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    Summary
    EudraCT Number:2019-004088-34
    Sponsor's Protocol Code Number:APHP180571
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-10-23
    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 number2019-004088-34
    A.3Full title of the trial
    Effect of two injections of synchronized methotrexate with the first injection of Adalimumab to prevent anti-adalimumab immunization in spondyloarthritis
    Effet de deux injections de MEthotrexate SYNchronisées avec la première injection d'ADalimumab pour prévenir l'immunisation anti-adalimumab dans les spondyloarthrites
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of two injections of synchronized methotrexate with the first injection of Adalimumab to prevent anti-adalimumab immunization in spondyloarthritis
    Effet de deux injections de MEthotrexate SYNchronisées avec la première injection d'ADalimumab pour prévenir l'immunisation anti-adalimumab dans les spondyloarthrites
    A.3.2Name or abbreviated title of the trial where available
    MESYNAD
    MESYNAD
    A.4.1Sponsor's protocol code numberAPHP180571
    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 SponsorASSISTANCE PUBLIQUE - HOPITAUX DE PARIS ( AP-HP)
    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 supportDGOS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS ( AP-HP)
    B.5.2Functional name of contact pointisabelle Vivaldo
    B.5.3 Address:
    B.5.3.1Street AddressDRCI Hôpital St Louis, 1 av claude vellefaux
    B.5.3.2Town/ cityparis
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.6E-mailisabelle.vivaldo@aphp.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 METHOTREXATE
    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 nameMETHOTREXATE
    D.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETHOTREXATE 10mg/0.20ml
    D.3.9.3Other descriptive nameMETHOTREXATE
    D.3.9.4EV Substance CodeSUB08856MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    adult patients with Axial Spondyloarthritis who have an indication for anti-TNF therapy
    patients adultes atteints de spondyloarthrite axiale et ayant une indication à la mise sous anti-TNF
    E.1.1.1Medical condition in easily understood language
    Spondyloarthritis
    spondyloarthrite
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10028395
    E.1.2Term Musculoskeletal and connective tissue disorders
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10071400
    E.1.2Term Axial spondyloarthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective: To assess if 2 infusions of methotrexate the day and the day before the first infusion of adalimumab (day 1 and day 2) could prevent anti adalimumab antibodies formation at month 6 in patients with spondyloarthritis (SpA)
    Objectif : Evaluer si deux injections de Méthotrexate (MTX) encadrant la première injection d'adalimumab permettent de prévenir l'apparition d'ADAb anti-adalimumab à 6 mois chez des patients traités pour une spondyloarthrite (SpA) axiale
    E.2.2Secondary objectives of the trial
    Secondary objectives:
    o To compare trough levels of adalimumab at month 1, 3, 6 and 12 in the 2 groups.
    o To compare the percentage of immunized patients at month 1, 3 and 12 in the 2 groups
    o To compare safety in the 2 groups
    o To compare response to adalimumab in the 2 groups
    o To study the mode of action for inducing tolerization at the cellular level.
    Objectifs secondaires :
    - Comparer le taux sérique résiduel d'adalimumab à 1, 3, 6 et 12 mois dans les deux groupes de traitement
    - Comparer le taux d’immunisation anti-adalimumab à 1, 3 et 12 mois dans les deux groupes de traitement
    - Comparer la tolérance de ces deux stratégies thérapeutiques
    - Comparer l'efficacité thérapeutique à 3, 6 et 12 mois
    - Etudier les mécanismes cellulaires à l’origine de cette tolérisation spécifique
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A specific biological evaluation will be carried out as part of an ancillary study for
    o Look for regulatory populations specific for adalimumab (regulatory T and B lymphocytes)
    o Evaluate whether the initial level of BAFF (B cell Activating Factor of the TNF Family is predictive of immunization prevention capacity
    Une évaluation biologique spécifique sera effectuée dans le cadre d’une étude ancillaire pour (dosages financés par des budgets spécifiques n’entrant pas dans le cadre de ce PHRC) :
    o Rechercher des populations régulatrices spécifiques de l’adalimumab (lymphocytes T et B régulateurs)
    o Evaluer si le taux de BAFF (B cell Activating Factor of the TNF Family) initial est prédictif de la capacité de prévention de l’immunisation
    E.3Principal inclusion criteria
    Inclusion criteria :
    - Patients aged from 18 to 90
    - Patients suffering from axial SpA, radiographic or non-radiographic according to ASAS criteria (peripheral involvement and/or Inflammatory bowel diseases could be present).
