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    Summary
    EudraCT Number:2021-000009-25
    Sponsor's Protocol Code Number:19PH226
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-02-02
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2021-000009-25
    A.3Full title of the trial
    Rituximab therapy in anti-MAG patients with characteristics of good responders:
    THERAMAG study
    Traitement par Rituximab de patients avec neuropathie anti-MAG et facteurs de bonne réponse: l’étude THERAMAG
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Rituximab therapy in anti-MAG patients with characteristics of good responders:
    THERAMAG study
    Traitement par Rituximab de patients avec neuropathie anti-MAG et facteurs de bonne réponse: l’étude THERAMAG
    A.3.2Name or abbreviated title of the trial where available
    THERAMAG
    THERAMAG
    A.4.1Sponsor's protocol code number19PH226
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCHU SAINT-ETIENNE
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCHU SAINT-ETIENNE
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU SAINT-ETIENNE
    B.5.2Functional name of contact pointProject manager
    B.5.3 Address:
    B.5.3.1Street AddressBâtiment recherche - Hôpital Nord
    B.5.3.2Town/ citySAINT-ETIENNE
    B.5.3.3Post code42055
    B.5.3.4CountryFrance
    B.5.4Telephone number33477120469
    B.5.5Fax number33477127820
    B.5.6E-mailcarine.labruyere@chu-st-etienne.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Rituximab
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMabThera
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Anti-MAG neuropathy
    neuropathie anti-MAG
    E.1.1.1Medical condition in easily understood language
    Anti-MAG neuropathy
    neuropathie anti-MAG
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10066137
    E.1.2Term Anti-MAG neuropathy
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Demonstrate the efficacy of rituximab versus placebo in a subgroup of anti-MAG patients presumed as good clinical responders to improve neurological disability assessed by I-RODS score between baseline and 12 months.
    Evaluer l'efficacité du rituximab par rapport au placebo chez des patients atteints de neuropathie anti-MAG potentiels bons répondeurs cliniques en terme d’amélioration clinique évaluée par le score I-RODS à 12 mois.
    E.2.2Secondary objectives of the trial
    1- Evaluate the efficacy of rituximab versus placebo in a subgroup of anti-MAG patients presumed as good clinical responders to improve neurological disability assessed by I-RODS score between baseline and 6 months.

    2- Evaluate the efficacy of rituximab versus placebo, between baseline, 6 months and 12 months, in a subgroup of anti-MAG patients presumed as good clinical responders to improve neurological disability assessed by:
    - Inflammatory Neuropathy Cause and Treatment (INCAT) disability score,
    - Six minute walk test,
    - Timed 25-foot walk test,
    - 9 hole peg test,
    - ENMG motor and sensory sum score
    - ENMG sensory sum score
    - MUNIX sum score

    3- Evaluate the tolerability and short-term safety of rituximab between baseline and 12 months.

    4- Explore the correlation between clinical response and change in anti-MAG antibody titre.
    1-Evaluer l'efficacité du rituximab par rapport au placebo chez des patients atteints de neuropathie anti-MAG potentiels bons répondeurs cliniques en terme d’amélioration clinique évaluée par le score I-RODS à 6 mois.

    2- Evaluer l'efficacité du rituximab par rapport au placebo chez des patients atteints de neuropathie anti-MAG potentiels bons répondeurs cliniques :
    - Score INCAT
    - Test de marche de 6minutes,
    - “ Timed 25-foot walk test”,
    - “9 hole peg test”,
    - Score ENMG moteur
    - Score ENMG sensitif
    - Score MUNIX
    3-Évaluer la tolérabilité et la sécurité à court terme du rituximab à 12 mois

