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    Summary
    EudraCT Number:2011-001729-25
    Sponsor's Protocol Code Number:RA0055
    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:2012-01-27
    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 number2011-001729-25
    A.3Full title of the trial
    A multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of certolizumab pegol in combination with methotrexate for inducing and sustaining clinical response in the treatment of dmard-naïve adults with early active rheumatoid arthritis.
    Estudio multicéntrico, aleatorizado, en doble ciego y controlado con placebo, para evaluar la eficacia y la seguridad de certolizumab pegol en combinación con metotrexato en la inducción y el mantenimiento de la respuesta clínica en adultos con artritis reumatoide activa en fase inicial no tratados previamente con Farme
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study designed to demonstrate the efficacy and safety of Certolizumab pegol in combination with Methotrexate in the treatment of subjects suffering from early, progressive active rheumatoid arthritis.
    Estudio diseñado para demostrar la eficacia y seguridad de Certolizumab pegol en combinación con Metrotrexato en el tratamiento de pacientes con artritis reumatoide con artritis reumatoide temprana, progresiva y activa
    A.3.2Name or abbreviated title of the trial where available
    -
    A.4.1Sponsor's protocol code numberRA0055
    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 SponsorUCB Pharma SA
    B.1.3.4CountryBelgium
    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 supportUCB Pharma SA
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUCB BIOSCIENCES GmbH
    B.5.2Functional name of contact pointCT Registries & Results Disclosure
    B.5.3 Address:
    B.5.3.1Street AddressAlfred-Nobel-Strasse 10
    B.5.3.2Town/ cityMannheim
    B.5.3.3Post code40789
    B.5.3.4CountryGermany
    B.5.4Telephone number+492173481515
    B.5.5Fax number+492173481572
    B.5.6E-mailclinicaltrials@ucb.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 Yes
    D.2.1.1.1Trade name Cimzia
    D.2.1.1.2Name of the Marketing Authorisation holderUCB Pharma SA
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCertolizumab pegol
    D.3.2Product code CDP870
    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 INNCERTOLIZUMAB PEGOL
    D.3.9.1CAS number 428863-50-7
    D.3.9.2Current sponsor codeCDP870
    D.3.9.4EV Substance CodeSUB25423
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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.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 Trexan
    D.2.1.1.2Name of the Marketing Authorisation holderOrion Corporation
    D.2.1.2Country which granted the Marketing AuthorisationPoland
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMethotrexate
    D.3.4Pharmaceutical form 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.3.9.1CAS number 59-05-2
    D.3.9.4EV Substance CodeSUB08856MIG
    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 placeboSolution for injection in pre-filled syringe
    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
    Early active rheumatoid arthritis
    Artritis reumatoide temprana y activa
    E.1.1.1Medical condition in easily understood language
    Rheumatoid arthritis
    Artritis reumatoide
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10003268
    E.1.2Term Arthritis rheumatoid
    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
    PERIOD 1
    To demonstrate that the combination of CZP + MTX is superior to PBO + MTX in achieving sustained remission by Week 52.
    PERIOD 2
    to demonstrate that both CZP + MTX dosing frequencies (the standard maintenance dose CZP 200mg every 2 weeks + MTX and the reduced frequency maintenance dose CZP 200mg every 4 weeks + MTX) are superior to PBO + MTX in maintaining subjects in LDA at Week 104
    Primer Periodo
    Demostrar que el tratamiento asociado con CZP + MTX es superior a PBO + MTX en el logro de una actividad baja mantenida de la enfermedad en la semana 52.
    Segundo periodo
    Demostrar que ambas frecuencias de dosificación de CZP + MTX (la dosis estándar de mantenimiento de 200 mg de CZP cada 2 semanas + MTX, y dosis de mantenimiento de frecuencia reducida de 200 mg de CZP cada 4 semanas + MTX) son superiores a PBO + MTX en el mantenimiento de los pacientes en actividad baja de la enfermedad en la semana 104.
