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    Summary
    EudraCT Number:2019-000868-18
    Sponsor's Protocol Code Number:202018
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2019-07-26
    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 number2019-000868-18
    A.3Full title of the trial
    A 24-week, phase 3, multicentre, randomised, double-blind, efficacy and safety study, comparing GSK3196165 with placebo and with sarilumab, in combination with conventional synthetic DMARDs, in participants with moderately to severely active rheumatoid arthritis who have an inadequate response to biological DMARDs and/or Janus Kinase inhibitors.
    Estudio en fase III, multicéntrico, aleatorizado, doble ciego, de 24 semanas de duración, para comparar la eficacia y la seguridad de GSK3196165 con placebo y con sarilumab, en combinación con FARME sintéticos convencionales, en participantes con artritis reumatoide con actividad de moderada a intensa que han obtenido una respuesta inadecuada a los FARME biológicos y/o los inhibidores de la quinasa de Janus.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of GSK3196165 versus placebo and sarilumab in participants with moderately to severely active rheumatoid arthritis who have an inadequate response to biological DMARDs and/or Janus Kinase inhibitors.
    Eficacia y seguridad de GSK3196165 frente a placebo y sarilumab en participantes con artritis reumatoide con actividad de moderada a intensa que han obtenido una respuesta inadecuada a los FARME biológicos y/o los inhibidores de la quinasa de Janus.
    A.3.2Name or abbreviated title of the trial where available
    contRAst-3
    contRAst-3
    A.4.1Sponsor's protocol code number202018
    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 SponsorGlaxoSmithKline Research & Development Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGlaxoSmithKline LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline
    B.5.2Functional name of contact pointCentro de Información
    B.5.3 Address:
    B.5.3.1Street AddressC/ Severo Ochoa 2 (P.T.M)
    B.5.3.2Town/ cityTres Cantos - Madrid
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number+34902202700
    B.5.5Fax number+34918070476
    B.5.6E-mailes-ci@gsk.com
    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 No
    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.3.2Product code GSK3196165
    D.3.4Pharmaceutical form Solution for injection
    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 INNOtilimab
    D.3.9.1CAS number 1638332-55-4
    D.3.9.2Current sponsor codeGSK3196165
    D.3.9.3Other descriptive nameAnti human granulocyte-macrophage colony-stimulating factor (GM-CSF) monoclonal
    D.3.9.4EV Substance CodeSUB177902
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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.IMP: 2
    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 Kevzara
    D.2.1.1.2Name of the Marketing Authorisation holdersanofi-aventis groupe
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameSarilumab
    D.3.4Pharmaceutical form Solution for injection
    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 INNSARILUMAB
    D.3.9.1CAS number 1189541-98-7
    D.3.9.4EV Substance CodeSUB177914
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rheumatoid Arthritis
    Artritis Reumatoide
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis (RA) is a chronic, systemic inflammatory
    autoimmune disease, characterised by a symmetrical polyarthritis that is associated with substantial disability and morbidity
    La artritis reumatoide (AR) es una enfermedad autoinmune inflamatoria sistémica crónica, caracterizada por una poliartritis simétrica que se
    asocia con una importante discapacidad y morbilidad.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    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
    To compare the efficacy of GSK3196165 at doses of 90 mg and 150 mg weekly versus placebo, for the treatment of participants with moderately to severely active RA who are on a stable background of csDMARD(s) and who have had an inadequate response to biological DMARDs and/or JAK inhibitors.
    Comparar la eficacia de GSK3196165 en dosis de 90 mg y 150 mg cada semana frente a placebo para el tratamiento de participantes con AR con actividad de moderada a intensa que reciben tratamiento de base estable con FARMEsc y cuya respuesta a los FARMEb y/o los inhibidores de JAK ha sido inadecuada.
    E.2.2Secondary objectives of the trial
    To compare:
    - Efficacy of GSK3196165 at doses of 90 mg and 150 mg weekly versus sarilumab, for the treatment of participants with moderately to severely active RA who are on a stable background of csDMARD(s) and who have had an inadequate response to biological DMARDs and/or JAK inhibitors.
