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    Summary
    EudraCT Number:2011-002067-20
    Sponsor's Protocol Code Number:RA0077
    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:2012-05-10
    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 number2011-002067-20
    A.3Full title of the trial
    A multicenter, single blind, randomized parallel group study to assess the short and long term efficacy of certolizumab pegol plus methotrexate compared with adalimumab plus methotrexate in subjects with moderate to severe rheumatoid arthritis responding inadequately to methotrexate.
    Estudio multicéntrico, aleatorizado, en simple ciego y de grupos paralelos, para evaluar la eficacia a corto y largo plazo de certolizumab pegol más metotrexato en comparación con adalimumab y metotrexato en sujetos con artritis reumatoide moderada a severa de respuesta inadecuada al metotrexato
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study designed to assess the short- and long-term efficacy of CZP compared with Adalimumab, both when used with methotrexate (MTX) in the treatment of subjects suffering from rheumatoid arthritis that are not responding adequately to MTX. Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF that has been approved for the treatment of moderate to severe active RA in the USA, the European Union, and a number of other countries worldwide.
    Estudio diseñado para valorar la eficacia a corto y largo plazo (CZP) en comparación con adalimumab (ADA), utilizados ambos con metotrexato (MTX) en el tratamiento de sujetos con artritis reumatoide (AR) moderada a severa de respuesta inadecuada al MTX. El adalimumab es un anticuerpo monoclonal humano recombinante de tipo IgG1 específico del TNF? humano que se encuentra aprobado para el tratamiento de la AR de actividad moderada a severa en Estados Unidos, la unión Europea y en otros países.
    A.3.2Name or abbreviated title of the trial where available
    -
    A.4.1Sponsor's protocol code numberRA0077
    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/ cityMonheim am Rhein
    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 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 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 Humira
    D.2.1.1.2Name of the Marketing Authorisation holderAbbott Laboratories 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.3.4Pharmaceutical 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.3.9.4EV Substance CodeSUB20016
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection 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
    Moderate to severe rheumatoid arthritis
    Moderada a severa artritis reumatoide
    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
    The primary objectives of this study in adult subjects with moderate to severe RA responding inadequately to MTX are as follows:
    -To demonstrate the superiority of short term (Week 12) treatment in CZP+MTX randomized subjects as compared with ADA+MTX randomized subjects
    -To demonstrate the superiority of long term (Week 104) treatment in CZP+MTX randomized subjects as compared with ADA+MTX randomized subjects, with subjects who switch treatment (Week 12 Non Responders) counted as treatment failures.
    Los objetivos principales de este estudio en sujetos adultos con AR moderada a severa de:
    respuesta inadecuada al MTX son los siguientes:
    -Demostrar la superioridad del tratamiento a corto plazo (semana 12) en los sujetos aleatorizados a CZP+MTX en comparación con los aleatorizados a ADA+MTX
    -Demostrar la superioridad del tratamiento a largo plazo (semana 104) en los sujetos aleatorizados a CZP+MTX en comparación con los aleatorizados a ADA+MTX, contándose como fracasos del tratamiento a los sujetos que se cambien de tratamiento (no respondedores en la semana 12)
    E.2.2Secondary objectives of the trial
    -To investigate whether a Week 12 decision point is better at predicting the long term (Week 104) treatment success with CZP+MTX as compared with a Week 12 decision point with ADA+MTX
    -To compare the % of subjects who meet ACR20 criteria at Week 6 between the CZP+MTX- and ADA+MTX randomized arms
    -To compare the % of subjects with DAS28(ESR) LDA at Week 6 between the CZP+MTX- and ADA+MTX randomized arms
    -To compare the % of subjects with DAS28(ESR) LDA at Week 12 between the CZP+MTX- and ADA+MTX randomized arms
    -To evaluate the % of subjects reaching DAS28(ESR) LDA at Week 104 in subjects responding (in accordance with the Week 12 Responder definition) at both Week 6 and Week 12 when treated with CZP+MTX compared with ADA+MTX
    -To evaluate the efficacy of CZP+MTX versus ADA+MTX in the physical function of Week 12 Responders at Week 104
    -To evaluate the time to discontinuation in Week 12 Responders treated with CZP+MTX versus ADA+MTX
    -Investigar si el punto de decisión de la sem 12 es mejor para predecir el éxito del tto a L/plazo (sem 104) con CZP+MTX en comparación con el punto de decisión de la sem 12 con ADA+MTX
    -Comparar el % de sujetos que cumplan los criterios ACR20 en la sem 6 entre los grupos aleatorizados a CZP+MTX y ADA+MTX
    -Comparar el % de sujetos con LDA en DAS28(ESR) en a sem 6 entre los grupos aleatorizados a CZP+MTX y ADA+MTX
    -Comparar el % de sujetos con LDA en DAS28(ESR) en la semana 12 entre los grupos aleatorizados a CZP+MTX y ADA+MTX
    -Evaluar el % de sujetos que alcancen LDA en DAS28(ESR) en la semana 104 entre los sujetos que respondan en las sem 6 y 12, en su tto con CZP+MTX en comparación con ADA+MTX
    -Evaluar la eficacia de CZP+MTX en comparación con ADA+MTX en cuanto a la función física que presenten en la sem 104 los respondedores en la sem 12
    -Evaluar tiempo hasta el abandono de los respondedores en la sem 12 tratados con CZP+MTX en comparación con los tratados con ADA+MTX
    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 for Pharmacogenomics and Pharmacogenetics at Screening following the same procedure and given the same considerations as the main Informed Consent Form. Each subject?s willingness to participate in the sub-study will be independent from his/her consent to participate in the main study.