    E.2.2Secondary objectives of the trial
    PERIOD 1? demonstrate that in DMARD-naïve subj. with adult-onset, early active RA present for <1 year that the combination therapy of CZP+MTX is superior to PBO+MTX in achieving sustained LDA at W 52
    ? Compare the efficacy of CZP+MTX to PBO+MTX based on: - Radiographic progression, - Clinical response, - Patient reported outcomes, - Productivity;PERIOD 2;? To demonstrate that for those subj. achieving sustained remission and treated with CZP+MTX during PER.1, both CZP+MTX dosing frequencies (standard dose /reduced one + MTX) are superior to PBO+MTX in maintaining subj. in remission at 104 weeks
    ? To evaluate for subjects who achieved sustained LDA at W 52 the efficacy of 3 different treatment options: - Radiographic progression; - Clinical response; - The proportion of subjects (also counting subjects who flared once) in LDA at W 104; - Time to flare using DAS28(ESR) in PER.2; - Patient reported outcomes; - Productivity within and outside home
    PERIODO 1 -Demostrar que pat sin tto previo con FARME, que padecen AR de inicio en edad adulta, temprana y activa, presente durante < 1 año, que el tto asociado con CZP + MTX es superior a PBO + MTX en la semana 52. - Eficacia de CZP + MTX, con PBO + MTX, basándose en: radiografías; clínica; inform de los pacientes; productividad. Periodo 2 -Demostrar que, en los pacientes que logran una remisión mantenida y que han recibido tto con CZP + MTX durante 1er periodo, ambas frecuencias de dosificación de CZP + MTX (la dosis estándar/reducida una + MTX)son> a PBO + MTX a las 104 semanas del inicio del tto.
    -Pat que han alcanzado una actividad baja mantenida en la sem 52, la eficacia de 3 diferentes opciones de mantenimiento del tto: ?radiografías,clínica; la proporción de pacientes (y pat con un solo brote) en actividad baja de la enfermedad en la sem 104;tiempo hasta el brote con el uso de la puntuación DAS28(ESR) en el segundo periodo,inform de los pacientes;productividad
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Subjects will be given the option to participate in a genetics, genomics, and proteomics sub-study. Subjects who decide to participate in the sub-study must complete a separate Informed Consent Form. The purpose is to explore candidate gene expression/DNA biomarkers/candidate blood borne protein biomarkers relative to risk, prognosis, and response to treatment with CZP. Each subject?s willingness to participate in the sub-study will be independent from his/her consent to participate in the main study.
    Pacientes tendrán la opción de participar en un subesturio de genómica, genética y proteómica. Los pacientes que decidan participar en este subestudio deberán completar un Consentimiento informado distinto.
    El propósito es explorar los genes de los candidatos/biomarcadores de ADN/biomarcadores proteínicos candidatos, transportados en la sangre, en relación con el riesgo, el pronóstico y la respuesta al tratamiento con CZP. Cada paciente que participe en el subestudio será independiente del consentimiento de participación del estudio principal.
    E.3Principal inclusion criteria
    1. An IRB/ IEC approved written Informed Consent form is signed and dated by the subject prior to any study procedure.
    2. To allow collection of blood samples for the genomic, genetic and proteomic analysis the subjects must have signed and dated an IRB/ IEC approved written Pharmacogenomics Informed Consent form.
    3. Subject is considered reliable and capable of adhering to the protocol (eg, able to understand and complete diaries), visit schedule, or medication intake according to the judgment of the Investigator.
    4. Subject is male or female and must be at least 18 years old at the Screening Visit.
    5. Female subjects must be either postmenopausal for at least 1 year, surgically incapable of childbearing, or effectively practicing an acceptable method of contraception (either oral/parenteral/implantable hormonal contraceptives, intrauterine device or barrier method and spermicide) at Screening. Abstinence only is not an acceptable method. Subjects must agree to use adequate contraception during the study and for at least 10 weeks (or longer if required by local regulations) after the last dose of study treatment. Male subjects must agree to ensure they or their female partner(s) use adequate contraception during the study and for at least 10 weeks (or longer if required by local regulations) after the subject receives their last dose of study treatment.
    6. Subjects must have a time since diagnosis of adult-onset RA less than 1 year as defined by the 2010 ACR / EULAR classification criteria from Screening Visit.
    7. Subjects must be DMARD-naïve at Screening and Baseline (except antimalarials, see Section 6.2.2 of the protocol).
    8. Subjects must have a positive RF or positive ACPA result at Screening.
    9. Subjects must have active RA disease as defined in the study protocol.
    1. Antes de cualquier intervención del estudio, el paciente firma y fecha el impreso de consentimiento informado escrito, aprobado por el CEIC.