    - The effect of GSK3196165 on Patient Reported Outcomes (PROs) versus placebo and the active comparator sarilumab.
    - Safety and tolerability of GSK3196165 versus placebo and the active comparator sarilumab

    -To determine the immunogenic potential of GSK3196165
    Comparar:
    • La eficacia de GSK3196165 en dosis de 90 mg y 150 mg cada semana frente a sarilumab para el tratamiento de participantes con AR con actividad de moderada a intensa que reciben tratamiento de base estable con FARMEsc y cuya respuesta a los FARMEb y/o los inhibidores de JAK ha sido inadecuada.
    • El efecto de GSK3196165 sobre los resultados notificados por los pacientes (RNP) frente al placebo y al comparador activo sarilumab.
    • Seguridad y tolerabilidad de GSK3196165 frente al placebo y al comparador activo sarilumab.

    - Determinar el potencial inmunogénico de GSK3196165.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥18 years at the time of signing informed consent.
    2. Meets ACR/EULAR 2010 RA Classification Criteria (see study reference manual [SRM]) with a duration of RA disease of ≥6 months at time of screening and participant not diagnosed before 16 years of age.
    3. Must have active disease at both screening and baseline, as defined by having both:
    a. ≥6/68 tender/painful joints (TJC), and
    b. ≥6/66 swollen joints (SJC).
    If surgical treatment of a joint has been performed, that joint cannot be counted in the TJC or SJC for enrolment purposes
    4. Must have a high sensitivity C-reactive protein (hsCRP) measurement ≥3 mg/L at screening.
    5. Must meet Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA (see SRM).
    6. Must have inadequate response despite currently taking at least one and at most two concomitant csDMARDs for at least 12 weeks prior to Day 1, from the following:
    a. Methotrexate (MTX): weekly 15-25 mg oral or injected, for at least 12 weeks at the maximum tolerated dose prior to Day 1, with no change in route of administration in this time. A lower dose of ≥7.5 mg/week is acceptable if reduced for reasons of intolerance to MTX, e.g. nausea/vomiting, hepatic or hematologic toxicity, or per local requirement (there must be clear documentation in the medical record). Exception: A lower dose of 6 mg/week is allowed if the minimum locally approved or recommended dose is lower than 7.5 mg/week.
    b. Hydroxychloroquine up to 400 mg/day or chloroquine up to 250 mg/day.
    c. Sulfasalazine up to 3000 mg/day.
    d. Leflunomide up to 20 mg/day. Note: concomitant use of leflunomide and methotrexate is not allowed, for safety reasons.
    e. Bucillamine up to 100 mg/day (or up to 300 mg/day if permitted per local requirements).
    f. Iguratimod up to 50 mg/day.
    g. Tacrolimus up to 3 mg/day.
    NOTE: The dose of csDMARD(s) must be stable and tolerated for at least 8 weeks prior to Day 1 and should remain stable throughout the study from screening to end of treatment period, except adjustment for safety reasons.
    7. Must have inadequate response to at least one biologic DMARD at an approved dose and/or at least one JAK inhibitor (JAKi) at an approved dose. In both cases this may be with or without combination with a csDMARD. Prior bDMARD or JAKi therapy must be discontinued before randomisation.
    8. Body weight ≥40 kg
    9. Male or female participants are eligible to participate so long as they meet the contraceptive eligibility criteria and agree to abide by the contraceptive requirements.
    10. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
    11. For participants on MTX: must be willing to continue or initiate treatment at screening, with oral folic acid (at least 5 mg/week) or equivalent and be treated during the entire study (mandatory co-medication for MTX treatment).
    1. Tiene ≥18 años de edad en el momento de firmar el formulario de consentimiento informado.
    2. Cumple los criterios de clasificación del ACR/EULAR de 2010 de AR (consulte el manual de referencia del estudio [MRE]) con una duración de la AR de ≥6 meses en el momento de la selección y el participante no ha sido diagnosticado antes de los 16 años de edad.
