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    Summary
    EudraCT Number:2014-000358-13
    Sponsor's Protocol Code Number:A3921187
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-22
    Trial results View 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 number2014-000358-13
    A.3Full title of the trial
    A PHASE 3b/4 RANDOMIZED DOUBLE BLIND STUDY OF 5 MG OF TOFACITINIB WITH AND WITHOUT METHOTREXATE IN COMPARISON TO ADALIMUMAB WITH METHOTREXATE IN SUBJECTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS
    ESTUDIO DE FASE 3B/4, ALEATORIZADO, DOBLE CIEGO DE 5 MG DE TOFACITINIB CON Y SIN METOTREXATO EN COMPARACIÓN CON ADALIMUMAB CON METOTREXATO EN PACIENTES CON ARTRITIS REUMATOIDE ACTIVA DE MODERADA A GRAVE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to assess a novel medicine in the treatment of patients with moderately to severely active rheumatoid arthritis
    Un ensayo clínico para evaluar un nuevo medicamento en el tratamiento de pacientes con artritis reumatoide activa de moderada a grave
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberA3921187
    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 SponsorPfizer Inc. 235 East 42nd Street, New York, NY 10017
    B.1.3.4CountryUnited States
    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 supportPfizer Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017, USA
    B.5.3.4CountryUnited States
    B.5.4Telephone number+3491 490 99 00
    B.5.5Fax number+13037391119
    B.5.6E-mailclinicaltrials.govcallcentre@pfizer.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.3.1Product nameTofacitinib citrate
    D.3.2Product code CP-690, 550 - 10
    D.3.4Pharmaceutical form Film-coated 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.3.9.2Current sponsor codeCP-690550
    D.3.9.3Other descriptive nameTOFACITINIB CITRATE
    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.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 Humira ® (Adalimumab) 40mg/0.8mL Pre-filled Syringe
    D.2.1.1.2Name of the Marketing Authorisation holderAbbvie Ltd.
    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 nameAdalimumab
    D.3.2Product code L04AB04
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    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 INNADALIMUMAB
    D.3.9.1CAS number 331731-18-1
    D.3.9.3Other descriptive nameHumira
    D.3.9.4EV Substance CodeSUB20016
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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 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.IMP: 3
    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 Humira® 40 mg/ 0.8 ml solution for injection in pre-filled syringe
    D.2.1.1.2Name of the Marketing Authorisation holderAbbvie Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 Solution for infusion in pre-filled syringe
    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 INNADALIMUMAB
    D.3.9.1CAS number 331731-18-1
    D.3.9.4EV Substance CodeSUB20016
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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 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.IMP: 4
    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 Methotrexate sodium 2.5mg tablets
    D.2.1.1.2Name of the Marketing Authorisation holderMercury Pharmaceuticals Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMethotrexate sodium 2.5mg tablets
    D.3.4Pharmaceutical form 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 INNMethotrexate
    D.3.9.3Other descriptive nameMETHOTREXATE SODIUM
    D.3.9.4EV Substance CodeSUB03225MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    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: 3
    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: 4
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Moderately to severely active Rheumatoid Arthritis
    ARTRITIS REUMATOIDE ACTIVA DE MODERADA A GRAVE
    E.1.1.1Medical condition in easily understood language
    Moderate to severe Rheumatoid Arthritis
    ARTRITIS REUMATOIDE ACTIVA DE MODERADA A GRAVE
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    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 5 mg BID of tofacitinib (with and without background MTX) to adalimumab with MTX as measured by American College of Rheumatology 50% improvement (ACR50) response rates at Month 6.

    To compare the efficacy of 5 mg BID of tofacitinib monotherapy to 5 mg BID tofacitinib with MTX as measured by ACR50 response rates at Month 6.
    Comparar la eficacia de 5 mg dos veces al día de tofacitinib (con y sin MTX de base) con la de adalimumab con MTX, medida por la mejora del 50 % en las tasas de respuesta según los criterios del Colegio Estadounidense de Reumatología (American College of Rheumatology, ACR50) en el mes 6.

    Comparar la eficacia de 5 mg dos veces al día de tofacitinib en monoterapia frente a 5 mg dos veces al día de tofacitinib con MTX, medida por las tasas de respuesta ACR50 en el mes 6.