    2. Para permitir la extracción de muestras de sangre para los análisis genómico, genético y proteómico, los pacientes deben haber firmado y fechado un impreso de consentimiento informado de farmacogenómica, escrito y aprobado por el CEIC.
    3. Se considera al paciente fiable y capaz de cumplir el protocolo (p. ej., capaz de entender y rellenar diarios), el calendario de visitas o la ingesta de medicamentos, según el criterio del Investigador.
    4. El paciente es de sexo femenino o masculino, y debe tener por lo menos 18 años en la visita de selección.
    5. Las pacientes mujeres deben ser posmenopáusicas durante un periodo mínimo de un año, quirúrgicamente no fértiles, o deben practicar eficazmente un método anticonceptivo aceptable (anticonceptivos hormonales orales, parenterales o implantables, dispositivo intrauterino o método de barrera y espermicida) en la visita de selección La abstinencia como método anticonceptivo único no es un método aceptable. Los pacientes deben dar su conformidad para usar un método anticonceptivo suficiente durante el estudio y durante al menos 10 semanas (o más si la normativa local lo exige) después de la última dosis del tratamiento del estudio. Los pacientes varones deben dar su conformidad para garantizar que sus parejas femeninas usen un método anticonceptivo suficiente durante el estudio y durante al menos 10 semanas (o más si la normativa local lo exige) después de la última dosis del tratamiento del estudio.
    6. El tiempo desde el diagnóstico de artritis reumatoide de inicio en la edad adulta en los pacientes debe ser inferior a un año, según la definición de los criterios de clasificación del ACR / EULAR de 2010, desde la visita de selección.
    7. Los pacientes no deben haber recibido tratamiento previo con FARME en la visita de selección y al inicio (excepto antipalúdicos; véase el apartado 6.2.2).
    8. Los pacientes deben tener un FR positivo o un resultado positivo de los ACPA en la visita de selección.
    9. Los pacientes deben presentar una artritis reumatoide activa, definida por el protocolo de este estudio
    E.4Principal exclusion criteria
    1. Female subjects who are breastfeeding, pregnant, or plan to become pregnant during the study or within 10 weeks following last dose of study drug.
    2. The subject has previously participated in this study and has received CZP treatment, or has previously received CZP in or outside of another clinical study.
    3. The subject has participated in another study of a medication or a medical device under investigation within the last 3 months or is currently participating in another study of a medication or medical device under investigation.
    4. The subject has a known hypersensitivity to any components of CZP or with a history of an adverse reaction to polyethylene glycol (PEG).
    5. Subjects must not have a secondary, noninflammatory type of musculoskeletal condition that in the Investigator?s opinion is symptomatic enough to interfere with evaluation of the effect of study drug on the subject?s primary diagnosis of RA.
    6. Subjects must not have a diagnosis of any other inflammatory arthritis nor have a Steinbrocker IV functional capacity.
    7. Subjects must not have received any experimental nonbiological therapy in the 3 past months or within 5 half-lives prior to Baseline (whichever is longer).
    8. Subjects must not have received any experimental or approved biological agent prior to Baseline.
    9. Subjects must not have used indicated medications in table 6.1 of the Protocol.
    10. Concurrent malignancy or a history of malignancy.
    11. Subjects with a history of a lymphoproliferative disorder including lymphoma or signs and symptoms suggestive of lymphoproliferative disease.
    12. Subjects with a history of blood dyscrasias.
    13. Subjects with a current or recent history, as determined by the Investigator, of severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, or cerebral disease or other significant immunological/inflammatory disease including systemic lupus erythematosus, inflammatory bowel disease.
    14. Subjects with congestive heart failure as defined by the New York Heart Association 1994 classification criteria.
    15. Subjects with a history of, or suspected, demyelinating disease of the central nervous system.
    16. Subjects with any other condition which in the Investigator?s judgment would make the subject unsuitable for inclusion in the study.
    17. Subject with a value >1.5x ULN for any of the following liver function tests (LFTs) at Screening: ? Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase [GOT]); ? Alanine aminotransferase (ALT) (glutamate?pyruvate transaminase [GPT]).