    3. Debe presentar enfermedad activa en la selección y al inicio, la cual se define por presentar tanto:
    a. ≥6/68 articulaciones dolorosas (RAD), y
    b. ≥6/66 articulaciones inflamadas (RAI).
    Si se ha realizado tratamiento quirúrgico de una articulación, dicha articulación no se puede incluir en el recuento de RAD o RAI a efectos de la inscripción.
    4. Debe tener una medición de la proteína C reactiva de alta sensibilidad (PCRas) ≥3 mg/l en la selección.
    5. Debe cumplir con las clases I, II o III de los criterios revisados de 1991 del ACR para el estado funcional global en la AR (consulte el MRE).
    6. Debe tener una respuesta insuficiente, a pesar de estar tomando actualmente al menos uno y como máximo dos FARMEsc concomitantes durante al menos 12 semanas antes del día 1, de entre los siguientes:
    a. Metotrexato (MTX): semanalmente 15-25 mg por vía oral o inyectado, durante al menos 12 semanas a la dosis máxima tolerada antes del día 1, sin cambios en la vía de administración en este momento. Una dosis más baja de ≥7,5 mg/semana es aceptable si se ha reducido por motivos de intolerancia a MTX, p. ej., náuseas/vómitos, toxicidad hepática o hematológica, o conforme a la normativa local (debe haber documentación clara en el historial clínico). Excepción: se permite una dosis más baja de 6 mg/semana si la dosis mínima local aprobada o recomendada es inferior a 7,5 mg/semana.
    b. Hidroxicloroquina hasta 400 mg/día o cloroquina hasta 250 mg/día.
    c. Sulfasalazina hasta 3000 mg/día.
    d. Leflunomida hasta 20 mg/día. Nota: el uso concomitante de leflunomida y
    metotrexato no está permitido por motivos de seguridad.
    e. Bucilamina hasta 100 mg/día (o hasta 300 mg/día, si lo permite la normativa local).
    f. Iguratimod hasta 50 mg/día.
    g. Tacrolimús hasta 3 mg/día.
    NOTA: la dosis de los FARMEsc debe ser estable y bien tolerada durante al menos 8 semanas antes del día 1 y debe permanecer estable a lo largo de todo el estudio, desde la selección hasta el final del periodo de tratamiento, excepto si se ajusta por motivos de seguridad. Consulte la sección 6.5.
    7. Debe tener una respuesta insuficiente al menos a un FARME biológico a una dosis aprobada y/o al menos a un inhibidor de JAK (JAKi) a una dosis aprobada. En ambos casos puede ser con o sin combinación con un FARMEsc. Se debe interrumpir el tratamiento anterior con FARMEb o JAKi antes de la aleatorización, según las directrices de la sección 6.5.2 Tratamientos prohibidos.
    8. Peso corporal 40 kg
    9. Los participantes hombres o mujeres son aptos para participar siempre que cumplan los criterios de aptitud para el uso de métodos anticonceptivos en la sección 10.4.4 y acepten cumplir los requisitos sobre los métodos anticonceptivos que se detallan en el Anexo 4.
    10. Ser capaz de dar su consentimiento informado firmado, lo que incluye el cumplimiento de los requisitos y restricciones enumerados en el formulario de consentimiento informado (FCI) y en este protocolo.
    11. Para los participantes con MTX: deben estar dispuestos a continuar o iniciar el tratamiento en el momento de la selección con ácido fólico oral (al menos 5 mg/semana), o equivalente, y recibir tratamiento durante todo el estudio (medicación concomitante obligatoria para el tratamiento con MTX).
    E.4Principal exclusion criteria
    1. Active infections (including localised infections), or history of recurrent infections (excluding recurrent fungal infections of the nail bed), or has required management of acute or chronic infections, as described in the protocol
    2. Symptomatic herpes zoster within 3 months prior to screening
    3. Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.
