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    Summary
    EudraCT Number:2019-000867-26
    Sponsor's Protocol Code Number:201791
    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:2019-07-09
    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 number2019-000867-26
    A.3Full title of the trial
    A 52-week, phase 3, multicentre, randomised, double blind, efficacy and safety study, comparing GSK3196165 with placebo and with tofacitinib in combination with conventional synthetic DMARDs, in participants with moderately to severely active rheumatoid arthritis who have an inadequate response to conventional synthetic DMARDs or biologic DMARDs
    Estudio en fase III, multicéntrico, aleatorizado, doble ciego, de 52 semanas de duración, para comparar la eficacia y la seguridad de GSK3196165 con placebo y con tofacitinib, 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 sintéticos convencionales o a los biológicos.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety study, comparing GSK3196165 (study drug) with placebo and with tofacitinib in combination with conventional synthetic antirheumatic drugs, in participants with moderately to severely active rheumatoid arthritis who have an inadequate response to conventional synthetic/biologic antirheumatic drugs
    Eficacia y seguridad de GSK3196165 frente a placebo y tofacitinib en participantes con artritis reumatoide con actividad de moderada a intensa que han obtenido una respuesta inadecuada a los FARME sintéticos convencionales o biológicos
    A.3.2Name or abbreviated title of the trial where available
    contRAst-2
    A.4.1Sponsor's protocol code number201791
    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 Xeljanz
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    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 nameTofacitinib
    D.3.4Pharmaceutical form Capsule
    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 citrate
    D.3.9.1CAS number 540737-29-9
    D.3.9.4EV Substance CodeSUB33105
    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
    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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral 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 20.0
    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 csDMARDs and who have had an inadequate response to csDMARDs or bDMARDs.
    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 FARMEsc o a los FARMEb 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 tofacitinib for the treatment of participants with moderately to severely active RA who are on a stable background of csDMARDs and who have had an inadequate response to csDMARDs or bDMARDs
    - Effect of GSK3196165 on Patient Reported Outcomes (PROs) versus placebo and the active omparator tofacitinib
    - Safety and tolerability of GSK3196165 versus placebo and the active comparator tofacitinib
    - To determine the immunogenic potential of GSK3196165
    Comparar:
    -la eficacia de GSK3196165 en dosis de 90 mg y 150 mg cada semana frente a tofacitinib 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 FARMEsc o a los FARMEb ha sido inadecuada;
    -el efecto de GSK3196165 sobre los resultados notificados por los pacientes (RNP) frente al placebo y al comparador activo tofacitinib;
    -seguridad y tolerabilidad de GSK3196165 frente al placebo y al comparador activo tofacitinib
    -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 at least 1 bone erosion present on hand/wrist or foot radiographs confirmed by central reading at screening.
    7. 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.
    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.
    8. Body weight ≥ 40 kg.
    9. Male or female participants are eligible to participate so long as they meet and agree to abide by the contraceptive criteria detailed in Appendix 4 of protocol.
    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 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 como mínimo 18 años de edad en el momento de firmar el formulario de consentimiento informado.
    2. Cumple los criterios de clasificación de la AR según el ACR/EULAR de 2010 (consulte el manual de referencia del estudio [MRE]) con una duración de la AR ≥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 (número de articulaciones dolorosas [NAD]), y
    b. ≥ 6/66 articulaciones tumefactas (número de articulaciones tumefactas [NAT]).
    Si se ha sometido a tratamiento quirúrgico de una articulación, dicha articulación no se puede incluir en el NAD o NAT a efectos de la inscripción.
    4. Debe contar con una medida de la proteína C reactiva de alta sensibilidad (PCRas) ≥3 mg/l en la selección.
    5. Debe cumplir la clase 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 al menos 1 erosión ósea presente en las radiografías de la mano/muñeca o de los pies confirmada mediante lectura central en la selección.
    7. Debe presentar una respuesta insuficiente, a pesar de estar tomando actualmente como mínimo 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 con la dosis máxima tolerada anterior al día 1, sin cambios en la vía de administración en este momento. Se acepta una dosis más baja de ≥7,5 mg/semana 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 la historia clínica). Excepción: Se permite una dosis más baja de 6 mg/semana si la dosis mínima recomendada o autorizada a nivel local 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: No se permite el uso concomitante de leflunomida y metotrexato 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.
