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    Clinical Trial Results:
    Intrathecal Rituximab in Progressive Multiple Sclerosis

    Summary
    EudraCT number
    		 2014-005493-11
    Trial protocol
    		 FR  
    Global end of trial date
    02 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Apr 2022
    First version publication date
    18 Apr 2022
    Other versions
    Summary report(s)
    		 article publié de l'étude EFFRITE

    Trial information

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    Trial identification
    Sponsor protocol code
    CHPAU2014/01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02545959
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centre Hospitalier de Pau
    Sponsor organisation address
    4 Boulevard Hauterive, Pau, France, 64046 cedex
    Public contact
    URC - Information sur Essai EFFRITE, Centre Hospitalier de Pau, +33 559726801, stephane.debeugny@ch-pau.fr
    Scientific contact
    URC - Information sur Essai EFFRITE, Centre Hospitalier de Pau, +33 559726801, stephane.debeugny@ch-pau.fr
    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
    18 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Our goal is to study the kinetics of action of a single dose of intrathecally-infused rituximab upon cerebro-spinal fluid (CSF) biological targets. The main objective of the trial is to study the osteopontin level in CSF at d4 after a single intrathecal infusion of rituximab. CSF level is expected to normalize.
    Protection of trial subjects
    - Avant la ponction lombaire : une prémédication par antihistaminique et 120 mg de méthylprednisolone sera préalablement administrée avant chaque injection de rituximab. - Après la ponction lombaire : mise en position de Trendelenburg pendant 4 heures pour favoriser la diffusion du traitement vers l’encéphale et éviter les événements secondaires (douleurs, céphalées)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 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: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    7
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Tous les patients ont été recrutés au CH de Pau de novembre 2015 à août 2018

    Pre-assignment
    Screening details
    		 Inclusion criteria: Age ≥45 years, male or female Secondary or primary progressive MS, in progressive phase since >2 years EDSS ≥6.0 Absence of alternative therapy Exclusion criteria: Relapsing phase of MS Contraindication to MRI, lumbar puncture Active infection or immunosuppressive state or treatment Dementia, severe psychiatric disorder

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 méthylprednisolone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    méthylprednisolone
    Investigational medicinal product code
    H02AB04
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    120 mg milligrams for intravenous use

    Arm title
    		 Rituximab IT
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    L01XC02
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    20 mg milligrams Rituximab solution for injection in intrathecal use

    Arm title
    		 Rituximab IT + IV
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    L01XC02
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use, Intrathecal use
    Dosage and administration details
    375 mg/m2 milligrams/square meter for intravenous use and 20 mg milligrams for intrathecal use

    Number of subjects in period 1
    		méthylprednisolone Rituximab IT Rituximab IT + IV
    Started
    2
    4
    4
    Completed
    2
    4
    4

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    méthylprednisolone
    Reporting group description
    		 -

    Reporting group title
    Rituximab IT
    Reporting group description
    		 -

    Reporting group title
    Rituximab IT + IV
    Reporting group description
    		 -

    Primary: Change in osteopontin level between D0 and D4

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    End point title
    		 Change in osteopontin level between D0 and D4
    End point description
    End point type
    Primary
    End point timeframe
    The primary end point consist to mesure changes in osteopontin level between D0 and D4
    End point values
    		 méthylprednisolone Rituximab IT Rituximab IT + IV
    Number of subjects analysed
    2
    4
    4
    Units: ng/ml
        arithmetic mean (standard deviation)
    7.2 ± 26.9
    25.7 ± 26.0
    4.5 ± 23.2
    Statistical analysis title
    		 changes D0-D4 in osteopontin levels
    Comparison groups
    méthylprednisolone v Rituximab IT v Rituximab IT + IV
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.44
    Method
    		 Kruskal-wallis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Période de novembre 2015 à septembre 2019
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    méthylprednisolone
    Reporting group description
    		 -

    Reporting group title
    Rituximab IT
    Reporting group description
    		 -

    Reporting group title
    Rituximab IT+IV
    Reporting group description
    		 -

    Serious adverse events
    		 méthylprednisolone Rituximab IT Rituximab IT+IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 méthylprednisolone Rituximab IT Rituximab IT+IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    Injury, poisoning and procedural complications
    Lumbar puncture abnormal
    Additional description: one lumbar puncture failed after multiple attempts at M6 for a patient of the IV+IT group.
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2018
    Description : Proposition pour les patients inclus dans le groupe contrôle (corticothérapie IV seule), à l’issue de leur suivi, de poursuivre l’étude en étant randomisés dans un des groupes de traitement actif (Rituximab IT ou Rituximab IT+IV) Reason : Depuis le début de cette étude, le contexte thérapeutique s'est modifié en raison de la mise sur le marché de traitements de la forme progressive (biotine) ou d'une utilisation croissante off-label du Rituximab IV. Pour des raisons éthiques évidentes, nous souhaitons proposer aux patients du groupe contrôle (corticoïdes IV seuls) de pouvoir bénéficier secondairement, c'est à dire dans l'année suivant l'inclusion, d'un des traitements de l'étude (Rituximab IT ou Rituximab IT+IV). Ainsi ces patients seraient leurs propres témoins dans le cadre de l'étude.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33763241
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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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