first-line treatment. Subjects with FL were administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Subjects with DLBCL were administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration was expected to last up to 7 months for subjects with DLBCL and up to 32 months for subjects with FL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab SC
    Investigational medicinal product code
    Other name
    MabThera Rituxan
    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 Rituximab
    Started
    140
    Completed
    106
    Not completed
    34
         Consent withdrawn by subject
    2
         Death
    4
         Unknown
    9
         Other Reason
    2
         Investigator Decision
    2
         Lost to follow-up
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Subcutaneous Rituximab
    Reporting group description
    		 Subjects with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab were treated with subcutaneous (SC) rituximab during first-line treatment. Subjects with FL were administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Subjects with DLBCL were administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration was expected to last up to 7 months for subjects with DLBCL and up to 32 months for subjects with FL.

    Reporting group values
    		 Subcutaneous Rituximab Total
    Number of subjects
    		 140 140
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 80 80
        From 65-84 years
    		 60 60
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.2 ± 12.4 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 65 65
        Male
    		 75 75
    Race/Ethnicity, Customized
    Units: Subjects
        Black
    		 1 1
        Caucasian
    		 139 139
    Subject analysis sets

    Subject analysis set title
    Diffuse Large B-Cell Lymphoma (DLBCL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab were treated with subcutaneous (SC) rituximab. Subjects with DLBCL were administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration was expected to last up to 7 months for subjects with DLBCL.

    Subject analysis set title
    Follicular Lymphoma (FL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with CD20+ non-Hodgkin's follicular lymphoma (FL), who had already received at least one full dose of intravenous (IV) rituximab were treated with subcutaneous (SC) rituximab. Subjects with FL were administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Treatment duration was expected to last to 32 months for subjects with FL.

    Subject analysis sets values
    		 Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects
    29
    111
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    14
    66
        From 65-84 years
    15
    45
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    62.5 ± 12.0
    59.6 ± 12.5
    Sex: Female, Male
    Units: Subjects
        Female
    12
    53
        Male
    17
    58
    Race/Ethnicity, Customized
    Units: Subjects
        Black
    0
    1
        Caucasian
    29
    110

    End points

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    End points reporting groups
    Reporting group title
    Subcutaneous Rituximab
    Reporting group description
    		 Subjects with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab were treated with subcutaneous (SC) rituximab during first-line treatment. Subjects with FL were administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Subjects with DLBCL were administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration was expected to last up to 7 months for subjects with DLBCL and up to 32 months for subjects with FL.

    Subject analysis set title
    Diffuse Large B-Cell Lymphoma (DLBCL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab were treated with subcutaneous (SC) rituximab. Subjects with DLBCL were administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration was expected to last up to 7 months for subjects with DLBCL.

    Subject analysis set title
    Follicular Lymphoma (FL)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with CD20+ non-Hodgkin's follicular lymphoma (FL), who had already received at least one full dose of intravenous (IV) rituximab were treated with subcutaneous (SC) rituximab. Subjects with FL were administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Treatment duration was expected to last to 32 months for subjects with FL.

    Primary: Percentage of Subjects with Administration-Associated Reactions (AARs)

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    End point title
    		 Percentage of Subjects with Administration-Associated Reactions (AARs) [1]
    End point description
    AARs were defined as all adverse events (AEs) occurring within 24 hours of rituximab SC 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. Safety Population included all enrolled subjects who received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to 32 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: Only descriptive analysis was planned to be reported for the Primary Endpoint. Therefore, no statistical analysis is provided.
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: percentage of subjects
    number (not applicable)
        At Least One AAR
    48.6
    34.5
    52.3
        At Least One AAR Grade ≥ 3
    2.1
    0
    2.7
        At Least One Serious AARs
    1.4
    0
    1.8
        Generalised or Remote from the Injection Site AARs
    15.1
    57.9
    11.1
        Localised at the injection site AARs
    84.9
    42.1
    88.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with At Least One Grade >/= 3 Adverse Event (AE)