    8. Peso corporal 40 kg
    9. Los participantes de sexo masculino o femenino son aptos para participar siempre que cumplan y acepten atenerse a los criterios 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 en tratamiento con MTX: deben estar dispuestos a continuar o iniciar un tratamiento con ácido fólico por vía oral (al menos 5 mg/semana) o equivalente y
    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 <60 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 tofacitinib 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 study intervention 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 for the purposes of 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/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/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/national guidelines
    20. Significant allergies to humanised monoclonal antibodies
    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 dermatosis,toxic epidermal necrolysis, and exfoliative dermatitis)
    22. Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
    23-35 Other exclusion criteria as mentionned in the protocol
    1. Infecciones activas (incluidas infecciones localizadas) o antecedentes de infecciones recurrentes (excluidas las infecciones fúngicas recurrentes del lecho ungueal) o haber requerido el tratamiento de infecciones agudas o crónicas, según se detalla a continuación:
    • actualmente está tomando algún tratamiento depresor antiinfeccioso para una infección crónica (como pneumocystis, citomegalovirus, virus del herpes simple, herpes zóster y micobacterias atípicas);
    • hospitalización para el tratamiento de la infección en las 26 semanas previas al día 1, O
    • uso de antimicrobianos por vía parenteral (intravenosa [i. v.]) o intramuscular (i. m.) (antibacterianos, antivíricos, antifúngicos o antiparasitarios) en las 26 semanas anteriores al día 1 o antimicrobianos por vía oral (aparte del uso de INH para el tratamiento de la TB latente) en los 14 días anteriores al día 1.
    2. Herpes zóster sintomático en los 3 meses anteriores a la selección.
    3. Trastorno de inmunodeficiencia adquirida o congénita, incluida la deficiencia de inmunoglobulina.
    4. Infección conocida por el virus de la inmunodeficiencia humana (VIH) o resultado positivo en la selección.
    5. Antecedentes de 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 bajas o infecciones urinarias recurrentes.
    6. Cualquier sintomatología inicial que, en opinión del investigador, podría confundir la detección precoz de proteinosis alveolar pulmonar en función de las características clínicas, como tos persistente (grado ≥2 de los CTC) o disnea persistente (grado ≥2 en 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 o hepatitis C aguda y/o crónica actual.
    9. Antecedentes o presencia de enfermedad renal o velocidad de filtración glomerular estimada (VFGe) según el cálculo resultante de la ecuación del grupo de colaboración en epidemiología de la enfermedad crónica renal (CKD-EPI) <60 ml/min/1,73m2 en la selección.
    10. Cáncer de mama en los últimos 10 años o linfoma, leucemia o cualquier otra neoplasia maligna en los últimos 5 años, excepto carcinoma cervicouterino in situ que se haya extirpado sin indicios de recidiva o de enfermedad metastásica, o cáncer cutáneo basocelular o epidermoide que se hayan extirpado sin indicios de recidiva o de enfermedad metastásica durante al menos 3 años.
    11. Antecedentes de cualquier trastorno linfoproliferativo, tales como 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 según el criterio del investigador, como, entre otras, enfermedades cardiovasculares (incluidas insuficiencia cardíaca en estadio III o IV según la clasificación de la New York Heart Association, infarto de miocardio en los 12 meses anteriores, angina de pecho inestable, hipertensión no controlada, hipercolesterolemia no controlada), neurológicas, endocrinas, gastrointestinales (incluida diverticulitis), enfermedad hepática, metabólica, enfermedad del sistema linfático o trasplante renal anterior que podrían afectar de manera negativa a su participación en este estudio.
    13. Cualquier afección o contraindicación según la información local del producto o la práctica clínica local para tofacitinib que impediría su participación en este protocolo.
    14. Antecedentes de otro trastorno reumático inflamatorio o trastorno autoinmunitario sistémico, distinto al síndrome de Sjögren secundario a la AR, que pueda confundir la evaluación del efecto de la intervención del estudio, tales como enfermedad mixta del tejido conectivo, artritis psoriásica, artritis crónica juvenil, espondiloartritis, síndrome de Felty, lupus eritematoso sistémico, esclerodermia, enfermedad de Crohn, colitis ulcerosa o vasculitis.
    15. Presencia de fibromialgia que, en opinión del investigador, podría dificultar la evaluación adecuada de 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 si se precisará de cirugía mayor durante el estudio que, en opinión del investigador en consulta con el supervisor médico, supondría un riesgo inaceptable para el participante.
