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    Summary
    EudraCT Number:2021-001560-14
    Sponsor's Protocol Code Number:FJD-RA-TOF-60418809
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-11
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2021-001560-14
    A.3Full title of the trial
    Single-center, open-label, uncontrolled clinical trial to evaluate the association between the expression of the JAK / STAT pathway and the response to tofacitinib in patients with refractory rheumatoid arthritis.
    Ensayo clínico unicéntrico, abierto, no controlado, para evaluar la asociación entre la expresión de la vía JAK/STAT y la respuesta a tofacitinib en pacientes con artritis reumatoide refractaria
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Use of tofacitinib in patients with treatment-refractory rheumatoid arthritis.
    Uso de tofaitinib en pacientes con AR refractaria a tratamiento
    A.4.1Sponsor's protocol code numberFJD-RA-TOF-60418809
    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 SponsorFUNDACION JIMENEZ DIAZ HEALTH RESEARCH INSTITUTE
    B.1.3.4CountrySpain
    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 supportINSTITUTO DE SALUD CARLOS III
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFUNDACION JIMENEZ DIAZ HEALTH RESEARCH INSTITUTE
    B.5.2Functional name of contact pointUNIDAD DE INVESTIGACION CLINICA
    B.5.3 Address:
    B.5.3.1Street AddressAVDA REYES CATOLICOS N2
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28040
    B.5.3.4CountrySpain
    B.5.4Telephone number+349155048003214
    B.5.6E-mailmireia.arcas@fjd.es
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 XELJANZ
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical form Prolonged-release tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTOFACITINIB
    D.3.9.1CAS number 477600-75-2
    D.3.9.4EV Substance CodeSUB33104
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Refractory rheumatoid arthritis
    Artritis reumatoide refractaria
    E.1.1.1Medical condition in easily understood language
    Refractory rheumatoid arthritis
    Artritis reumatoide refractaria
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate in patients with rheumatoid arthritis refractory to classic synthetic DMARDs and one or more biological DMARDs, the association of the JAK / STAT gene signature in synovial tissue with the clinical response to tofacitinib.
    Evaluar en pacientes con artritis reumatoide refractaria a FAME sintéticos clásicos y a uno o más FAME biológicos, la asociación de la firma génica JAK/STAT en el tejido sinovial con la respuesta clínica a tofacitinib.
    E.2.2Secondary objectives of the trial
    To study the association of JAK / STAT protein expression in synovial tissue with the clinical response to tofacitinib.
    Define the synovial pathotype (lymphoid-myeloid, diffuse myeloid, and pauci-immune) associated with the clinical response to tofacitinib.
    To study the association of the synovial JAK / STAT signature with the ultrasound response in the biopsied joint.
    Estudiar la asociación de la expresión proteica JAK/STAT en el tejido sinovial con la respuesta clínica a tofacitinib.
    Definir el patotipo sinovial (linfoide-mieloide, mieloide difuso y pauci-inmune) asociado a la respuesta clínica a tofacitinib.
    Estudiar la asociación de la firma JAK/STAT sinovial con la respuesta ecográfica en la articulación biopsiada.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients, male or female, over 18 years of age.
    2. Patients capable of providing written informed consent.
    3. Patients mentally competent to understand and agree to carry out the study procedures, as well as tolerate blood draws, local anesthesia, and synovial biopsy.
    4. Patients diagnosed with rheumatoid arthritis according to the ACR / EULAR 2010 classification criteria.
    5. Patients with active rheumatoid arthritis (DAS28> 3.2) with at least 3 painful and swollen joints out of the 28 joints evaluated in the DAS28 (shoulders, elbows, carpals, metacarpophalangeal, proximal interphalangeal of the hands and knees), in which at least one of them is among the following: carpals, 2nd metacarpophalangeal and knees, and in which the presence of synovial hypertrophy at least grade 2 (on a scale of 0-3) is confirmed by ultrasound.
    6. Patients with refractory rheumatoid arthritis, defined as failure to one or more classic synthetic DMARDs (methotrexate, leflunomide, sulfasalazine, leflunomide, or hydroxychloroquine) followed by failure to one or more biological DMARDs (TNF, abatacept, tocilizumab, rituximab).