    E.2.2Secondary objectives of the trial
    1. To compare the efficacy of tofacitinib 5 mg BID monotherapy vs. 5 mg BID combined with MTX as measured by Disease Activity Score 28-4 (C-reactive protein) (DAS28-4 (CRP)), ACR20, ACR70, Rates of remission, Low Disease Activity (LDA), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), DAS28-4 erythrocyte sedimentation rate (ESR), at Month 6.
    2. To compare the efficacy of tofacitinib 5 mg BID with and without MTX vs. adalimumab with MTX for the treatment of signs and symptoms of RA as measured by ACR20, ACR70, Rates of remission, LDA, SDAI, CDAI, DAS28-4 (ESR) and DAS28-4 (CRP) at Month 6.
    Items 3-6 detailed in the Protocol.
    1.Comparar la eficacia de tofacitinib 5 mg dos veces al día en monoterapia frente a 5 mg dos veces al día con MTX, medida por la puntuación de la actividad de la enfermedad (Disease Activity Score, DAS) 28-4 (proteína C reactiva) (DAS28-4 (PCR)), ACR20, ACR70, tasas de remisión, actividad baja de la enfermedad (Low Disease Activity, LDA), índice simplificado de actividad de la enfermedad (Simplified Disease Activity Index, SDAI), índice clínico de actividad de la enfermedad (Clinical Disease Activity Index, CDAI), y DAS28-4 utilizando la velocidad de sedimentación globular (VSG), en el mes 6.
    2. Comparar la eficacia de 5 mg dos veces al día de tofacitinib con y sin MTX frente a adalimumab con MTX para el tratamiento de signos y síntomas de la AR, medida por la ACR20, ACR70, tasas de remisión, LDA, SDAI, CDAI, DAS28-4 (VSG) y DAS28-4 (PCR) en el mes 6.
    Los puntos de 3 al 6 se detallan en el protocolo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
    2. Must be at least 18 years of age or older.
    3. Specific criterion for administration of the zoster vaccine - details contained in the Protocol
    4. Has ?4 tender/painful joints on motion and ?4 swollen joints (28 joint count) at Screening and Baseline/Visit 2
    5. Screening C-reactive protein (CRP) >7 mg/L in the central laboratory
    6. Has moderate to severe rheumatoid arthritis inadequately controlled with methotrexate
    7. Has a score of 6 or greater on the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis (Appendix 1 of Protocol)
    8. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA where usual self-care activities including dressing, feeding, bathing, grooming, and toileting; avocational (recreational and/or leisure) and vocational (work, school, homemaking) activities are subject-desired and age- and sex-specific. (Details re Class I, II, III contained in the Protocol)
    9. Has been receiving a MTX treatment regimen continuously for at least 4 months prior to the Screening visit and has taken a stable weekly dose of oral methotrexate with supplemental folic or folinic acid for at least 6 weeks prior to the Baseline/Visit 2. (Conversion from parenteral to oral will require ?stabilization? over this period of time as well). (Further details contained in the Protocol).
    10. Female subjects of childbearing potential must test negative for pregnancy.
    11. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and for at least 3 months after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
    12. Female subjects who are not of childbearing potential (ie, meet at least one of the following criteria):
    a. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    b. Have medically confirmed ovarian failure or;
    c. Achieved post-menopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle-stimulating hormone (FSH) level within the laboratory´s reference range for postmenopausal females
    Please refer to Protocol for information related to inclusion criteria 13-14
    1.Prueba de un documento de consentimiento informado, firmado y fechado personalmente, que indique que se ha informado al paciente (o a su representante legalmente aceptable) de todos los aspectos pertinentes del estudio.
    2.Tener al menos 18 años o más.
    3.Criterios específicos para la administración de la vacuna del herpes zóster-detallado en el protocolo.
    4. Tener ≥4 articulaciones sensibles/dolorosas durante el movimiento y ≥4 articulaciones inflamadas (recuento de 28 articulaciones) en la selección y en el momento basal/visita 2.
    5.Proteína C reactiva (PCR) en la selección>7 mg/l en lab. central.
    6.Tener artritis reumatoide (AR) moderada a grave, mal controlada con metotrexato.
    7.Tener una puntuación de 6 o ˃ en los criterios de clasificación de 2010 del Colegio Americano de Reumatologia,/Liga Europea contra el Reumatismo para la AR.