    17. Tuberculosis (TB) activa actual o previa por Mycobacterium tuberculosis, independientemente del tratamiento.
    18-25. 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
    Week 12 versus placebo:
    - Proportion of participants achieving CDAI
    total score ≤10 (CDAI LDA).
    - Change from baseline in HAQ-DI.
    Non-inferiority versus tofacitinib at Week 12:
    - Proportion of participants achieving ACR20.

    Other Secondary Efficacy Endpoints
    Week 12 (vs. placebo and vs. tofacitinib), Week 24 and Week 52 (vs. tofacitinib): Proportion of participants 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.
    - No radiographic progression defined as a change from baseline in van der Heijde mTSS score of ≤0.5.

    Change from baseline in:
    - CDAI total score.
    - DAS28-CRP/DAS28-ESR.
    - van der Heijde mTSS.
    2) Change from baseline at Week 12 (vs. placebo and vs. tofacitinib), Week 24 and Week 52 (vs. tofacitinib) 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 laboratory parameters.
    - Proportion of participants with NCI-CTCAE ≥Grade 3 haematological/clinical chemistry abnormalities.
    4) Safety Biomarker Endpoints
    - GM-CSF autoantibody concentrations.
    - Anti-GSK3196165 antibodies.
    Principales criterios secundarios de valoración de la eficacia
    En la semana 12, en comparación con placebo:
    • proporción de participantes que alcanzan una puntuación de CDAI total ≤10 (LDA según CDAI);
    • cambio respecto al inicio en HAQ-DI.

    Ausencia de inferioridad frente a tofacitinib en la semana 12:
    • Proporción de participantes que alcanzan la ACR20.

    Otros criterios secundarios de valoración de la eficacia
    Semana 12 (frente a placebo y frente a tofacitinib), semanas 24 y 52 (frente a tofacitinib): Proporción de participantes que alcanzan lo siguiente:
    • puntuación total de CDAI ≤10 (LDA según CDAI);
    • puntuación total de CDAI ≤2,8 (remisión según CDAI);
    • ACR20/50/70;
    • PCR según DAS28 ≤3,2 y VSG según DAS28 ≤3,2 (LDA según DAS28);
    • PCR según DAS28 <2,6 y VSG según DAS28 <2,6 (remisión según DAS28);
    • respuesta EULAR buena/moderada;
    • remisión según ACR/EULAR;
    • sin progresión radiográfica, definida como un cambio desde el inicio en la puntuación mTSS y de Van der Heijde de ≤0,5.
    Cambio desde el inicio en:
    • la puntuación total de CDAI;
    • DAS28-PCR o DAS28-VSG;
    mTSS y de van der Heijde.
    Cambio desde el inicio a las semanas 12 (frente a placebo y frente a tofacitinib), 24 y 52 (frente a tofacitinib) en lo siguiente:
    • HAQ-DI;
    • EVA del dolor de la artritis;
    • puntuaciones de los componentes físico y mental, y puntuaciones de dominio del cuestionario SF-36;
    FACIT-Fatiga.
    • Incidencia de AA, AAG y AAEI
    • Cambios con respecto al inicio en los principales parámetros analíticos
    Proporción de participantes con anomalías bioquímicas clínicas/hemáticas de grado ≥3 según los CTCAE de NCI
    Criterios de valoración de los biomarcadores de la seguridad
    • Concentraciones de autoanticuerpos contra el FEC-MG
    Anticuerpos anti-GSK3196165
    E.5.2.1Timepoint(s) of evaluation of this end point
    At various timepoint up to week 52 as defined in the protocol
    En varios punto hasta la semana 52 según 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
    - Investigación sobre biomarcadores
    - Investigación genética 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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    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
    Australia
    Brazil
    Bulgaria
    China
    Colombia
    Estonia
    France
    Germany
    Hungary
    Japan
    Korea, Republic of
    Mexico
    Poland
    Russian Federation
    Spain
    Thailand
    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 years2
    E.8.9.1In the Member State concerned months9
    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 months9
    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: 1584
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 216
    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 333
    F.4.2.2In the whole clinical trial 1800
    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 52-week treatment period visit may have the option to transition into long term extension study 209564. Any participant who does not transition into Study 209564 will undergo a safety follow-up visit at 8 weeks post last dose of SC study intervention.
    Los participantes que completen las visitas de tratamiento a la Semana 52 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 8 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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