    4. Known infection with human immunodeficiency virus (HIV) or positive test at screening.
    5. History of infected joint prosthesis at any time, with the prosthesis still in situ. History of chronic leg ulcers, permanent in-dwelling catheters, chronic sinusitis, recurrent chest infections or recurrent urinary tract infections.
    6. Any baseline symptomatology that in the investigator’s opinion would confound the early detection of pulmonary alveolar proteinosis based upon clinical features, such as persistent cough (CTC grade ≥2) or persistent dyspnoea (dyspnoea scale Grade ≥2).
    7. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis.
    8. Current acute or chronic Hepatitis B and/or Hepatitis C.
    9. Current or history of renal disease or estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) calculation <30 mL/min/1.73m2 at screening.
    10. Breast cancer within the past 10 years or lymphoma, leukaemia, or any other malignancy within the past 5 years except for cervical carcinoma in situ that has been resected with no evidence of recurrence or metastatic disease, or basal cell or squamous epithelial cancers of the skin that have been resected with no evidence of recurrence or metastatic disease for at least 3 years.
    11. History of any lymphoproliferative disorder, such as Epstein Barr Virus (EBV) related lymphoproliferative disorder, or signs and symptoms suggestive of current lymphatic disease.
    12. History or presence of significant other concomitant illness according to the Investigator judgment such as, but not limited to cardiovascular (including Stage III or IV cardiac failure according to New York Heart Association classification, myocardial infarction within 12 months, unstable angina pectoris, uncontrolled hypertension, uncontrolled hypercholesterolemia), neurological, endocrinological, gastrointestinal (including diverticulitis), hepatic disease, metabolic, lymphatic disease, or previous renal transplant that would adversely affect the participant’s participation
    13. Any condition or contraindication as addressed in the local product information or local clinical practice for sarilumab that would preclude the participant from participating in this protocol.
    14. History of other inflammatory rheumatologic or systemic autoimmune disorder, other than Sjögren’s syndrome secondary to RA, that may confound the evaluation of the effect of the investigational product such as mixed connective tissue disease, psoriatic arthritis, juvenile chronic arthritis, spondyloarthritis, Felty’s Syndrome, systemic lupus erythematosus, scleroderma, Crohn’s disease, ulcerative colitis, or vasculitis.
    15. Presence of fibromyalgia that, in the investigator’s opinion, would make it difficult to appropriately assess RA activity in this study.
    16. Undergone any major surgery within 8 weeks prior to study entry or will require major surgery during the study that, in the opinion of the investigator in consultation with the medical monitor, would pose an unacceptable risk to the participant.
    17. Current or previous active Mycobacterium tuberculosis (TB) regardless of treatment.
    18. Evidence of latent TB (as documented by a positive QuantiFERON-TB Gold plus test or T-SPOT.TB test at screening, no findings on medical history or clinical examination consistent with active TB, and a normal chest radiograph) except for participants that either:
    - Are willing to complete at least 4 weeks of anti-TB therapy as per WHO or national guidelines prior to randomisation and agree to complete the remainder of treatment while in the study OR
    - Are documented as having evidence of satisfactory anti-TB treatment as per WHO or national guidelines within the last 5 years following review by a physician specialising in TB.
    19. Previous close contact with a person with active TB and did not receive satisfactory anti-tuberculosis treatment as per WHO or national guidelines.
    20. Significant allergies to humanised monoclonal antibodies or known hypersensitivity to sarilumab or any of its inactive ingredients.
    21. Clinically significant multiple or severe drug allergies or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
    22-34. Other exclusion criteria as mentionned in the protocol
    1. Infecciones activas (incluidas las infecciones localizadas), antecedentes de infecciones recurrentes (excluidas las infecciones fúngicas recurrentes del lecho ungueal) o ha requerido tratamiento para infecciones agudas o crónicas, como se describe en el protocolo.
    2. Herpes zóster sintomático en los 3 meses anteriores a la selección.
    3. Síndrome de inmunodeficiencia adquirida o hereditaria.
    4. Infección conocida con el virus de la inmunodeficiencia humana (VIH) o prueba positiva.
    5. Antecedentes de una prótesis articular infectada en cualquier momento, con la prótesis todavía en su lugar original. Antecedentes de úlceras crónicas en las piernas, catéteres permanentes, sinusitis crónica, infecciones recurrentes de las vías respiratorias o infecciones recurrentes del tracto urinario.
