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    Clinical Trial Results:
    A randomized phase III trial evaluating two strategies of rituximab administration for the treatment of first line/low tumor burden follicular lymphoma (Follicular Lymphoma IV/SC Rituximab Therapy)

    Summary
    EudraCT number
    		 2014-000128-22
    Trial protocol
    		 FR  
    Global end of trial date
    29 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2022
    First version publication date
    30 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FLIRT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02303119
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LYSARC
    Sponsor organisation address
    CH Lyon Sud - Batiment 2D, Pierre-Bénite, France,
    Public contact
    Stéphanie Doyen, LYSARC, +33 4 72 66 93 33, stephanie.doyen@lysarc.org
    Scientific contact
    Pr Guillaume Cartron, LYSA, +33 4 67 33 83 62,
    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
    29 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the efficacy of two therapeutic strategies (rituximab SC vs rituximab IV), based on the progression free survival (PFS) assessed according to response criteria for malignant lymphoma 1999 (Cheson 1999), in patients with previously untreated low tumor burden follicular lymphoma.
    Protection of trial subjects
    Premedication consisting of acetaminophen and an antihistamine should be administered before each rituximab infusion
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 223
    Worldwide total number of subjects
    223
    EEA total number of subjects
    223
    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)
    160
    From 65 to 84 years
    62
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment was performed from 02-February-2015 to 29-June-2018 in France

    Pre-assignment
    Screening details
    		 The subject’s eligibility is evaluated during the baseline period prior to the first administration of the study drug. The assessments were : Tumor biopsy, Ann Arbor Staging, Evaluation of FLIPI 1 and 2, Clinical examination, hematology and Biochemistry tests, serology. 263 patients screened, 223 patients included with 202 randomized

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard
    Arm description
    		 Rituximab IV
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    4 cycles of rituximab IV (375 mg/m²) at D1, D8, D15 and D22.

    Arm title
    		 Experimental
    Arm description
    		 Rituximab SC after 1 rituximab IV
    Arm type
    		 Experimental

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients randomized in experimental arm B will receive 8 cycles of rituximab: Rituximab IV (375 mg/m²) at the first cycle and then, in absence of grade 3-4 infusion related reaction (IRR) during cycle 1, rituximab SC (1400mg) at D8, D15, D22, M3, M5, M7 and M9

    Number of subjects in period 1 [1]
    		Standard Experimental
    Started
    102
    100
    Completed
    95
    89
    Not completed
    7
    11
         Physician decision
    -
    1
         Adverse event, non-fatal
    -
    3
         Death
    -
    1
         Progression
    5
    1
         Concurrent illness
    1
    -
         Protocol deviation
    1
    4
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In this study, we do not have 2 real periods but 2 distinct cohorts that we represent in these 2 periods. Period 1 is the principal cohort on which the main objective is analyzed
    Period 2
    Period 2 title
    overall additional trial
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 rituximab SC as of C1 cohort
    Arm description
    		 only rituximab SC
    Arm type
    		 Experimental

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients 1 to 4: In cycle 1, the administration will be split to 200mg at D1 and the second part of the split dose (1200mg) will be given on the following day, at least 12 hours after the first administration in absence of Rituximab related grade 3-4 AE Patients 5 to 20: Patients will receive 8 cycles of the full dose of Rituximab SC (1400mg) at D1, D8, D15, D22, M3, M5, M7 and M9

    Number of subjects in period 2 [2]
    		rituximab SC as of C1 cohort
    Started
    21
    Completed
    19
    Not completed
    2
         Adverse event, non-fatal
    1
         Lack of efficacy
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Period 2 is a separate cohort with additional patients independent of period 1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard
    Reporting group description
    		 Rituximab IV

    Reporting group title
    Experimental
    Reporting group description
    		 Rituximab SC after 1 rituximab IV

    Reporting group values
    		 Standard Experimental Total
    Number of subjects
    		 102 100 202
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 71 72 143
        From 65-84 years
    		 31 27 58
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 59.5 (33 to 80) 59 (32 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 57 44 101
        Male
    		 45 56 101
    Subject analysis sets

    Subject analysis set title
    Intent-to-Treat Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set includes all patients randomized regardless of study drug being received or not. Patients will be analyzed based on the assigned treatment group at the time of randomization.