    - Expected Treatment with adalimumab: ie resistant to at least 2 lines of NSAIDs and without contraindications to adalimumab such as: Hypersensitivity, developing tuberculosis or other severe infections such as sepsis and opportunistic infections, heart failure Insufficiency moderate to severe (NYHA classes III / IV)
    - No previous treatment with MTX in the last 3 months
    - Stable dosage of steroids (less than 10mg/day of prednisone equivalent) and/or of NSAIDs for at least 10 days
    - Contraception
    - Informed and written consent
    - Social insurance
    E.4Principal exclusion criteria
    Non-inclusion criteria :
    - Contraindication to MTX
    - Previous treatment with adalimumab
    - Steroids more than 10mg/day of prednisone equivalent
    - Previous treatment with:
    o Etanercept in the last month
    o Infliximab, golimumab, certolizumab in the last 2 months
    o Previous treatment hereafter these dates with anti-TNF except adalimumab or secukinumab are not a counterindication
    - Current immunosuppressive drugs except MTX
    - Current and proven pregnancy
    - Project of pregnancy in the next 3 months following inclusion
    - Legal safeguards
    - Inclusion in another interventional research project
    E.5 End points
    E.5.1Primary end point(s)
    percentage of patients with ADAb anti-adalimumab at 6 months.
    pourcentage de patients présentant des ADAb anti-adalimumab à 6 mois.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 mois
    E.5.2Secondary end point(s)
    - The residual serum drug level at 1.3, 6 and 12 months. This rate will be measured by the same MSD technique validated by ABIRISK study. In patients who have had to change their treatment, the last remaining adalimumab level will be considered.
    - The proportion of patients immunized at 1, 3 and 12 months in both treatment groups
    - The tolerance of the two therapeutic strategies will be evaluated by the number of adverse effects (AE: adverse events and SAE: serious adverse events)
    - Therapeutic efficacy at 3, 6 and 12 months will be evaluated by
    (a) the number of patients with clinically relevant ASDAS (Ankylosing Spondylitis Disease Activity Score) improvement (at least 1.1 points),
    (b) an improvement of at least two points of BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) under the original treatment (adalimumab) (for these 2 criteria patients who had to change their treatment before the evaluation will be classified as failing therapeutic),
    (c) therapeutic maintenance with adalimumab at 3, 6 and 12 months and
    (d) Nonsteroidal anti-inflammatory drug (NSAID) savings assessed by the ASAS-NSAIDS score.
    - A specific biological evaluation will be carried out via an ancillary study.
    - Le taux sérique résiduel de médicament à 1,3, 6 et 12 mois. Ce taux sera mesuré par la même technique MSD validée par ABIRISK. Chez les patients ayant dû changer de traitement (switcher), on considèrera le dernier taux résiduel sous adalimumab.
    - La proportion de patients immunisés à 1, 3 et 12 mois dans les deux groupes de traitement
    - La tolérance des deux stratégies thérapeutiques sera évaluée par le nombre d’effets indésirables (AE : adverse events et SAE : serious adverse events)
    - L'efficacité thérapeutique à 3, 6 et à 12 mois sera évaluée par
    (a) le nombre de patients présentant une amélioration cliniquement pertinente d’ASDAS (Ankylosing Spondylitis Disease Activity Score) (au moins 1,1 points),
    (b) une amélioration d’au moins deux points de BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) sous le traitement d’origine (adalimumab) (pour ces 2 critères les patients ayant dû changer de traitement avant l’évaluation seront classés en échec thérapeutique),
    (c) le maintien thérapeutique sous adalimumab à 3, 6 et 12 mois et
    (d) l’épargne en anti-inflammatoire non stéroïdien (AINS) évaluée par le score ASAS-NSAIDS.
    - Une évaluation biologique spécifique sera effectuée via une étude ancillaire.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1, 3, 6 and 12 months
    1, 3, 6 et 12 mois
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) Yes
    E.8.2.2Placebo No
    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 concerned17
    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 No
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 83
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 41
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state124
    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
    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 Decision2019-12-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-02-27
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