    6. Cualquier sintomatología al inicio que podría ser un elemento de confusión en la detección temprana de la proteinosis alveolar pulmonar basada en las características clínicas, como tos persistente (grado ≥2, según los CTC) o disnea persistente (grado ≥2, según la escala de disnea).
    7. Enfermedad hepática o biliar actual inestable según la evaluación del investigador definida por la presencia de ascitis, encefalopatía, coagulopatía, hipoalbuminemia, varices esofágicas o gástricas, ictericia persistente o cirrosis.
    8. Hepatitis B y/o hepatitis C crónica o aguda actual.
    9. Enfermedad o antecedentes de nefropatía o tasa de filtración glomerular estimada (TFGe), según los cálculos con la ecuación de la Colaboración Epidemiológica para la Enfermedad Renal Crónica [Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI], de <30 ml/min/1,73 m2 en la selección.
    10. Cáncer de mama en los últimos 10 años; linfoma, leucemia, o cualquier otra neoplasia maligna en los últimos 5 años, excepto carcinoma cervicouterino in situ que se ha resecado sin evidencia de recidiva o de enfermedad metastásica; cáncer basocelular o epidermoide epitelial de la piel que se ha resecado sin evidencia de recidiva o de enfermedad metastásica durante al menos 3 años.
    11. Antecedentes de cualquier trastorno linfoproliferativo, como el trastorno linfoproliferativo relacionado con el virus de Epstein-Barr (VEB) o signos y síntomas indicativos de una enfermedad linfática actual.
    12. Antecedentes o presencia de otras enfermedades concomitantes significativas, entre otras, enfermedades cardiovasculares (incluida la insuficiencia cardíaca en estadio III o IV según la clasificación de la New York Heart Association, infarto de miocardio en los últimos 12 meses, angina de pecho inestable, hipertensión no controlada, hipercolesterolemia no controlada), neurológicas, endocrinas, gastrointestinales (inc diverticulitis), hepáticas, metabólicas, linfáticas o un trasplante renal anterior que pudiera afectar de forma negativa a la participación en el estudio.
    13. Cualquier afección o contraindicación según la ficha técnica local del producto o la práctica clínica local para sarilumab que impediría que el participante participara en este protocolo.
    14. Antecedentes de otros trastornos reumatológicos inflamatorios o trastornos sistémicos autoinmunes, distintos al síndrome de Sjögren secundario a la AR, que podrían confundir la evaluación del efecto del producto en investigación, como enfermedad mixta del tejido conjuntivo, artritis psoriásica, artritis crónica juvenil, espondiloartritis, síndrome de Felty, lupus eritematoso sistémico, esclerodermia, enfermedad de Crohn, colitis ulcerosa,vasculitis.
    15. Presencia de fibromialgia que podría hacer que sea difícil evaluar debidamente la actividad de la AR para los propósitos de este estudio.
    16. Haberse sometido a cualquier cirugía mayor en las 8 semanas anteriores a la entrada en el estudio o precisará cirugía mayor durante el estudio que, supondría un riesgo para el participante.
    17. Tuberculosis (TB) activa actual o previa causada por Mycobacterium tuberculosis.
    18. Indicios de TB latente (según lo documentado por un resultado positivo en la prueba QuantiFERON-TB Gold plus o en la prueba T-SPOT.TB en la selección, sin hallazgos en los antecedentes médicos o en la exploración clínica que coincidan con TB activa y una radiografía de tórax normal), excepto:
    que estén dispuestos a completar al menos 4 semanas de tratamiento antituberculoso antes de la aleatorización y estén de acuerdo en completar el resto del tratamiento mientras estén en el estudio; O que esté documentado que presentan indicios de tratamiento antituberculoso satisfactorio de en los últimos 5 años.