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    End point title
    		 Percentage of Subjects with At Least One Grade >/= 3 Adverse Event (AE)
    End point description
    An adverse event was any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can, therefore, be any unfavorable 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 worsen during a study are also considered as adverse events. Grading was completed according to the CTCAE, version 4.0. Safety Population included all enrolled subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: percentage of subjects
        number (not applicable)
    38.6
    48.3
    36.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with At Least One Grade >/= 3 Infusion/ Injection Related Reaction (IIRR)

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    End point title
    		 Percentage of Subjects with At Least One Grade >/= 3 Infusion/ Injection Related Reaction (IIRR)
    End point description
    Grading of IIRRs was completed according to the CTCAE, version 4.0. Safety Population included all enrolled subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: percentage of subjects
        number (not applicable)
    2.1
    0.0
    2.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with At Least One Serious Adverse Event (SAE)

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    End point title
    		 Percentage of Subjects with At Least One Serious Adverse Event (SAE)
    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. Safety Population included all enrolled subjects who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: percentage of subjects
        number (not applicable)
    30.0
    37.9
    27.9
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS)

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    End point title
    		 Event-Free Survival (EFS)
    End point description
    EFS was defined as the time from first dose of rituximab IV to first occurrence of progressive disease (PD) or relapse, according to the International Working Group (IWG) response criteria or initiation of a non–protocol-specified anti-lymphoma therapy or death, whichever occurs first. PD: >/= 50% increase lymph nodes and nodal mass size, any new lesion, enlarged liver/spleen, reappearance bone marrow abnormalities. Intent-to-Treat (ITT) population included all enrolled subjects.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: months
        arithmetic mean (confidence interval 95%)
    52.314 (49.162 to 55.466)
    25.79 (20.800 to 30.776)
    54.39 (51.416 to 57.362)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    PFS was defined as the time from first dose of rituximab IV to the first occurrence of progressive disease (PD) or relapse, according to the International Working Group (IWG) response criteria or death from any cause. PD: >/= 50% increase lymph nodes and nodal mass size, any new lesion, enlarged liver/spleen, reappearance bone marrow abnormalities. The ITT population included all enrolled subjects.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: months
        arithmetic mean (confidence interval 95%)
    53.118 (50.108 to 56.127)
    27.952 (23.443 to 32.460)
    54.389 (51.416 to 57.362)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time from first dose of rituximab IV to death from any cause. The ITT population included all enrolled subjects.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: months
        arithmetic mean (confidence interval 95%)
    59.516 (57.999 to 61.033)
    37.42 (33.354 to 41.485)
    60.61 (59.692 to 61.535)
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS)

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    End point title
    		 Disease-Free Survival (DFS)
    End point description
    DFS was assessed in subjects achieving complete response (CR) including complete response unconfirmed (Cru) and was defined as the period from the date of the initial CR/CRu until the date of relapse or death from any cause. CR: 1) disappearance of all evidence/symptoms of disease, 2) lymph nodes and nodal masses normal size, 3) enlarged spleen must have regressed in size, 4) normal bone marrow; CRu: see 1) and 3) of CR plus > 75% decrease in residual lymph node mass, indeterminate bone marrow. The ITT population included all enrolled subjects. Here, 99999 signifies that there were no events in this arm, therefore mean and 95% Confidence Interval could not be calculated.
    End point type
    Secondary
    End point timeframe
    Up to 32 months
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: months
        arithmetic mean (confidence interval 95%)
    33.044 (31.489 to 34.600)
    26.062 (23.510 to 28.613)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Treatment Response Rate

