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    Summary
    EudraCT Number:2014-000443-33
    Sponsor's Protocol Code Number:CHS-0214-02
    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:2014-07-04
    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 number2014-000443-33
    A.3Full title of the trial
    A Double-Blind, Randomized, Parallel-Group, Active-Control Study to Compare the Efficacy and Safety of CHS-0214 Versus Enbrel® in Subjects With Rheumatoid Arthritis and Inadequate Response to Treatment With Methotrexate
    Estudio doble ciego, randomizado, de grupos paralelos y controlado con producto activo para comparar la eficacia y la seguridad de CHS-0214 frente a Enbrel® en pacientes con artritis reumatoide y respuesta inadecuada al tratamiento con metotrexato
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Coherus RA Study
    Estudio Coherus AR
    A.3.2Name or abbreviated title of the trial where available
    ETA 302
    A.4.1Sponsor's protocol code numberCHS-0214-02
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02115750
    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 SponsorCoherus Biosciences, Inc
    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 supportDaiichi Sankyo Company Ltd
    B.4.2CountryJapan
    B.4.1Name of organisation providing supportCoherus Biosciences Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace UK
    B.5.2Functional name of contact pointDirector of Regulatory Submissions
    B.5.3 Address:
    B.5.3.1Street AddressKingfisher House, Elmfield Way
    B.5.3.2Town/ cityBromley
    B.5.3.3Post codeBR1 1LT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number00447825587853
    B.5.5Fax number00442083156793
    B.5.6E-mailb.mcdougall@medpace.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code CHS-0214
    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 INNEtanercept
    D.3.9.2Current sponsor codeCHS-0214
    D.3.9.3Other descriptive nameCHS-0214
    D.3.9.4EV Substance CodeSUB166284
    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: 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 Enbrel
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    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 nameEtanercept
    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 INNETANERCEPT
    D.3.9.1CAS number 185243-69-0
    D.3.9.4EV Substance CodeSUB01984MIG
    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.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rheumatoid arthritis
    Artritis reumatoide
    E.1.1.1Medical condition in easily understood language
    Rheumatoid arthritis
    Artritis reumatoide
    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 LLT
    E.1.2Classification code 10042952
    E.1.2Term Systemic rheumatoid arthritis
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objectives of Part 1 of the study are to compare the efficacy and safety of CHS 0214 manufactured in the EU, to Enbrel (EU) at 24 weeks in subjects with RA who have an inadequate response to methotrexate and no more than 3 other non-biologic disease modifying anti rheumatic drugs and who are naïve to biologic therapies.
    The objectives of Part 2 of the study are to evaluate the longer term safety and the durability of response to open-label CHS 0214.
    Los objetivos de la parte 1 son comparar la eficacia y la seguridad en la semana 24 de CHS-0214 fabricado en la Unión Europea (UE), al que nos referiremos en este documento como CHS-0214 (UE) y Enbrel autorizado en la UE, Enbrel (UE), en pacientes con artritis reumatoide (AR) que han tenido una respuesta inadecuada (RI) a metotrexato (MTX) y han recibido un máximo de 3 fármacos antirreumáticos moduladores de la enfermedad (FARME) no biológicos diferentes y ningún tratamiento biológico.
    Los objetivos de la parte 2 son evaluar la seguridad a largo plazo y la durabilidad de la respuesta a CHS-0214 en abierto
    E.2.2Secondary objectives of the trial
    Not applicable
    No aplicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet the following criteria to be enrolled in Part 1 of the study:
    1.Male or female adult ? 18 years of age (? 20 years of age in Japan);
    2.Have a diagnosis of RA, as defined by the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 or 1987 criteria for RA with disease duration of at least 6 months.
    3.Have had an adequate trial of methotrexate (MTX) defined as having been on MTX for at least 3 months and on a stable, approved dose (? 8 mg/week to ? 25 mg/week) for at least 6 weeks prior to Screening;
    4.Have active disease, defined as: ? 6 tender joints, ? 6 swollen joints (based on 66 SJC and 68 TJC) (Scott & Houssien, 1996), CRP ? 0.5 mg/dL, and DAS28-CRP[4] ? 3.2 at Screening;
    5.Have had an inadequate response to MTX and may have failed no more than 3 other conventional non-biologic disease modifying anti-rheumatic drugs (DMARDs) (eg, hydroxychloroquine, oral or injectable gold, azathioprine, D penicillamine, sulfasalazine, and leflunomide), and are candidates for tumor necrosis factor alpha (TNF ?) inhibitor therapy;
    6.Have discontinued treatment with all DMARDs, except MTX, at least 2 weeks prior to Screening;
    7.Women who meet one of the following:
    a.Women of childbearing potential with a negative urine pregnancy test at Screening who agree to use one or more approved methods of birth control during the study. Approved methods of birth control are: hormonal contraception, intrauterine device, diaphragm plus spermicide, and female condom plus spermicide.
    b.Women who have been postmenopausal for at least 2 years (with amenorrhea for at least 1 year) or have had a hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation prior to signing the informed consent; and
    8.Able and willing to give written informed consent prior to performance of any study related procedures.

    Part 2: Subjects must meet the following criteria to be enrolled in Part 2 of the study:
    1.Completed the evaluations and achieved at least an ACR20 response at Week 24;
    2.Tolerated study drug in Part 1 with no SAEs or unresolved Grade 3 or higher adverse events related to study drug.