    4- Explorer la corrélation entre la réponse clinique et le changement de titre des anticorps anti-MAG.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age over 18
    - Disease duration of 24 months or less and documented clinical worsening (clinical or ENMG or disability) over the past 12 months
    - IgM gammopathy, either MGUS or WM
    - Demyelinating polyneuropathy according to European Federation of Neurological Societies/Peripheral Nerve Society guidelines for chronic inflammatory demyelinating polyneuropathy on nerve conduction studies.
    - Anti-MAG titre of 10 000 BTU or more
    - Total INCAT score of 1 point or more at baseline
    - Absence of immunoglobulin treatment within 3 months prior to inclusion.
    - Absence of immunosuppressive therapy within 6 months prior to inclusion, including steroid therapy of 2 months or more as part of the management of neuropathy.
    - Negative β-HCG in women of childbearing potential.
    - plus de 18 ans
    - Diagnostic datant de moins de 24 mois avec une aggravation(Clinique, ENMG, handicap) au cours des 12 derniers mois
    - Gammopathie à IgM (MGUS ouWM )
    - Polyneuropathie démyélinisante avec accord avec les recommandations de la Fédération européenne des sociétés neurologiques / Société des nerfs périphériques
    - Titre Anti-MAG ≥10 000 BTU
    - Score INCAT ≥ 1 point à l’inclusion
    - Absence de traitement par immunoglobulines dans les 3 mois précédant l’inclusion.
    - Absence de traitement immunosuppresseur dans les 6 mois précédant l’inclusion, incluant l’absence de corticothérapie d’une durée de 2 mois ou plus (prescrite dans le cadre de la prise en charge de la neuropathie anti-MAG).
    - β-HCG négative chez les femmes en âge de procréer.
    E.4Principal exclusion criteria
    - Unable to give informed consent
    - History of severe allergic or anaphylactic reaction to chimeric monoclonal antibody
    - Previous treatment with rituximab
    - Diseases known to cause polyneuropathy (e.g. diabetes, uncontrolled thyroid disease, vitamin B1 or B12 deficiency, renal (GFR < 60ml ml/min/1,73 m2- MDRD formula) or liver disorder, myeloma, amyloidosis, cryoglobulinemia)
    - Indication of specific immunosuppressive therapy for WM
    - Significant uncontrolled disease at baseline such as cardiovascular (including cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine or gastrointestinal or any other significant disease that may prevent patient from participating in the study
    - Congestive heart failure (NYHA III or IV)
    - Known active bacterial, viral, fungal mycobacterial infection
    - History or known presence of recurrent or chronic infection (e.g. viral hepatitis, HIV syphilis, tuberculosis).
    - History of cancer, including solid tumors and haematological malignancies (except basal cell and in situ squamous carcinoma of the skin, in situ carcinoma of the cervix of the uterus that have been excised and resolved, with documented clear margins on pathology)
    - History of alcohol (more than two drinks a day for a woman, more than 4 glasses a day for a man [(WHO definition])) or other drug abuse within 6 months prior to randomization
    - History or currently active primary or secondary immunodeficiency
    - White blood cell count < 1500/mm3 or platelet count < 75 000/mm3
    - Incapacité à donner son consentement
    - Antécédents de réaction allergique ou anaphylactique grave à un anticorps monoclonal chimérique
    - Patient déjà traité par rituximab
    - Pathologies connues pour provoquer une polyneuropathie (par exemple diabète, maladie de la thyroïde, carence en vitamine B1 ou B12, maladie rénale (DFG < 60ml ml/min/1,73 m2- formule MDRD) ou trouble du foie, myélome, amyloïdose, cryoglobulinémie)
    - Indication d'une thérapie immunosuppressive spécifique pour la MW
    - Pathologie non contrôlée à l‘inclusion, telle que les maladies cardiovasculaires (y compris l'arythmie cardiaque), pulmonaires (y compris les maladies pulmonaires obstructives), rénales, hépatiques, endocriniennes ou gastro-intestinales ou toute autre maladie significative qui pourrait empêcher le patient de participer à l'étude
    - Insuffisance cardiaque congestive (NYHA III ou IV)
    - Infection bactérienne, virale, mycobactérienne, fongique active connue
    - Antécédents ou présence connue d'une infection récurrente ou chronique (par exemple, hépatite virale, syphilis VIH, tuberculose).
    - Antécédents de cancer, y compris de tumeurs solides et de malignités hématologiques (à l'exception du carcinome basocellulaire et du carcinome malpighien in situ de la peau, du carcinome in situ du col de l'utérus qui ont été excisés et résolus, avec des marges claires documentées sur la pathologie)
    - Antécédents d'alcool (≥ 2verres par jour pour une femme, ≥ 4 verres par jour pour un homme (selon la définition de l'OMS)) ou d'autres drogues dans les 6 mois précédant l’inclusion
    - Antécédents ou présence d’une ou immunodéficience primaire ou secondaire
    - Numération des globules blancs < 1500/mm3
    - Numération des plaquettes < 75 000/mm3
    E.5 End points
    E.5.1Primary end point(s)
    Demonstrate the efficacy of rituximab versus placebo in a subgroup of anti-MAG patients presumed as good clinical responders to improve neurological disability assessed by I-RODS score between baseline and 12 months.
    A patient will be considered with clinical response if an increase of I-RODS ≥ 4 points within 12 months is observed.
    Evaluer l'efficacité du rituximab par rapport au placebo chez des patients atteints de neuropathie anti-MAG potentiels bons répondeurs cliniques en terme d’amélioration clinique évaluée par le score I-RODS à 12 mois.
    Amélioration clinique en cas d’augmentation du score I-RODS≥ 4 points.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Months: 0, 12
    à l'inclusion et 12 mois après
    E.5.2Secondary end point(s)
    1- Evaluate the efficacy of rituximab versus placebo in a subgroup of anti-MAG patients presumed as good clinical responders to improve neurological disability assessed by I-RODS score between baseline and 6 months.

