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    Clinical Trial Results:
    Efficacy of Rituximab at low doses in Multiple Sclerosis – A prospective, randomized, double-blind, active controlled, pilo trial

    Summary
    EudraCT number
    		 2017-000426-35
    Trial protocol
    		 AT  
    Global end of trial date
    31 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Mar 2025
    First version publication date
    16 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1.0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Spitalgasse 23, Vienna, Austria, 1090
    Public contact
    Office of the Dept. of Neurology, Medical University of Vienna - Department of Neurology, +43 1 4040031230, neurologie-sekretariat@meduniwien.ac.at
    Scientific contact
    Office of the Dept. of Neurology, Medical University of Vienna - Department of Neurology, +43 1 4040031230, neurologie-sekretariat@meduniwien.ac.at
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2025
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to investigate whether 100mg rituximab every 10-12 weeks are equally effective compared to other, currently used dosing regimens. This will be evaluated by the annualized relapse rate at 48 weeks
    Protection of trial subjects
    Only patients with already existing treatment with rituximab or patients in whom physicians intended to use rituximab were included in the study. More frequent control visits were conducted compared to the clinical routine. Emergency treatment (additional doses) were possible in the interventional group.
    Background therapy
    		 Regular treatment for Multiple was possible and this study did not interfere with the physicians decision to treat patients.
    Evidence for comparator
    		 standard dose rituximab was the comparator. As mentioned only patients in whom physicians intended rituximab treatment were included to reduce the risks for participants.
    Actual start date of recruitment
    26 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    23
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All 24 patients were recruited at the Department of Neurology, Medical University of Vienna, Austria, between 26.3.2019 and 5.8.2021.

    Pre-assignment
    Screening details
    		 The study population consisted of patients with a diagnosis of MS and an already existing treatment with rituximab, or an intended treatment with rituximab. The plan was to recruit both, treatment naive and pretreated patients.

    Period 1
    Period 1 title
    Active Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 Treatment with 100mg Rituximab at week 0, 10-12, 20-24 and 30-36
    Arm type
    		 Experimental

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100mg intravenous infusion over 60 minutes, after dilution of the appropriate amount to 20mL (Infusion speed 20mL/h) for the 100mg dose

    Arm title
    		 Control
    Arm description
    		 Standard dose rituximab 375mg/m2 at Week 0 and Week 24
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received 375mg/m2 at Week 0 and at Week 24

    Number of subjects in period 1
    		Intervention Control
    Started
    16
    8
    Completed
    12
    7
    Not completed
    4
    1
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Treatment with 100mg Rituximab at week 0, 10-12, 20-24 and 30-36

    Reporting group title
    Control
    Reporting group description
    		 Standard dose rituximab 375mg/m2 at Week 0 and Week 24

    Reporting group values
    		 Intervention Control Total
    Number of subjects
    		 16 8 24
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 15 8 23
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.4 ( 10.3 ) 38.4 ( 12.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 4 13
        Male
    		 7 4 11
    pretreatment
    Number of patients pretreated with rituximab
    Units: Subjects
        pretreatment
    		 6 3 9
        treatment-naive
    		 10 5 15
    Subject analysis sets

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients who received at least one infusion of rituximab

    Subject analysis sets values
    		 mITT
    Number of subjects
    24
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    23
        From 65-84 years
    1
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.7 ( 10.9 )
    Gender categorical
    Units: Subjects
        Female
    11
        Male
    13
    pretreatment
    Number of patients pretreated with rituximab
    Units: Subjects
        pretreatment
    9
        treatment-naive
    15

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Treatment with 100mg Rituximab at week 0, 10-12, 20-24 and 30-36

    Reporting group title
    Control
    Reporting group description
    		 Standard dose rituximab 375mg/m2 at Week 0 and Week 24

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All patients who received at least one infusion of rituximab

    Primary: CD20+ suppression

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    End point title
    		 CD20+ suppression
    End point description
    The primary endpoint are CD20+ cell counts at week 48 -successful suppression is defined as an >90% reduction from baseline
    End point type
    Primary
    End point timeframe
    week 48
    End point values
    		 Intervention Control mITT
    Number of subjects analysed
    12
    7
    19
    Units: subjects
        successful suppression
    10
    6
    16
        unsuccessful suppression
    2
    1
    3
    Statistical analysis title
    		 primary endpoint analysis Intervention
    Statistical analysis description
    Mean and 95% confidence intervals, a descriptive comparison of the control group and the intervention group is performed in a pilot non-inferiority study
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 mean (%) and 95% CI
    Point estimate
    83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 61
         upper limit
    		 100
    Notes
    [1] - pilot study, not powered for non-inferiority/superiority
    Statistical analysis title
    		 Primary Endpoint Analysis Control group
    Statistical analysis description
    Mean and 95% confidence intervals, a descriptive comparison of the control group and the intervention group is performed in a pilot non-inferiority study
    Comparison groups
    Control v Intervention
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    		 95% confidence intervals
    Parameter type
    		 mean (%) and 95% Confidence Intervals
    Point estimate
    86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 58
         upper limit
    		 100
    Notes
    [2] - pilot study, not powered for non-inferiority/superiority

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening to End of Study Visit (approximately 48 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Intervention Group
    Reporting group description
    		 all patients receiving low-dose rituximab: 100mg at week 0, week 10-12, week 20-24, week 30-36

    Reporting group title
    Control Group
    Reporting group description
    		 patients receiving standard dose rituximab 375mg/m2 at week 0 and 24

    Serious adverse events
    		 Intervention Group Control Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Cardiac disorders
    Myocardial infarction
    Additional description: one patient suffered from myocardial infarction and was hospitalized
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ulcus ventriculi
    Additional description: Patient required surgery and was hospitalized
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
    Additional description: suicide of a patient with a pre-existing depression
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention Group Control Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 16 (43.75%)
    4 / 8 (50.00%)
    Vascular disorders
    arterial hypertension
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    fatigue
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 8 (25.00%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Itching
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    anterior cruciate ligament tear
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    COVID-19
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1

    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.
    The study was prematurely terminated because of recruitment problems during the covid-19 pandemic. The study would have required immunocompromised patients to visit the hospital more often then necessary, which was against their best interest.
    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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