    1. Pacientes, masculinos o femeninos, mayores de 18 años.
    2. Pacientes capaces de proporcionar un consentimiento informado por escrito.
    3. Pacientes mentalmente competentes para entender y aceptar llevar a cabo los procedimientos del estudio, así como tolerar las extracciones sanguíneas, anestesia local y la biopsia sinovial.
    4. Pacientes con diagnóstico de artritis reumatoide de acuerdo con los criterios de clasificación ACR/EULAR 2010 (18).
    5. Pacientes con artritis reumatoide activa (DAS28 > 3.2) (2)con al menos 3 articulaciones dolorosas y tumefactas de entre las 28 articulaciones evaluadas en el DAS28 (hombros, codos, carpos, metacarpofalángicas, interfalángicas proximales de las manos y rodillas), en las que al menos una de ellas esté entre las siguientes: carpos, 2ª metacarpofalángica y rodillas, y en las que se confirme por ecografía la presencia de hipertrofia sinovial al menos de grado 2 (en escala de 0-3) (16).
    6. Pacientes con artritis reumatoide refractaria, definida como fallo a uno o más FAME sintéticos clásicos (metotrexato, leflunomida, sulfasalazina, leflunomida o hidroxicloroquina) seguido de un fallo a uno o más FAME biológicos (iTNF, abatacept, tocilizumab, rituximab).
    E.4Principal exclusion criteria
    1. Diagnosis of another type of arthritis other than rheumatoid arthritis.
    2. Contraindication to the use of targeted synthetic DMARDs (active infection, previously untreated latent tuberculosis, neoplasia). In cases of latent tuberculosis, after 1 month of tuberculosis treatment, the inclusion of the patient in the study could be considered.
    3. Known allergy or hypersensitivity to tofacitinib.
    4. Patients taking medications that may interact with tofacitinib or any other contrindication to the use of tofacitinib.
    5. Patients in treatment with any drug that may affect the evaluation of the study. Patients must have a washout period prior to the start of the study. Unless there is intolerance, adverse effects, or other specific reason, patients can continue their treatment with classic synthetic DMARDs. In relation to the use of NSAIDs or corticosteroids, concomitant stable doses of NSAIDs or corticosteroids (less than / equal to 10mg of prednisone per day or its equivalent) will be allowed.
    6. Anticoagulated patients.
    7. Pregnant or lactating patients.
    8. Patients participating in another clinical trial or who have participated in another clinical trial in the 3 months prior to signing the IC.
    9. Known HIV, HBV, or HCV infection.
    10. Patients considered in the investigator's judgment as ineligible for the study based on their medical history, physical examination, medication, and concomitant pathologies.
    11. Potentially fertile women who are unwilling to use a contraceptive method that is considered effective *.

    * A woman is considered to have reproductive potential (WOCBP), that is, fertile, after menarche and until she becomes postmenopausal, unless she is permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
    Highly effective methods are considered: combined hormonal contraception (containing estrogens and progestogens) associated with inhibition of ovulation (oral, intravaginal, transdermal route), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable ), intrauterine device (IUD), intrauterine hormone releasing system (IUS), bilateral tubal occlusion, vasectomized couple, sexual abstinence.
    12. Patients who do not want to participate or are not willing to give their IC in writing.
    1. Diagnóstico de otro tipo de artritis distinta a artritis reumatoide.
    2. Contraindicación para el uso de FAME sintéticos dirigidos (infección activa, tuberculosis latente no tratada previamente, neoplasia). En los casos de tuberculosis latente, tras 1 mes de tratamiento con tuberculostáticos, se podría considerar la inclusión del paciente en el estudio.
    3. Alergia o hipersensibilidad conocida a tofacitinib.
    4. Pacientes que tomen medicaciones que puedan interaccionar con tofacitinib o cualquier otra contrindicación para el uso de tofacitinib.
    5. Pacientes en tratamiento con cualquier fármaco que pueda afectar la evaluación del estudio. Los pacientes deberán tener un periodo de lavado previo al inicio del estudio. A menos que exista intolerancia, efectos adversos u otra razón específica, los pacientes pueden mantener su tratamiento con FAME sintéticos clásicos. En relación con el uso de AINES o corticoides, dosis estables concomitantes de AINES o corticoides (menor/igual a 10mg de prednisona al día o su equivalente) serán permitidas.