    8.Cumplir con la clase I, II o III según los criterios revisados de 1991 del ACR para el estado funcional global en AR, donde las actividades habituales de cuidado personal incl. vestirse, alimentarse, bañarse, acicalarse y asearse, las actividades lúdicas (recreativas o de ocio) y laborales (trabajo, colegio, tareas domésticas) son deseadas por el paciente y específicas de la edad y el sexo ( detalles de Clase I,II y III en el protocolo)
    9. Haber recibido régimen de tratamiento con MTX de manera continua durante al menos 4 meses antes de la visita de seleccióny haber tomado una dosis estable semanal de metotrexato con un suplemento de ácido fólico o ácido folínico durante al menos 6 semanas antes del momento basal/visita 2. (El cambio de parenteral a oral exigirá “estabilización” durante este período también). ( Det. Adic. en el protocolo).
    10.Las pacientes en edad fértil deben presentar una prueba neg. de embarazo.
    11. Los pacientes ( hombres y mujeres) en edad fértil y en riesgo de embarazo deben acceder a utilizar 2 métodos anticonceptivos de eficacia elevada durante todo el estudio y durante, al menos, 3 meses después de la última dosis del tto. asignado. Se considera que un paciente está en edad fértil si, a juicio del investigador, está capacitado biológicamente para tener hijos y es sexualmente activo.
    12.Las mujeres que no están en edad fértil (es decir, cumplen al menos uno de los siguientes criterios): a)se han sometido a una histerectomía o a una ooforectomía bilateral documentadas; b)se les ha confirmado médicamente insuficiencia ovárica; o c)están en la postmenopausia según la definición siguiente: cese de la menstruación regular durante al menos 12 meses consecutivos sin presencia de una causa alternativa patológica o fisiológica, y niveles séricos de hormona estimulante del folículo (FSH) dentro del rango de referencia del laboratorio para mujeres postmenopáusicas.
    Refiéranse al protocolo para información relativa a los criterios de inclusión 13-14
    E.4Principal exclusion criteria
    1. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.
    2. Subjects who have an allergy or hypersensitivity to MTX, subjects who have experienced a serious toxicity when administered MTX, or have any contraindication to treatment with MTX according to the local label for treatment of RA with MTX.
    3. Subjects who have Class III or Class IV heart failure according to the New York Heart Association (NYHA) functional classification system or any other contraindication to treatment with adalimumab.
    4. Pregnant female subjects; breastfeeding female subjects; males and females of childbearing potential who are unwilling or unable to use two methods of highly effective contraception as outlined in this protocol for the duration of the study and for at least 3 months after last dose of investigational product.
    5. Subjects with infections or history of infections (additional details in Protocol)
    6. Subjects with any current malignancy or a history of malignancy, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
    7. Subjects with any uncontrolled clinically significant laboratory abnormality or any of the following laboratory abnormalities:
    a. Evidence of hematopoietic disorder or hemoglobin <9 g/dL
    b. Absolute lymphocyte count <0.75 x 10^9/L (<750/mm3)
    c. Absolute neutrophil count <1.2 x 10^9/L (<1200/mm3)
    d. Platelet count <100 x 10^9/L (<100,000/mm3)
    e. Alanine aminotransferase (ALT), or aspartate aminotransferase (AST) >1.5 times the upper limit of normal (x ULN)
    f. Estimated glomerular filtration rate (GFR) <40 mL/min using the Cockcroft-Gault formula (Appendix 3 of Protocol).
    8. Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks or 5 half-lives (whichever is longer) after discontinuation of the investigational compound before the current study begins and/or during study participation, unless further restrictions to class of compound are specified in Section 4.2 and Section 5.8.
    9. Subjects requiring or have received any prohibited concomitant medication or dietary supplement as outlined in Appendix 2 of the Protocol.
    10. Subjects with a screening 12-lead electrocardiogram that demonstrates clinically significant abnormalities requiring urgent treatment (eg, acute myocardial infarction, serious tachy- or bradyarrhythmias) or that is indicative of serious underlying heart disease (eg, cardiomyopathy, major congenital heart disease, low voltage in all leads).
    11. Subjects who had significant trauma or surgical procedure within 1 month prior to the Baseline/Visit 2.
    12. Subjects with any rheumatic autoimmune disease, other than RA and Sjogren?s syndrome.
    13. Subjects who are classified Class IV of the ACR 1991 Revised Criteria for Global Functional Status in RA (ie, are limited in their ability to perform usual self-care, vocational, and avocational activities).
    14. Subjects with lymphoproliferative disorders (eg, Epstein Barr Virus (EBV) related lymphoproliferative disorder), a history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.