    Subject analysis set title
    Efficacy Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Efficacy set includes all patients included in the ITT set with histopathologically confirmed follicular lymphoma by central review having: - received at least one dose of rituximab o For patients randomized in the arm B, only patients who correctly switched to rituximab SC after one IV cycle will be included in this set - baseline tumor assessments - at least one post baseline tumor assessment

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set includes all patients who took at least one dose of study drug. Patients will be analyzed according to the actual treatment received ("as treated")

    Subject analysis sets values
    		 Intent-to-Treat Set Efficacy Set Safety Set
    Number of subjects
    202
    175
    200
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    143
    123
    141
        From 65-84 years
    58
    51
    58
        85 years and over
    1
    1
    1
    Age continuous
    Units: years
        median (full range (min-max))
    59 (32 to 85)
    60 (32 to 85)
    59 (32 to 85)
    Gender categorical
    Units: Subjects
        Female
    101
    86
    99
        Male
    101
    89
    101

    End points

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    End points reporting groups
    Reporting group title
    Standard
    Reporting group description
    		 Rituximab IV

    Reporting group title
    Experimental
    Reporting group description
    		 Rituximab SC after 1 rituximab IV
    Reporting group title
    rituximab SC as of C1 cohort
    Reporting group description
    		 only rituximab SC

    Subject analysis set title
    Intent-to-Treat Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT set includes all patients randomized regardless of study drug being received or not. Patients will be analyzed based on the assigned treatment group at the time of randomization.

    Subject analysis set title
    Efficacy Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Efficacy set includes all patients included in the ITT set with histopathologically confirmed follicular lymphoma by central review having: - received at least one dose of rituximab o For patients randomized in the arm B, only patients who correctly switched to rituximab SC after one IV cycle will be included in this set - baseline tumor assessments - at least one post baseline tumor assessment

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set includes all patients who took at least one dose of study drug. Patients will be analyzed according to the actual treatment received ("as treated")

    Primary: PFS

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    End point title
    		 PFS
    End point description
    FLIRT SC: The Median-PFS was not reached at the end of study.
    End point type
    Primary
    End point timeframe
    6 years PFS
    End point values
    		 Standard Experimental rituximab SC as of C1 cohort
    Number of subjects analysed
    102
    100
    21
    Units: percent
        number (not applicable)
    36.1
    73.8
    0
    Attachments
    		 PFS by randomization arm - ITT set
    PFS since inclusion – Rituximab SC as of C1 cohort
    Statistical analysis title
    		 PFS by randomization arm - Stratified analysis
    Statistical analysis description
    Model is performed on 202 patients (101 events and 101 censoring) For Likelihood Ratio Chi-Square=7.07 DF=1 and Pr > Chi-Square=0.008. HR and 95% CI are from Cox regression model stratified on FLIPI at randomization
    Comparison groups
    Standard v Experimental
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.0076 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.585
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.393
         upper limit
    		 0.871
    Notes
    [1] - A two-sided log-rank test will be used for testing the difference in PFS between the two treatment arms. The significance level for the primary analysis will be 0.05. The hypothesis will be: H0: PFS (rituximab SC) = PFS (rituximab IV) vs HA: PFS (rituximab SC) ≠ PFS (rituximab IV)
    [2] - To provide 90% power to detect Hazard Ratio (HR) of 0.52 (hazard of rituximab SC versus rituximab IV) with two-sided alpha (type I error) of 0.05, a total of 102 events from both arms were required. HR of 0.52 corresponds to an increase of the median

    Secondary: OS

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    End point title
    		 OS
    End point description
    FLIRT-RANDO: The Median-OS was not reached for the both arms at the end of study. FLIRT-SC: no death were recorded.
    End point type
    Secondary
    End point timeframe
    6 years OS
    End point values
    		 Standard Experimental
    Number of subjects analysed
    102
    100
    Units: percent
        number (not applicable)
    0
    0
    Attachments
    		 OS by randomization arm - ITT set
    Statistical analysis title
    		 OS by randomization arm - Stratified analysis
    Comparison groups
    Standard v Experimental
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3354
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.551
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.161
         upper limit
    		 1.885