    18. Subject has history of chronic alcohol or drug abuse within the last 1 year.
    19. Subject has any medical or psychiatric condition that, in the opinion of the Investigator, can jeopardize or would compromise the subject?s ability to participate in this study.
    20. Subjects with history of or current clinically active infection (including infections verified by chest X-ray) with histoplasma, coccidiodes, paracoccidioides, pneumocystis, nontuberculous mycobacteria, blastomyces, or aspergillus.
    21. Subjects with a history of chronic or recurrent infections (>3 episodes requiring antibiotics or antivirals during the preceding year), recent serious or life-threatening infection within the 6 months prior to the Baseline Visit (including herpes zoster), hospitalization for any infection in the last 6 months or any current sign or symptom that may indicate an infection.
    22. Subjects at a high risk of infection (eg, leg ulcers, indwelling urinary catheter, and persistent or recurrent chest infections and subjects who are permanently bedridden or wheelchair bound).
    23. Subjects with concurrent acute or chronic viral hepatitis B or C.
    24. Subjects with known human immunodeficiency virus (HIV) infection.
    25. Subjects receiving live or attenuated vaccination within 8 weeks prior to Baseline. Live or attenuated vaccines are not allowed to be used concurrently with CZP during the period of the study.
    26.Subjects with known TB disease, high risk of acquiring TB infection, or latent TB infection as defined in the protocol.
    1. Pacientes mujeres que están en lactancia, embarazadas o que tienen previsto quedarse embarazadas durante el estudio o en las 10 semanas siguientes a la última dosis del fármaco del estudio.
    2. El paciente ha participado anteriormente en este estudio y ha recibido tratamiento con CZP, o ha recibido CZP dentro o fuera de otro estudio clínico.
    3. El paciente ha participado en otro estudio de un medicamento o un dispositivo médico en investigación en los 3 últimos meses, o está participando en otro estudio de un medicamento o un dispositivo médico en investigación.
    4. El paciente tiene una hipersensibilidad comprobada a cualquier componente del CZP o tiene antecedentes de una reacción adversa al polietilenglicol (PEG).
    5. Los pacientes no deben padecer un tipo secundario, no inflamatorio de afección osteomuscular, sea lo suficientemente sintomático como para interferir con la evaluación del efecto del fármaco del estudio sobre el diagnóstico principal de artritis reumatoide.
    6. Los pacientes no deben tener un diagnóstico de ninguna otra artritis inflamatoria) ni deben tener una capacidad funcional IV de Steinbrocker.
    7. Los pacientes no deben haber recibido ningún tratamiento no biológico experimental en los tres últimos meses ni en el lapso de cinco semividas antes del inicio
    8. Los pacientes no deben haber recibido ningún fármaco biológico experimental o aprobado antes del inicio.
    9. Los pacientes no deben haber usado los siguientes medicamentos de la manera detallada en la columna de criterios de exclusión de la tabla 6.1 del protocolo.
    10. Neoplasia maligna actual o antecedentes de neoplasia maligna 11. Pacientes con antecedentes de trastorno linfoproliferativo, incluido el linfoma, o signos y síntomas que sugieran una enfermedad linfoproliferativa.
    12. Pacientes con antecedentes de discrasias sanguíneas.
    13.Pacientes con enfermedad actual o antecedentes, determinado por el Investigador, de enfermedad renal, hepática, hematológica, digestiva, endocrina, pulmonar, cardiaca, neurológica o cerebral, grave, progresiva o no controlada, u otra enfermedad inmunológica o inflamatoria significativa, incluidos el lupus eritematoso, la enfermedad intestinal inflamatoria.
    14. Pacientes con insuficiencia cardiaca congestiva, según la definición de los criterios de clasificación de 1994 de la New York Heart Association.
    15. Pacientes con antecedentes o sospecha de enfermedad desmielinizante del sistema nervioso central.
    16. Pacientes con alguna otra afección que a juicio del Investigador, harían al paciente inadecuado para su inclusión en el estudio.
    17. Paciente con un valor > 1,5 x LSN para cualquiera de las siguientes pruebas de función hepática en la visita de selección: Aspartato aminotransferasa (AST) (transaminasa glutámico-oxaloacética [GOT]); Alanina aminotransferasa (ALT) (transaminasa glutámico-pirúvica [GPT])
    18.El paciente tiene antecedentes de abuso crónico del alcohol o las drogas en el último año.