    15. Alcohol or substance abuse unless in full remission for greater than 6 months prior to first dose of study drug.
    16. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
    17. Specific exclusion criteria for administration of the zoster vaccine in eligible subjects (refer to Protocol)
    1.Pacientes que sean miembros del personal del centro de investigación directamente implicados en la realización del estudio, así como sus familiares, miembros del personal del centro supervisados de alguna otra manera por el investigador o empleados de Pfizer directamente implicados en la realización del estudio.2.Pacientes que tienen una alergia o hipersensibilidad a MTX, pacientes que han experimentado una toxicidad grave cuando se les administró MTX, o tienen cualquier contraindicación para el tratamiento con MTX, de acuerdo con la ficha técnica local para el tratamiento de la AR con MTX.3.Pacientes que presentan una insuficiencia cardiaca de clase III o clase IV según el sistema de clasificación funcional de la New York Heart Association, NYHA o cualquier otra contraindicación para el tratamiento con adalimumab.4.Pacientes mujeres embarazadas; pacientes mujeres en período de lactancia; hombres y mujeres en edad fértil que no desean o no pueden usar dos métodos anticonceptivos de elevada eficacia tal como se describe en el protocolo durante todo el estudio y durante al menos 3 meses después de la última dosis del producto en investigación.5.Pacientes con infecciones o antecedentes de infecciones( detalles adicionales en el protocolo). 6.Los pacientes con presencia o antecedentes de neoplasia maligna, a excepción del carcinoma basocelular o el carcinoma espinocelular de la piel, o el carcinoma cervical in situ, no metastásicos y debidamente tratados o extirpados. 7.Los pacientes con cualquier anomalía de laboratorio clínicamente relevante y no controlada o cualquiera de las siguientes anomalías de laboratorio: a)Evidencias de trastornos hematopoyéticos o niveles de hemoglobina < 9 g/dl. b)Recuento absoluto de linfocitos < 0,75 x 109/l (< 750/mm3).c)Recuento absoluto de neutrófilos < 1,2 x 109/l (< 1200/mm3).d)Recuento de plaquetas < 100 x 109/l (< 100 000/mm3). e)Alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST) > 1,5 veces el límite superior de la normalidad (x LSN).f)Tasa de filtración glomerular (TFG) calculada < 40 ml/min usando la fórmula de Cockcroft-Gault (apéndice 3 del protocolo). 8.Participación en otros estudios que incluyan fármaco(s) de investigación (fases I-IV) en las 4 semanas o 5 semividas (lo que sea más largo) tras la interrupción del compuesto en investigación antes de que empiece el presente estudio o durante la participación en el mismo, a menos que se especifiquen más restricciones en el tipo de compuesto en la sección 4.2 y la sección 5.8. 9.Pacientes que requieren o han recibido cualquiera de las medicaciones concomitantes prohibidas o suplementos dietéticos tal como se describen en el (apéndice 2 del protocolo). 10.Pacientes con un electrocardiograma de 12 derivaciones en la selección que demuestre anomalías clínicamente relevantes que requieren un tratamiento urgente (p. ej., infarto agudo de miocardio, bradiarritmias o taquiarritmias graves) o que presente indicios de una cardiopatía grave subyacente (p. ej., miocardiopatía, cardiopatía congénita grave, bajo voltaje en todas las derivaciones). 11. Pacientes que sufrieron un traumatismo o un procedimiento quirúrgico importantes en el mes anterior al momento basal/visita 2. 12. Pacientes con cualquier enfermedad autoinmune reumática, que no sea la AR y el síndrome de Sjogren.13.Pacientes que se clasifican en la clase IV según los criterios revisados de 1991 del ACR para el estado funcional global en AR (es decir, limitación en la capacidad para realizar las actividades habituales de cuidado personal, laborales y lúdicas). 14.Pacientes con cualquier trastorno linfoproliferativo (p. ej., síndrome linfoproliferativo asociado al virus de Epstein-Barr [VEB]), antecedentes de linfoma, leucemia, o signos y síntomas indicativos de una enfermedad linfática actual. 15. Alcoholismo o toxicomanía, salvo que el paciente lleve en remisión completa más de 6 meses antes de la primera dosis del fármaco del estudio. 16. Tras enfermedades de grado intenso, agudas o crónicas, médicas o psiquiátricas, o anomalías de laboratorio que puedan aumentar el riesgo asociado con la participación en el estudio o con la administración del producto en investigación, o que puedan interferir en la interpretación de los resultados del estudio y, a juicio del investigador, hagan que el paciente no sea apto para incorporarse a este estudio. 17.Criterios específicos de exclusión para la administración de la vacuna del herpes zóster en pacientes elegibles ( ver protocolo).