    Secondary: TTNLT

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    End point title
    		 TTNLT
    End point description
    The Median-TTNLT was not reached for the Experimental Arm at the end of study.
    End point type
    Secondary
    End point timeframe
    6 years
    End point values
    		 Standard Experimental
    Number of subjects analysed
    102
    100
    Units: percent
        number (not applicable)
    60.6
    0
    Attachments
    		 TTNLT by randomization arm - ITT set
    Statistical analysis title
    		 TTNLT by randomization arm - Stratified analysis
    Statistical analysis description
    Model is performed on 202 patients (85 events and 117 censoring). For Likelihood Ratio Chi-Square=0.98 DF=1 and Pr > Chi-Square=0.322. HR and 95% CI are from Cox regression model stratified on FLIPI at randomization.
    Comparison groups
    Standard v Experimental
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3218
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.806
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.526
         upper limit
    		 1.236

    Secondary: ORR at M3

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    End point title
    		 ORR at M3
    End point description
    Response according to Cheson 1999 criteria. Patients without response assessment (due to whatever reason) are considered as non-responders.
    End point type
    Secondary
    End point timeframe
    M3 or treatment discontinuation
    End point values
    		 Standard Experimental rituximab SC as of C1 cohort
    Number of subjects analysed
    102
    100
    21
    Units: percent
        number (confidence interval 95%)
    83.3 (74.7 to 90)
    80 (70.8 to 87.3)
    85.7 (63.7 to 97)
    Statistical analysis title
    		 ORR at M3 - Chi2
    Comparison groups
    Experimental v Standard
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.54
    Method
    		 Chi-squared
    Confidence interval

    Secondary: CRR at M3

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    End point title
    		 CRR at M3
    End point description
    Response according to Cheson 1999 criteria. Patients without response assessment (due to whatever reason) are considered as non-responders.
    End point type
    Secondary
    End point timeframe
    M3 or treatment discontinuation
    End point values
    		 Standard Experimental rituximab SC as of C1 cohort
    Number of subjects analysed
    102
    100
    21
    Units: percent
        number (confidence interval 95%)
    38.2 (28.8 to 48.4)
    29 (20.4 to 38.9)
    33.3 (14.6 to 57)
    Statistical analysis title
    		 CRR at M3 - Chi2
    Comparison groups
    Experimental v Standard
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.165
    Method
    		 Chi-squared
    Confidence interval

    Secondary: ORR at EoT

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    End point title
    		 ORR at EoT
    End point description
    Response according to Cheson 1999. Patients without response assessment (due to whatever reason) are considered as non-responders.
    End point type
    Secondary
    End point timeframe
    End of treatment or treatment discontinuation
    End point values
    		 Standard Experimental rituximab SC as of C1 cohort
    Number of subjects analysed
    102
    100
    21
    Units: percent
        number (confidence interval 95%)
    69.6 (59.7 to 78.3)
    80 (70.8 to 87.3)
    85.7 (63.7 to 97)
    Statistical analysis title
    		 ORR at EoT - Chi2
    Comparison groups
    Standard v Experimental
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.089
    Method
    		 Chi-squared
    Confidence interval

    Secondary: CRR at EoT

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    End point title
    		 CRR at EoT
    End point description
    Response according to Cheson 1999. Patients without response assessment (due to whatever reason) are considered as non-responders.
    End point type
    Secondary
    End point timeframe
    End of treatment or treatment discontinuation
    End point values
    		 Standard Experimental rituximab SC as of C1 cohort
    Number of subjects analysed
    102
    100
    21
    Units: percent
        number (confidence interval 95%)
    46.1 (36.2 to 56.2)
    55 (44.7 to 65)
    57.1 (34 to 78.2)
    Statistical analysis title
    		 CRR at EoT - Chi2
    Comparison groups
    Standard v Experimental
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.205
    Method
    		 Chi-squared
    Confidence interval