    2- Evaluate the efficacy of rituximab versus placebo, between baseline, 6 months and 12 months, in a subgroup of anti-MAG patients presumed as good clinical responders to improve neurological disability assessed by:
    - Inflammatory Neuropathy Cause and Treatment (INCAT) disability score,
    - Six minute walk test,
    - Timed 25-foot walk test,
    - 9 hole peg test,
    - ENMG motor and sensory sum score
    - ENMG sensory sum score
    - MUNIX sum score

    3- Evaluate the tolerability and short-term safety of rituximab between baseline and 12 months.
    - Adverse events.

    4- Explore the correlation between clinical response and change in anti-MAG antibody titre.
    - Anti-MAG titre.
    1-Evaluer l'efficacité du rituximab par rapport au placebo chez des patients atteints de neuropathie anti-MAG potentiels bons répondeurs cliniques en terme d’amélioration clinique évaluée par le score I-RODS à 6 mois.

    2- Evaluer l'efficacité du rituximab par rapport au placebo chez des patients atteints de neuropathie anti-MAG potentiels bons répondeurs cliniques :
    - Score INCAT
    - Test de marche de 6minutes,
    - “ Timed 25-foot walk test”,
    - “9 hole peg test”,
    - Score ENMG moteur
    - Score ENMG sensitif
    - Score MUNIX

    3-Évaluer la tolérabilité et la sécurité à court terme du rituximab à 12 mois
    - Evénements indésirables.

    4- Explorer la corrélation entre la réponse clinique et le changement de titre des anticorps anti-MAG.
    - titre des anticorps anti-MAG.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1- Months: 0, 6
    2- Months: 0, 6, 12
    3- Months: 0, 12
    4- Months: 12
    1- à l'inclusion et 6 mois après
    2- à l'inclusion, 6 et 12 mois après
    3- à l'inclusion et 12 mois après
    4- 12 mois après l'inclusion
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    therapeutic
    thérapeutique
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned22
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    dernière visite du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Aucuns
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-04-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-16
    P. End of Trial
    P.End of Trial StatusOngoing
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