    19. El paciente padece alguna afección médica o psiquiátrica que, a juicio del Investigador, pudiera poner en peligro o pudiera afectar a la capacidad del paciente para participar en este estudio.
    20. Pacientes con antecedentes de infección clínicamente activa (o existencia actual); (incluidas las infecciones verificadas mediante la radiografía de tórax) por Histoplasma, Coccidiodes, Paracoccidioides, Pneumocystis, micobacterias no tuberculosas, Blastomyces o Aspergillus.
    21.Pacientes con antecedentes de infecciones crónicas o recurrentes (> 3 episodios que requieren antibióticos o antivíricos durante el año anterior), infección grave o potencialmente mortal, reciente, en los seis meses anteriores a la visita inicial (incluido el herpes zóster), hospitalización por alguna infección en los seis últimos meses, o algún signo o síntoma que pueda indicar una infección.
    22. Pacientes con un riesgo alto de infección (p. ej., úlceras en las extremidades inferiores, sonda urinaria permanente, e infecciones respiratorias persistentes o recurrentes, y pacientes que están permanentemente en la cama o en una silla de ruedas).
    23. Pacientes con una hepatitis vírica, B o C, aguda o crónica, concomitante.
    24. Pacientes con una infección comprobada por el virus de la inmunodeficiencia humana (VIH).
    25. Pacientes que reciben una vacuna viva o atenuada en las ocho semanas anteriores al inicio. No está permitido el uso de vacunas vivas o atenuadas simultáneamente con el CZP durante el periodo del estudio.
    26. Pacientes con tuberculosis comprobada, alto riesgo de adquirir tuberculosis o infección latente por tuberculosis definida por protocolo de este estudio.
    E.5 End points
    E.5.1Primary end point(s)
    PERIOD 1
    1) proportion of subjects in sustained remission (defined as DAS28[ESR] <2.6 at Week 40 and Week 52 visits)
    PERIOD 2
    2) proportion of subjects who maintain LDA (DAS28[ESR] ?3.2) from Week 52 through Week 104 without flaring
    Periodo 1
    1) Proproción de sujetos en remisión mantenida de DAS28(ESR) (definida como una puntuación DAS28[ESR] < 2,6 en las visitas de las semanas 40 y 52) en la semana 52.
    Periodo 2
    2)periodo es la proporción de pacientes que mantienen una actividad baja de la enfermedad (DAS28[ESR] ? 3,2) desde la semana 52 hasta la 104, sin brotes.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) Week 52
    2) Week 52 through Week 104
    1)Semana 52
    2)Semana 52 hasta semana 104
    E.5.2Secondary end point(s)
    PERIOD 1
    1) proportion of subjects in sustained LDA (defined as DAS28[ESR] ?3.2 at Week 40 and Week 52 visits).
    2) Radiographic variables: ? change in the van der Heijde modified total sharp score (mTSS), ? proportion of subjects with radiographic nonprogression, defined as change in mTSS ? 0.5; ? change in joint erosion score; ? change in joint narrowing score.
    3) Clinical variables: ? American College of Rheumatology (ACR)20, ACR50, ACR70 response rates in relation to Baseline, ? proportion of subjects achieving a good or moderate EULAR clinical response (according to the DAS28(ESR)-based EULAR response criteria), ? changes from Baseline in individual components of the ACR criteria, including tender joint count (TJC), swollen joint count (SJC), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient Assessment of Arthritis Pain-Visual Analog Scale (PtAAP), Patient Global Assessment of Disease Activity (PtGADA), Physician Global Assessment of Disease Activity (PhGADA), CRP (ratio to Week 0) and erythrocyte sedimentation rate (ESR, ratio to Week 0), ? changes from Baseline in DAS28(ESR), Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI), ? proportion of subjects in remission as defined by: - the new ACR/EULAR 2011 remission criteria (TJC ?1, SJC ?1, CRP ?1mg/dl and PtGADA ?1); - the new ACR/EULAR 2011 remission criteria simplified for clinical practice (TJC ?1, SJC ? 1 and PtGADA ?1); - DAS28(ESR) <2.6;- CDAI ?2.8; - SDAI ?3.3.