    Los sujetos tendrán la opción de participar en el subestudio de genética, genómica y proteinómica. Los sujetos que decidan participar en el subestudio tendrán que cumplimentar en la selección otro documento de consentimiento informado aparte para farmacogenómica y farmacogenética, siguiendo el mismo procedimiento y con las mismas consideraciones que el documento de consentimiento informado para el estudio principal. La voluntad del sujeto de participar en el subestudio será independiente de su consentimiento para participar en el estudio principal.
    E.3Principal inclusion criteria
    1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form is signed and dated by the subject.
    2. 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.
    3. Subject is >=18 years of age at Screening.
    4. Subject must have a diagnosis of RA at Screening, as defined by the 2010 EULAR/ACR classification criteria (Aletaha D et al, 2010).
    5. Subject must have a positive rheumatoid factor (RF) and/or a positive anti cyclic citrullinated peptide antibody (anti-CCP) at Screening.
    6. Subject must have moderate to severe RA disease at Screening and Baseline as defined by:
    ->=4 swollen joints (of 28 prespecified joints).
    - DAS28(ESR) >3.2.
    - CRP concentration >10mg/L (or 1.0mg/dL) and/or ESR (Westergren) >=28mm/hr.
    7. Subject must have inadequately responded previously to MTX. Methotrexate-inadequate response is defined as not having achieved DAS28(ESR) =<3.2 during the 3 to 6 months prior to the Screening Visit according to the Investigator.
    8. Subject is using MTX 15 to 25mg/week orally or subcutaneously at Baseline and has used the same MTX regimen (dose and route) during the 56 days prior to Baseline. A MTX dose at a minimum of 10mg/wk orally or subcutaneously is acceptable for subjects considered by the Investigator to be intolerant to a higher dose of MTX.
    9. Subject, if using oral corticosteroids at Baseline, is receiving at a stable dose of <=10mg (unchanged for at least 28 days prior to Baseline).
    10. The subject, if female, must be either postmenopausal for at least 1 year, surgically incapable of childbearing, or effectively practicing an acceptable method of contraception (oral/parenteral/implantable hormonal contraceptives, intrauterine device, or barrier and spermicide). Abstinence only is not an acceptable method. Subjects must agree to use adequate contraception from Screening through at least 10 weeks (or longer if required by local regulations) after the final dose of IMP. Male subjects must agree to ensure they or their female partner(s) use adequate contraception from Screening through at least 10 weeks (or longer if required by local regulations) after the final dose of IMP.
    1.El sujeto ha firmado y fechado el documento de consentimiento informado por escrito aprobado por el comité ético (IRB/CEIC).
    2. Se considera que el sujeto es fiable y capaz de cumplir el protocolo (por ejemplo capaz de comprender y rellenar los diarios), el calendario de visitas o la administración de la
    medicación, a juicio del investigador.
    3. El sujeto tiene >=18 años de edad en la selección.
    4. El sujeto presenta un diagnóstico de AR en la selección, según la definición de los criterios de clasificación de la EULAR/ACR de 2010 (Aletaha D et al., 2010).
    5. El sujeto presenta factor reumatoide (FR) positivo y/o anticuerpo anti-péptido cíclico citrulinado (anti-CCP) positivo en la selección.
    6. El sujeto presenta AR moderada a severa en la selección y en el momento basal definida por:
    ->=4 articulaciones con tumefacción (28 articulaciones preestablecidas).
    -DAS28(ESR) >3,2.