    6. Pacientes anticoagulados.
    7. Pacientes gestantes o en lactancia.
    8. Pacientes participando en otro ensayo clínico o que hayan participado en otro ensayo clínico en los 3 meses previos a la firma del CI.
    9. Infección conocida por VIH, VHB o VHC.
    10. Pacientes considerados a juicio del investigador como no elegibles para el estudio basado en su historia clínica, examen físico, medicación y patologías concomitantes.
    11. Mujeres potencialmente fértiles que no estén dispuestas a utilizar un método anticonceptivo que se considere efectivo*.
    *se considera que una mujer tiene potencial de procreación (WOCBP), es decir, fértil, después de la menarca y hasta llegar a ser posmenopáusica, a menos que sea permanentemente estéril. Los métodos de esterilización permanente incluyen histerectomía, salpingectomía bilateral y ooforectomía bilateral.
    Se consideran métodos altamente efectivos: anticoncepción hormonal combinada (que contiene estrógenos y progestágenos) asociado con la inhibición de la ovulación (vía oral, intravaginal, transdérmico), anticoncepción hormonal de progestágeno solo asociada con la inhibición de la ovulación (oral, inyectable, implantable), dispositivo intrauterino (DIU), sistema de liberación de hormonas intrauterinas (SIU), oclusión tubárica bilateral, pareja vasectomizada, abstinencia sexual.
    12. Pacientes que no quieran participar o no estén dispuestos a dar su CI por escrito.
    E.5 End points
    E.5.1Primary end point(s)
    The primary analysis of the study will be the specific clinical response to treatment with tofacitinib at 12 weeks, measured by the ACR response criteria (number of swollen joints, number of painful joints, HAQ-DI, global assessment of the disease by the patient and the physician, C-reactive protein value) and DAS28 (1,2), and their association with the JAK / STAT signature in synovial tissue.
    El análisis primario del estudio será la respuesta clínica específica al tratamiento con tofacitinib a las 12 semanas, medida por los criterios de respuesta ACR(número de articulaciones tumefactas, número de articulaciones dolorosas, HAQ-DI, valoración global de la enfermedad por el paciente y el médico, valor de proteína C reactiva) y la DAS28(1,2) , y su asociación con la firma JAK/STAT en el tejido sinovial.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks
    E.5.2Secondary end point(s)
    - The specific synovial tissue pathotype, through the cellular infiltrated analysis (Defined as lynfoid-myeloid, difusse myeloid and pauci-inmune pathotype) and its association with tofacitinib response.
    - The distribution of patients with refractary RA in the different pathotypes to check if this distribution is similar or different from the distribution in cohorts of early arthritis already described.
    - The protein synthesis of mediators of the JAK/STAT signature in synovial tissue and its association with the tofacitinib
    - The cellular infiltrate and its association with the indicated gene expression markers and the analysis of a posible clinical prediction model of response to tofacitinib integrating these findings.
    - The intensity of the synovial JAK/STAT signature at baseline and its association with the intensity global and/or local inflammation in the biopsed joint of the pacient, measured by ultrasound.
    - El patotipo tisular sinovial especifico, mediante el análisis del infiltrado celular, (definido como patotipo linfoide-mieloide, mieloide difuso y pauci-inmune)(12) y su asociación a la respuesta a tofacitinib
    - La distribución de los pacientes con AR refractaria en los diferentes patotipos, para comprobar si esta distribución es similar o diferente a la distribución en cohortes de artritis precoz ya descritas (12,13).
    - La síntesis proteica de mediadores de la firma JAK/STAT en el tejido sinovial y su asociación con la respuesta a tofacitinib.
    - El infiltrado celular y su asociación con los marcadores de expresión génica señalados, y el análisis de un posible modelo de predicción clínica de respuesta a tofacitinib integrando estos hallazgos.
    - La intensidad de la firma JAK/STAT sinovial en el momento basal y su asociación a la intensidad de inflamación global y/o local, en la articulación biopsiada, del paciente medida por ecografía.
    E.5.2.1Timepoint(s) of evaluation of this end point
    4, 8 and 12 weeks
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    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 state42
    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. AFTER THE END OF THE TRIAL, PATIENTS WILL BE MANAGED ACCORDING TO LOCAL STANDARD OF CARE
    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 Decision2021-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-07-30
    P. End of Trial
    P.End of Trial StatusOngoing
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