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    End point title
    		 Treatment Response Rate
    End point description
    Treatment response rate was classified according to the International Working Group (IWG) response criteria: CR/Cru, partial response (PR), stable disease (SD) and PD. CR: 1) disappearance of all evidence/symptoms of disease, 2) lymph nodes and nodal masses normal size, 3) enlarged spleen must have regressed in size, 4) normal bone marrow; CRu: see 1) and 3) of CR plus > 75% decrease in residual lymph node mass, indeterminate bone marrow; PR: >/= 50% decrease lymph nodes and nodal mass size; decrease in liver/spleen size, no new sites; SD: less than a PR, but is not PD; PD: >/= 50% increase lymph nodes and nodal mass size, any new lesion, enlarged liver/spleen, reappearance bone marrow abnormalities. ITT population included all enrolled subjects.
    End point type
    Secondary
    End point timeframe
    4-6 weeks after the last dose of Induction (Up to approximately 8 months)
    End point values
    		 Subcutaneous Rituximab Diffuse Large B-Cell Lymphoma (DLBCL) Follicular Lymphoma (FL)
    Number of subjects analysed
    140
    29
    111
    Units: percentage of subjects
    number (not applicable)
        Complete Response (CR)
    64.3
    62.1
    66.7
        Complete Response Unconfirmed (CRu)
    5.4
    3.4
    7.4
        Partial Response (PR)
    7.1
    3.4
    11.1
        Stable Disease (SD)|
    1.8
    0.0
    3.7
        Progressive disease (PD)
    12.5
    17.2
    7.4
        Unable to Assess (UA)
    3.6
    6.9
    0.0
        Not Evaluable
    5.4
    6.9
    3.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 32 months
    Adverse event reporting additional description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. Safety Population included all enrolled subjects who received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Subcutaneous Rituximab
    Reporting group description
    		 Subjects with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab were treated with subcutaneous (SC) rituximab during first-line treatment. Subjects with FL were administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Subjects with DLBCL were administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration was expected to last up to 7 months for subjects with DLBCL and up to 32 months for subjects with FL.

    Serious adverse events
    		 Subcutaneous Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 140 (30.00%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastric neoplasm
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    12 / 140 (8.57%)
         occurrences causally related to treatment / all
    5 / 15
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    10 / 140 (7.14%)
         occurrences causally related to treatment / all
    8 / 13
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Intestinal obstruction
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Paraesthesia oral
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 140 (2.14%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 140 (2.86%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    4 / 140 (2.86%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Subcutaneous Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    117 / 140 (83.57%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 140 (5.00%)
         occurrences all number
    8
    Headache
         subjects affected / exposed
    11 / 140 (7.86%)
         occurrences all number
    15
    Paraesthesia
         subjects affected / exposed
    14 / 140 (10.00%)
         occurrences all number
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 140 (9.29%)
         occurrences all number
    23
    Neutropenia
         subjects affected / exposed
    24 / 140 (17.14%)
         occurrences all number
    39
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    31 / 140 (22.14%)
         occurrences all number
    41
    Injection site erythema
         subjects affected / exposed
    12 / 140 (8.57%)
         occurrences all number
    29
    Pain
         subjects affected / exposed
    9 / 140 (6.43%)
         occurrences all number
    10
    Pyrexia
         subjects affected / exposed
    14 / 140 (10.00%)
         occurrences all number
    17
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 140 (9.29%)
         occurrences all number
    13
    Diarrhoea
         subjects affected / exposed
    22 / 140 (15.71%)
         occurrences all number
    34
    Dyspepsia
         subjects affected / exposed
    8 / 140 (5.71%)
         occurrences all number
    8
    Nausea
         subjects affected / exposed
    12 / 140 (8.57%)
         occurrences all number
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 140 (10.00%)
         occurrences all number
    20
    Productive cough
         subjects affected / exposed
    9 / 140 (6.43%)
         occurrences all number
    9
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    36 / 140 (25.71%)
         occurrences all number
    97
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 140 (9.29%)
         occurrences all number
    16
    Back pain
         subjects affected / exposed
    15 / 140 (10.71%)
         occurrences all number
    15
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    23 / 140 (16.43%)
         occurrences all number
    32
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 140 (8.57%)
         occurrences all number
    19
    Urinary tract infection
         subjects affected / exposed
    11 / 140 (7.86%)
         occurrences all number
    13
    Viral upper respiratory tract infection
         subjects affected / exposed
    21 / 140 (15.00%)
         occurrences all number
    29

    More information

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

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

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