    -Concentración de proteína C reactiva (CRP) >10 mg/L (o 1,0 mg/dL) y/o velocidad de sedimentación globular (ESR, Westergren) >=28 mm/h.
    7. El sujeto ha presentado anteriormente una respuesta inadecuada al metotrexato (MTX) lo que se define como no haber alcanzado un valor de DAS28(ESR) =<3,2 durante los 3 a 6 meses anteriores a la visita de selección, a juicio del investigador.
    8. El sujeto recibe de 15 a 25 mg/semana de MTX por vía oral o subcutánea en el momento basal y ha estado con el mismo régimen de MTX (dosis y vía) durante los 56 días anteriores al momento basal. Se acepta una dosis mínima de 10 mg/semana de MTX por vía oral o subcutánea en los sujetos que el investigador considere intolerantes a una dosis mayor de MTX.
    9. El sujeto, si toma corticosteroides orales en el momento basal, recibe una dosis estable <=10 mg (sin cambios desde al menos 28 días antes del momento basal).
    10. Si es mujer, debe ser posmenopáusica desde hace por lo menos un año, haber sido esterilizada quirúrgicamente o practicar efectivamente un método anticonceptivo aceptable (anticonceptivos hormonales orales, parenterales o implantables, dispositivo intrauterino, o método de barrera y espermicida). La abstinencia sexual sola no es un método aceptable. La sujeto debe comprometerse a utilizar un método anticonceptivo
    adecuado desde la selección hasta por lo menos 10 semanas (o más si lo requiere la reglamentación local) después la última dosis del medicamento en investigación. Los varones deben comprometerse a asegurarse de que su pareja femenina utilice un
    anticonceptivo adecuado desde la selección hasta por lo menos 10 semanas (o más requiere la reglamentación local) después la última dosis del medicamento en investigación)
    E.4Principal exclusion criteria
    1. Subject has previously participated in this study or subject has previously received any bDMARD during another clinical study or independent of another clinical study.
    2. Subject has participated in another study of medication or a medical device within the previous 3 months or is currently participating in another study of a medication or medical device under investigation.
    3. If a female subject, is breastfeeding, pregnant, or plans to become pregnant during the study or within 10 weeks following final dose of IMP or thereafter according to local regulations.
    4. Subject has a known hypersensitivity to any components of CZP or ADA, or a history of an adverse reaction to polyethylene glycol (PEG).
    5. Subject has a contraindication to the use of CZP, ADA, or MTX.
    6. Subject must not have a secondary, noninflammatory type of musculoskeletal condition (eg, osteoarthritis or fibromyalgia) that in the Investigator?s opinion is symptomatic enough to interfere with evaluation of the effect of the IMP on the subject?s primary diagnosis of RA.
    7. Subject must not have a diagnosis of any other inflammatory arthritis (eg, psoriatic arthritis or ankylosing spondylitis) or have a Steinbrocker IV functional capacity.
    8. Subject must not have previously received any experimental nonbiological therapy.
    9. Subject must be free of prohibited use or a limited use of concomitant medication as detailed in Table 6:1 of the Protocol.
    10.Subject with concurrent malignancy or a history of malignancy (subjects with fewer than 3 excised basal cell carcinomas or with cervical carcinoma in situ successfully surgically treated more than 5 years prior to Screening may be included).
    11. Subject 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. Subject 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 or irritable bowel syndrome.
    14. Subject with class III or IV congestive heart failure as defined by the New York Heart Association 1964 classification criteria.
    15. Subject with a history of, or suspected, demyelinating disease of the central nervous system (eg, multiple sclerosis or optic neuritis).
    16. Subject with any other condition (ie, clinically significant laboratory values) which, in the judgment of the Investigator, would make the subject unsuitable for inclusion in the study.
    17. Subject with a value >=1.2xULN for any of the following liver function tests (LFTs):
    -Aspartate aminotransferase (AST) (glutamic oxaloacetic transaminase [GOT]).
    -Alanine aminotransferase (ALT) (glutamate pyruvate transaminase [GPT]).
    -Gamma-glutamyl transferase (GGT).
    18. Subject has history of chronic alcohol or drug abuse within the previous 6 months.
    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. Subject with history of or current clinically active infection (including chest x-ray) with Histoplasma, Coccidioides, Paracoccidioides, Pneumocystis, Mycobacteria (other than tuberculosis), Blastomyces, or Aspergillus.
    21. Subject 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 previous 6 months, or any current sign or symptom that may indicate an infection.
    22. Subject at a high risk of infection (eg, subject has leg ulcers, indwelling urinary catheter, or persistent or recurrent chest infections; or subject who is permanently bedridden or wheelchair bound).