    Secondary: OMR at EoT

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    End point title
    		 OMR at EoT
    End point description
    Response according to Lugano 2014. Patients without response assessment (due to whatever reason) are considered as non-responders.
    End point type
    Secondary
    End point timeframe
    End of treatment or treatment discontinuation
    End point values
    		 Standard Experimental rituximab SC as of C1 cohort
    Number of subjects analysed
    102
    100
    21
    Units: percent
        number (confidence interval 95%)
    52 (41.8 to 62)
    73 (63.2 to 81.4)
    66.7 (43 to 85.4)
    Statistical analysis title
    		 OMR at EoT - Chi2
    Comparison groups
    Standard v Experimental
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.002
    Method
    		 Chi-squared
    Confidence interval

    Secondary: CMR at EoT

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    End point title
    		 CMR at EoT
    End point description
    Response according to Lugano 2014. Patients without response assessment (due to whatever reason) are considered as non-responders.
    End point type
    Secondary
    End point timeframe
    End of treatment or treatment discontinuation
    End point values
    		 Standard Experimental rituximab SC as of C1 cohort
    Number of subjects analysed
    102
    100
    21
    Units: percent
        number (confidence interval 95%)
    36.3 (27 to 46.4)
    59 (48.7 to 68.7)
    52.4 (29.8 to 74.3)
    Statistical analysis title
    		 CMR at EoT - Chi2
    Comparison groups
    Standard v Experimental
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    infections and neurological toxicities of grade 2-5 + other toxicities of grade 3-5 regardless of their relationship to investigational product occurring from the date of informed consent signature and up to 30 days after last drug administration
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Standard
    Reporting group description
    		 -

    Reporting group title
    Experimental
    Reporting group description
    		 -

    Reporting group title
    rituximab SC as of C1 cohort
    Reporting group description
    		 -

    Serious adverse events
    		 Standard Experimental rituximab SC as of C1 cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 103 (3.88%)
    12 / 97 (12.37%)
    1 / 21 (4.76%)
         number of deaths (all causes)
    3
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin cancer
         subjects affected / exposed
    0 / 103 (0.00%)
    3 / 97 (3.09%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Administration related reaction
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuralgic amyotrophy
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Injection site hypersensitivity
         subjects affected / exposed
    1 / 103 (0.97%)
    2 / 97 (2.06%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ULCER GASTRODUODENAL
         subjects affected / exposed
    1 / 103 (0.97%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pyoderma gangrenosum
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Standard Experimental rituximab SC as of C1 cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 103 (15.53%)
    30 / 97 (30.93%)
    13 / 21 (61.90%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin cancer
         subjects affected / exposed
    0 / 103 (0.00%)
    3 / 97 (3.09%)
    0 / 21 (0.00%)
         occurrences all number
    0
    3
    0
    Benign neoplasm
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Thyroid cancer
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    2 / 103 (1.94%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    3
    Induration
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    3
    Injection site pain
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Injection site rash
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Inflammation
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Injection site discomfort
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Injection site hypersensitivity
         subjects affected / exposed
    2 / 103 (1.94%)
    2 / 97 (2.06%)
    0 / 21 (0.00%)
         occurrences all number
    2
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumopathy
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Mixed anxiety and depressive disorder
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Administration related reaction
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    0
    5
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgic amyotrophy
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    3 / 103 (2.91%)
    2 / 97 (2.06%)
    0 / 21 (0.00%)
         occurrences all number
    3
    2
    0
    Gastrointestinal disorders
    ULCER GASTRODUODENAL
         subjects affected / exposed
    1 / 103 (0.97%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Large intestine polyp
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    3 / 21 (14.29%)
         occurrences all number
    0
    1
    3
    Rash
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Pyoderma gangrenosum
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Renal injury
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    3 / 103 (2.91%)
    10 / 97 (10.31%)
    0 / 21 (0.00%)
         occurrences all number
    3
    16
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 103 (0.97%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 103 (0.00%)
    2 / 97 (2.06%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal infection
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Genital infection
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphadenitis bacterial
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 97 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Acarodermatitis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Tinea cruris
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    0 / 103 (0.00%)
    0 / 97 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 97 (1.03%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2018
    Addition of a new cohort receiving exclusively subcutaneous rituximab, i.e. from the first injection, unlike the patients randomized in the experimental arm receiving intravenous on D1 followed by subcutaneous

    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
    For support, Contact us.
    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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