    19. Contacto cercano previo con una persona con TB activa y que no recibió tratamiento antituberculoso.
    20. Alergias importantes a anticuerpos monoclonales humanizados o hipersensibilidad conocida a sarilumab o a sus componentes inactivos.
    21. Alergias a medicamentos múltiples o graves clínicamente significativas o reacciones de hipersensibilidad graves posteriores al tratamiento
    22 - 34 Otros criterios de exclusion que aparecen en el Protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of participants achieving ACR20.
    Proporción de participantes que alcanzan la ACR20.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At Week 12.
    Semana 12.
    E.5.2Secondary end point(s)
    1) Major Secondary Efficacy Endpoints
    Change from baseline at Week 12 (versus placebo) in:
    - HAQ-DI.
    Change from baseline at Week 12 (versus sarilumab) in:
    - CDAI total score.
    - Arthritis pain VAS.

    Other Secondary Efficacy Endpoints
    Proportion of participants at Week 12 (vs. placebo and vs. sarilumab) and Week 24 (vs. sarilumab) achieving:
    - CDAI total score ≤10 (CDAI LDA).
    - CDAI total score ≤2.8 (CDAI Remission).
    - ACR20/50/70.
    - DAS28-CRP ≤3.2 and DAS28(ESR) ≤3.2 (DAS28 LDA).
    - DAS28(CRP) <2.6 and DAS28(ESR) <2.6 (DAS28 Remission).
    - A good/moderate EULAR response
    - ACR/EULAR Remission.

    Change from baseline at Week 12 (vs. placebo and vs. sarilumab) and Week 24 (vs. sarilumab) in:
    - CDAI total score.
    - DAS28(CRP)/DAS28(ESR).

    2)Change from baseline at Week 12 (vs.placebo and vs. sarilumab) and Week 24 (vs.sarilumab) in:
    - HAQ-DI.
    - Arthritis pain VAS.
    - SF-36 physical and mental component scores, and domain scores.
    - FACIT-Fatigue.

    3)- Incidence of AEs, SAEs and AESIs.
    - Change from baseline in key lab parameters.
    - Proportion of participants with NCICTCAE ≥Grade 3 haematology/clinical chemistry abnormalities.

    4) Safety Biomarker Endpoints
    - GM-CSF autoantibody concentrations.
    - Immunogenicity.
    Principales criterios secundarios de valoración de la eficacia
    Cambio con respecto al inicio en la semana 12 (frente a placebo) en:
    • HAQ-DI.
    Cambio con respecto al inicio en la semana 12 (frente a sarilumab) en:
    • la puntuación total de CDAI;
    • EVA del dolor de la artritis.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At various timepoint up to week 24 as defined in the protocol
    Diferentes momentos hasta la semana 24 como se define en el protocolo.
    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 Yes
    E.6.7Pharmacodynamic Yes
    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
    - Immunogenicity
    - Research on Biomarkers
    - Optional Genetics research
    Inmunogenicidad
    Biomarcadores
    Investigación Genetica opcional
    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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial6
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA62
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Belgium
    Canada
    China
    Czech Republic
    Germany
    Hungary
    Italy
    Japan
    Korea, Republic of
    Lithuania
    Netherlands
    Poland
    South Africa
    Spain
    Ukraine
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months2
    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: 528
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 72
    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 state37
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 161
    F.4.2.2In the whole clinical trial 600
    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)
    Participants who complete the treatment visits to Week 24 may be eligible to transition into the long-term extension study 209564. Any participant who does not transition into Study 209564 will undergo a safety follow-up visit at 12 weeks post last dose of SC study intervention.
    Los participantes que completen las visitas de tratamiento a la Semana 24 pueden ser elegibles para la transición al estudio de extensión a largo plazo 209564. Cualquier participante que no realice la transición al Estudio 209564 se someterá a una visita de seguimiento de seguridad a las 12 semanas posteriores a la última dosis de la intervención del estudio SC.
    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 Decision2019-11-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-16
    P. End of Trial
    P.End of Trial StatusRestarted
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