    23. Subject with concurrent acute or chronic viral Hepatitis B or C infection.
    24. Subject with known human immunodeficiency virus infection.
    25. Subject receiving live or attenuated vaccination during the 8 weeks (56 days) prior to Baseline. Live or attenuated vaccines are not allowed to be used concurrently with CZP or ADA during the study.
    26. Subjects with known Tuberculosis (TB) disease, high risk of acquiring TB infection, or latent TB infection as defined in the Protocol
    1. El sujeto ha participado anteriormente en este estudio o ha recibido antes algún fármaco antirreumático modificador de la enfermedad biológico (FARMEb) en otro estudio clínico
    2. El sujeto ha participado en otro estudio con un medicamento o producto sanitario en el plazo de los 3 meses anteriores o se encuentra participando actualmente en otro estudio con un medicamento o pdto sanitario en investigación.
    3. Si es mujer, se encuentra en periodo de lactancia, está embarazada o tiene previsto quedarse embarazada durante el estudio o en las 10 sem posteriores a la última dosis
    del medicamento en investigación, o el plazo que establezca la reglamentación local.
    4. El sujeto presenta hipersensibilidad conocida a alguno de los componentes de CZP o ADA, o antecedentes de una reacción adversa al polietilenglicol (PEG).
    5. El sujeto tiene contraindicado el uso de CZP, ADA o MTX.
    6. El sujeto no debe padecer un trastorno secundario no inflamatorio de tipo musculoesquelético (artrosis o fibromialgia) con un grado de sintomatología que, en opinión del investigador, vaya a interferir en la evaluación del efecto del medicamento en investigación sobre el diagnóstico principal del sujeto de AR.
    7. El sujeto no debe presentar ninguna otra artritis inflamatoria (artritis psoriásica o espondilitis anquilosante) ni una capacidad funcional de Steinbrocker de IV.
    8. El sujeto no debe haber recibido antes ningún tratamiento no biológico experimental.
    9. El sujeto no debe estar recibiendo medicamentos concomitantes prohibidos o de uso limitado tabla 6:1 del protocolo.
    10. Sujetos con neoplasia maligna actual o antecedentes de neoplasia maligna (sí se podrá incluir a los sujetos con menos de 3 carcinomas basocelulares extirpados o con carcinoma in situ de cuello uterino tratado quirúrgicamente con éxito más de 5 años antes de la selección).
    11. Sujetos con antecedentes de trastornos linfoproliferativos, como el linfoma, o con signos y síntomas indicativos de enfermedad linfoproliferativa.
    12. Sujetos con antecedentes de discrasias sanguíneas.
    13. Sujetos con presencia o antecedentes recientes, a juicio del investigador, de enfermedades severas, progresivas y/o no controladas de tipo renal, hepático, hematológico, gastrointestinal, endocrino, pulmonar, cardiaco, neurológico o cerebral, otras enfermedades inmunológicas/inflamatorias importantes, incluido el lupus eritematoso sistémico o el síndrome de colon irritable.
    14. Sujetos con insuficiencia cardiaca congestiva de clase III o IV según la definición de los criterios de clasificación de 1964 de la New York Heart Association.
    15. Sujetos con antecedentes o sospecha de enfermedad desmielinizante del sistema nervioso central (por ejemplo, esclerosis múltiple o neuritis óptica).
    16. Sujetos con cualquier otro trastorno (valores de laboratorio clínicamente importantes)
    que, a juicio del investigador, desaconsejara su inclusión en el estudio.
    17. Sujetos con un valor >=1,2 veces el límite superior de la normalidad de cualquiera de las siguientes pruebas funcionales hepáticas:
    -Aspartato-aminotransferasa (AST) (transaminasa glutámico oxalacética [GOT]).
    -Alanina-aminotransferasa (ALT) (glutamato-piruvato-transaminasa [GPT]).
    -Gammaglutamil-transferasa (GGT).
    18. Sujetos con antecedentes de alcoholismo crónico o abuso de sustancias en los 6 meses anteriores.
    19. Sujetos con cualquier trastorno médico o psiquiátrico que, en opinión del investigador, pudiera poner en peligro o comprometer la capacidad del sujeto para participar en este estudio.
    20. Sujetos con antecedentes o presencia de infección clínicamente activa (incluida radiografía de tórax) por Histoplasma, Coccidioides, Paracoccidioides, Pneumocystis, Mycobacteria (distintas de tuberculosis), Blastomyces o Aspergillus.