    4) Patient-reported variables: ? proportion of subjects reaching normative physical function (HAQ-DI score ?0.5), ? change from Baseline in Bristol RA Fatigue Multidimensional Questionnaire (BRAF?MDQ) total, ? scores of the individual questions of the Work Productivity Survey RA (WPS-RA).
    PERIOD 2
    5) the proportion of subjects who are in sustained remission at Week 52 and maintain their remission (DAS28[ESR] <2.6) from Week 52 through Week 104 without flaring.
    6) Radiographic variables: ? change in the van der Heijde modified total sharp score (mTSS), ? proportion of subjects with radiographic nonprogression, defined as change in mTSS ? 0.5, ? change in joint erosion score, ? change in joint narrowing score.
    7) Clinical variables: ? ACR20, ACR50, ACR70 response rates in relation at Week 0, ? proportion of subjects achieving a good or moderate EULAR clinical response (according to the DAS28[ESR]-based EULAR response criteria), ? changes from Week 0 and from Week 52 in individual components of the ACR criteria, including TJC, SJC, HAQ-DI, PtAAP, PtGADA, PhGADA, CRP (ratio to Week 0) and ESR (ratio to Week 0), ? changes from Week 0 and from Week 52 in DAS28(ESR), CDAI and SDAI, ? proportion of subjects in remission as defined by: - the new ACR/EULAR 2011 remission criteria (TJC ?1, SJC ?1, CRP ?1mg/dl and PtGADA ?1); - the new ACR/EULAR 2011 remission criteria simplified for clinical practice (TJC ?1, SJC? 1 and PtGADA ?1); - DAS28(ESR) <2.6; - CDAI ?2.8; - SDAI ?3.3; ? proportion of subjects in LDA (including all subjects who had a single flare but were brought back into LDA), ? time to flare, defined as an increase of DAS28(ESR) ?0.6 above Week 52 DAS28(ESR) level, having a DAS28(ESR) ?3.2 and judged by the Investigator as due to RA and all 3 criteria confirmed at an additional visit 2 weeks thereafter, from Week 52 onwards.
    8) Patient-reported variables: ? proportion of subjects reaching normative physical function (HAQ-DI score ?0.5), ? change from Week 0 in BRAF?MDQ total, ? scores of the individual questions of the Work Productivity Survey RA (WPS-RA)
    PERIODO 1
    1) Proporción de pacientes que mantienen una actividad baja de la enfermedad (DAS28[ESR] ? 3,2) desde la semana 52
    2)Variables radiográficas:el cambio en la puntuación total de Sharp modificada por van der Heijde (mTSS); la proporción de pacientes con ausencia de progresión radiográfica, definida como el cambio en la puntuación mTSS ? 0,5; el cambio en la puntuación de erosión articular; el cambio en la puntuación de estrechamiento articular.
    3) Variables Clínicas,las tasas de respuesta del American College of Rheumatology (ACR)20, ACR50, ACR70 en relación con el valor basal; proporción de pacientes que logran una respuesta clínica EULAR buena o moderada (según los criterios de respuesta EULAR basados en la puntuación DAS28(ESR); los cambios con respecto a los valores basales de los componentes individuales de los criterios del ACR, incluidos el recuento de articulaciones con dolor a la palpación (TJC), el recuento de articulaciones inflamadas (SJC), el cuestionario de evaluación de la salud - índice de discapacidad (HAQ-DI), la escala visual-analógica de la evaluación de la artritis por parte del paciente (PtAAP), la evaluación global de la actividad de la enfermedad por parte del paciente (PtGADA), la evaluación global de la actividad de la enfermedad por parte del médico (PhGADA), la PCR (índice hasta la semana 0) y la velocidad de sedimentación globular (VSG, índice hasta la semana 0);los cambios con respecto a los valores basales de la puntuación DAS28(ESR), el índice clínico de actividad de la enfermedad (CDAI) y el índice simplificado de actividad de la enfermedad (SDAI),la proporción de pacientes en remisión definida por:o Los nuevos criterios de remisión ACR/EULAR 2011 (TJC ?1, SJC?1, PCR ? 1 mg/dl y PgGADA ? 1);o Los nuevos criterios de remisión ACR/EULAR 2011 simplificados por la práctica clínica (TJC ?1, SJC ? 1 y PtGADA ?1);o DAS28(ESR) < 2,6;oCDAI ?2,8;oSDAI ?3,3.