    E.5 End points
    E.5.1Primary end point(s)
    ACR 50 response rates at Month 6
    Tasas de respuesta ACR50 en el mes 6.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Month 6
    Mes 6
    E.5.2Secondary end point(s)
    1. Change from Baseline in SDAI, CDAI at Month 6.
    2. Change from Baseline in DAS28-4 (CRP) and DAS28-4 (ESR) at Month 6.
    3. Rate of remission at Month 6, as assessed by: ACR-EULAR Boolean remission criteria;4 SDAI ? 3.3; CDAI ?2.8; DAS28-4 (ESR) < 2.6 and DAS28-4 (CRP) < 2.6.
    4. Rate of LDA at Month 6, as assessed by: SDAI ? 11; CDAI ?10; DAS 28-4 (ESR) <3.2 and DAS28-4 (CRP) <3.2.
    5. ACR20 and ACR70 response rates at Month 6.
    6. Change from Baseline in HAQ-DI at Month 6.
    7. Percentage HAQ-DI responders (decrease of at least 0.22) at Month 6.
    8. Change from Baseline in the SF-36 8 domain scores and 2 component scores at Month 6.
    9. Change from Baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire at Month 6.
    10. Change from Baseline in the EuroQol EQ-5D at Month 6.
    11. Change from Baseline in the FACIT-Fatigue scale at Month 6.
    1. Cambio con respecto al momento basal en el SDAI y el CDAI en el mes 6.
    2. Cambio con respecto al momento basal en la DAS28-4 (PCR) y la DAS28-4 (VSG) en el mes 6.
    3. Tasa de remisión en el mes 6, evaluada por: Criterios de remisión según los criterios del Colegio Americano de Reumatología-Liga Europea contra el Reumatismo (American College of Rheumatology-European League Against Rheumatism, ACR-EULAR) booleanos (4); SDAI ≤ 3,3; CDAI ≤ 2,8; DAS28 4 (VSG) < 2,6 y DAS28-4 (PCR) < 2,6.
    4. Tasa LDA en el mes 6, evaluada por: SDAI ≤ 11; CDAI ≤ 10; DAS 28-4 (VSG) < 3,2 y DAS28-4 (PCR) < 3,2.
    5. Tasas de respuesta de ACR20 y ACR70 en el mes 6.
    6. Cambio con respecto al momento basal en HAQ-DI en el mes 6.
    7. Porcentaje de pacientes con respuesta en el HAQ-DI (reducción de al menos 0,22) en el mes 6.
    8. Cambio con respecto al momento basal en las puntuaciones de los 8 dominios del SF-36 y las puntuaciones de los 2 componentes en el mes 6.
    9. Cambio con respecto al momento basal en el cuestionario de deterioro de la actividad y productividad laboral (WPAI) en el mes 6.
    10. Cambio con respecto al momento basal en el EQ-5D en el mes 6.
    11. Cambio con respecto al momento basal en el cuestionario de FACIT Escala de Fatiga en el mes 6
    E.5.2.1Timepoint(s) of evaluation of this end point
    Month 6
    Mes 6
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Yes
    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 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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA63
    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
    Bosnia and Herzegovina
    Bulgaria
    Canada
    Chile
    Croatia
    Czech Republic
    Estonia
    Israel
    Korea, Republic of
    Latvia
    Lithuania
    Mexico
    Peru
    Philippines
    Poland
    Romania
    Russian Federation
    Serbia
    South Africa
    Spain
    Taiwan
    Thailand
    Turkey
    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
    The time at which it is deemed that sufficient subjects have been recruited and completed the study as stated in the regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the Member State.
    El momento en que se considere que suficientes pacientes han sido reclutados y han completado el estudio, tal y como se indica en la solicitud de evaluación (es decir, la solicitud de ensayo clínico (CTA)) y solicitud al Comité etico del estado Miembro
    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 months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 270
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 810
    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 state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 280
    F.4.2.2In the whole clinical trial 1080
    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
    Ninguno
    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 Decision2015-01-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-12-16
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