    21. Sujetos con antecedentes de infecciones crónicas o recurrentes (>3 episodios que hayan precisado antibióticos o antivirales durante el año anterior), reciente grave o potencialmente mortal en el plazo de los 6 meses anteriores a la visita basal (incluido el herpes zóster), hospitalización por cualquier infección en los 6 meses anteriores o cualquier signo o síntoma actual indicativo de infección.
    22. Sujetos con alto riesgo de infección (por ejemplo, úlceras en las piernas, sonda urinaria permanente o infecciones torácicas recurrentes; o sujetos encamados o en silla de ruedas de forma permanente).
    23. Sujetos con infección aguda o crónica concomitante por los virus de la hepatitis B o C.
    24. Sujetos con infección conocida por el virus de la inmunodeficiencia humana.
    25. Sujetos que hayan recibido vacunas de microorganismos vivos o atenuados en las 8 semanas (56 días) anteriores al momento basal. No se permite la administración de vacunas de microorganismos vivos o atenuados de forma concomitante con CZP o ADA durante el estudio.
    26. Sujetos con tuberculosis (TB) conocida, alto riesgo de contraer una TB o con TB latente, como está definido en el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    1) Percentage of subjects meeting ACR20 criteria [American College of Rheumatology 20% criteria] in the CZP+MTX randomized group compared with the ADA+MTX randomized group;
    2) Percentage of subjects with DAS28(ESR) LDA [Disease Activity Score-28 joint count(erythrocyte sedimentation rate) Low disease activity] in the CZP+MTX randomized group compared with the ADA+MTX randomized group (Group A versus Group C using all randomized subjects in the FAS)
    1)Porcentaje de sujetos que cumplan los criterios del 20% según el American College of Rheumatology (ACR20) en el grupo aleatorizado a CZP+MTX frente a los del grupo aleatorizado a ADA+MTX
    2)Porcentaje de sujetos con ?LDA en DAS28[ESR]?) definida por una puntuación DAS28 [Disease Activity Score - recuento de 28 articulaciones (con la velocidad de sedimentación globular) con una baja actividad de la enfermedad] en CZP+MTX frente a los del grupo aleatorizado a ADA+MTX. (grupo A frente a grupo C con todos los sujetos aleatorizados en el FAS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    1) Week 12
    2) Week 104
    1) Semana 12
    2) Semana 104
    E.5.2Secondary end point(s)
    Among the others:
    1) The percentage of subjects with DAS28(ESR) LDA at Week 104 comparing the Week 12 Responder groups (Group A versus Group C).
    2) The percentage of subjects with DAS28(ESR) LDA at Week 6 using all subjects, comparing the CZP+MTX randomized arm and the ADA+MTX randomized arm
    3) The percentage of subjects with DAS28(ESR) LDA at Week 12 using all subjects, comparing randomized treatment groups CZP+MTX and ADA+MTX
    4) The percentage of subjects with DAS28(ESR) LDA at Week 104 comparing the Week 12 Responder groups (Group A versus Group C), who also responded at Week 6 (ie, DAS28(ESR) <=3.2 or a DAS28(ESR) CFB reduction of >=1.2)
    1) Porcentaje de sujetos que alcancen LDA en DAS28(ESR) en la semana 104 entre los sujetos que respondan (según la definición de respondedor en la semana 12?) (Grupo A versus Grupo C).
    2) Porcentaje de sujetos con LDA en DAS28(ESR) en la semana 6 con todos los sujetos, comparando CZP+MTX frente a los del
    brazo aleatorizado a ADA+MTX
    3)Porcentaje de sujetos con LDA en DAS28(ESR) en la semana 12 con sujetos, comparando grupos de tratamiento CZP+MTX ADA+MTX
    4)Porcentaje de sujetos con LDA en DAS28(ESR) en la semana 104 con comparación de los grupos de respondedores en la semana 12 (grupo A frente a grupo C) que también
    respondieron en la semana 6 (es decir, DAS28(ESR) <=3,2 o una reducción del CFB en DAS28(ESR) >=1,2)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Week 104
    2) Week 6
    3) Week 12
    4) Week 104
    1) Semana 104
    2) Semana 6
    3) Semana 12
    4) Semana 104
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic 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) No
    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 Yes
    E.8.1.4Double blind No
    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 No
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA85
    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
    Australia
    Canada
    Mexico
    Switzerland
    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 ultimo 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 months8
    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 months8
    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: 446
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 446
    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 state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 448
    F.4.2.2In the whole clinical trial 892
    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
    Atención médica
    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 Decision2012-06-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-06-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-01-13
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