    4) Varibles reportadas de los pacientes, la proporción de pacientes que alcanzan una función física normativa (puntuación HAQ-DI ? 0,5); el cambio con respecto al valor inicial del cuestionario multidimensional de cansancio de Bristol en la artritis reumatoide (BRAF-MDQ); las puntuaciones de las preguntas individuales de la encuesta de productividad en el trabajo en la artritis reumatoide (WPS-RA).
    PERIODO 2-5) Proporción de pacientes que mantienen una actividad baja de la enfermedad (DAS28[ESR] ? 3,2) desde la semana 52; desde la semana 52 hasta la 104, sin brotes.
    6)Variables radiográficas:?el cambio en la puntuación total de Sharp modificada por van der Heijde (mTSS); la proporción de pacientes con ausencia de progresión radiográfica, definida como el cambio en la puntuación mTSS ? 0,5; el cambio en la puntuación de erosión articular; el cambio en la puntuación de estrechamiento articular.
    7) Variables Clínicas,las tasas de respuesta del (ACR)20, ACR50, ACR70 en relación con el valor basal; proporción de pacientes que logran una respuesta clínica EULAR buena o moderada (según los criterios de respuesta EULAR basados en la puntuación DAS28(ESR); los cambios con respecto a los valores basales de los componentes individuales de los criterios del ACR, incluidos el recuento de articulaciones con dolor a la palpación (TJC), el recuento de articulaciones inflamadas (SJC), el cuestionario de evaluación de la salud - índice de discapacidad (HAQ-DI), la escala visual-analógica de la evaluación de la artritis por parte del paciente (PtAAP), la evaluación global de la actividad de la enfermedad por parte del paciente (PtGADA), la evaluación global de la actividad de la enfermedad por parte del médico (PhGADA), la PCR (índice hasta la semana 0) y la velocidad de sedimentación globular (VSG, índice hasta la semana 0);los cambios con respecto a los valores basales de la puntuación DAS28(ESR), el índice clínico de actividad de la enfermedad (CDAI) y el índice simplificado de actividad de la enfermedad (SDAI),la proporción de pacientes en remisión definida por:o
    Los nuevos criterios de remisión ACR/EULAR 2011 (TJC ?1, SJC?1, PCR ? 1 mg/dl y PgGADA ? 1);oLos nuevos criterios de remisión ACR/EULAR 2011 simplificados por la práctica clínica (TJC ?1, SJC ? 1 y PtGADA ?1);o DAS28(ESR) < 2,6;oCDAI ?2,8;oSDAI ?3,3.
    8) Varibles reportadas de los pacientes, la proporción de pacientes que alcanzan una función física normativa (puntuación HAQ-DI ? 0,5); el cambio con respecto al valor inicial del cuestionario multidimensional de cansancio de Bristol en la artritis reumatoide (BRAF-MDQ); las puntuaciones de las preguntas individuales de la encuesta de productividad en el trabajo en la artritis reumatoide (WPS-RA).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Week 52
    2) Baseline-Week 52
    3) Week 12-24-52/withdrawal visit
    4) Week 12-24-52/withdrawal visit
    5) Week 52 through Week 104
    6) Week 0 to Week 104/withdrawal visit or Week 52 to Week 104/withdrawal visit
    7) Week 104/withdrawal visit
    8) Week 104/withdrawal visit
    1)Semana 52
    2)Visita basal- Semana 52
    3)Semana 12-24-52/visita de retirada
    4)Semana 12-24-52/visita de retirada
    5)Semana 52 hasta semana 104
    6)Semana 0 hasta Semana 104/visita de retirada o semana 52 hasta semana 104/visita de retirada
    7) Week 104/visita de retirada
    8) Week 104/visita de retirada
    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 Yes
    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) 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 No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA106
    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
    Canada
    Colombia
    Mexico
    Switzerland
    Turkey
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 400
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 800
    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)
    standard care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-03-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-08
    P. End of Trial
    P.End of Trial StatusCompleted
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