    Los pacientes debe cumplir los criterios siguientes para incluirlos (randomizarlos) en la Parte 1 de este estudio:
    1. Varones o mujeres adultos ? 18 años (? 20 años en Japón);
    2. Diagnóstico de AR, definida según los criterios de 2010 o de 1987 del American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) para la AR, con una duración mínima de la enfermedad de 6 meses
    3. Haber recibido MTX a una dosis que se ha comprobado que permite obtener una respuesta adecuada, lo que se define como haber estado en tratamiento con MTX durante 3 meses como mínimo y haber recibido una dosis estable autorizada de este fármaco (de ? 8 mg/semana a ? 25 mg/semana) durante un mínimo de 6 semanas antes del periodo de screening.
    4. Tener enfermedad activa, definida como: ? 6 articulaciones dolorosas, ? 6 articulaciones tumefactas (según un recuento de 66 articulaciones tumefactas [RAT] y un recuento de 66 articulaciones dolorosas [RAD]), PCR ?CRn el per y DAS28-PCR(4) ? 3,2 en el screening;
    5. Haber tenido una RI a MTX y no haber tenido fracaso terapéutico con más de otros 3 FARME no biológicos convencionales (p. ej., hidroxicloroquina, oro oral o inyectable, azatioprina, D-penicilamina, sulfasalazina y leflunomida) y reunir los requisitos para recibir tratamiento con un inhibidor del factor de necrosis tumoral alfa (TNF-?);
    6. Haber suspendido el tratamiento con todos los FARME, salvo MTX, como mínimo 2 semanas antes del screening;
    7. Mujeres que cumplan uno de los siguientes criterios:
    a. Mujeres en edad fértil que hayan dado negativo en una prueba de embarazo en orina en el periodo de screening y que se comprometan a utilizar uno o más métodos anticonceptivos autorizados durante el estudio. Los métodos anticonceptivos autorizados son: anticonceptivos hormonales orales, dispositivo intrauterino, diafragma más espermicida y preservativo femenino más espermicida.
    b. Las mujeres posmenopáusicas desde hace un mínimo de 2 años (con amenorrea desde hace 1 año como mínimo) o que hayan sido sometidas a histerectomía, salpingooforectomía bilateral o ligadura de trompas antes de la firma del consentimiento informado; y
    8. Pacientes que puedan y quieran dar su consentimiento informado por escrito antes de realizarse cualquier procedimiento relacionado con el estudio.

    Los pacientes deben cumplir los siguientes criterios para incluirlos en la Parte 2 del estudio:
    1. Haber completado las evaluaciones y haber alcanzado como mínimo una respuesta ACR20 en la semana 24; y
    2. Haber tolerado el fármaco del estudio en la Parte 1 sin AAG o acontecimientos adversos de grado 3 no resueltos relacionados con el fármaco del estudio.
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria will be excluded from participation in the study:
    1.Use of parenteral glucocorticoids within 4 weeks prior to initiation of Screening or use of intra articular glucocorticoids within 4 weeks prior to randomization;
    2.Use of oral glucocorticoids (such as > 10 mg prednisone per day (or equivalent corticosteroid), or a change in dosage within 2 weeks prior to initiation of Screening (Note: the dose of prednisone ? 10 mg per day [or equivalent corticosteroid] should remain stable throughout Screening and should be expected to remain stable during Part 1 of the study for the subject to be eligible);
    3.Use of more than 1 NSAID or use of a single NSAID at greater than the recommended daily dose for that NSAID;
    4.Prior treatment with any biologic for any indication (including but not limited to: tocilizumab [RoACTEMRA, Actemra], certolizumab pegol [CIMZIA], etanercept [Enbrel], adalimumab [HUMIRA], anakinra [Kineret], abatacept [ORENCIA], infliximab [REMICADE], rituximab [MabThera, Rituxan], and golimumab [SIMPONI]); (Note: insulin for diabetes mellitus and hormonal replacement therapy and hormonal birth control are allowed);
    5.Participation in an investigational drug or device trial within 30 days prior to randomization or a period equal to 5 times the half-life of the investigational agent, whichever is longer;
    6.Functional class IV RA according to ACR revised classification, 1991, ie, limited ability to perform usual self care, vocational, and avocational activities (Hochberg, et al., 1992)
    7.Diagnosis of other rheumatic disease, autoimmune disease, connective tissue disease, or immune deficiency disease (eg, psoriasis, psoriatic arthritis, primary Sjögren?s syndrome, systemic lupus erythematosus, multiple sclerosis);
    8.History of alcohol or drug abuse within 2 years prior to Screening;
    9.White blood cell count < 4000 cells/mm3, lymphocyte count < 1000 cells/mm3, platelet count ? 125,000 cells/mm3, serum creatinine ? 2 mg/dL (177 µmol/L), alanine transaminase or aspartate transaminase ? 2.0 × the upper limit of normal of the reference range, or hemoglobin ? 8.5 g/dL at Screening;
    10.Presence or history of malignancy (except for successfully treated non metastatic basal or squamous cell carcinoma of the skin and carcinoma in situ of the cervix);
    11.Presence of tuberculosis (TB) based on positive blood test (QuantiFERON® TB Gold test for TB), subjects testing positive on QuantiFERON-TB Gold Test or subjects with known recent exposure to a patient with active TB, should be excluded from the study; Note: patients with an intermediate QuantiFERON-TB test may be rescreened one time with a fresh sample and if a negative result may participate in the study
    12.Abnormal chest x-ray obtained within 6 months prior to randomization demonstrating active lung disease processes other than RA (eg, evidence of TB);
    13.History of positive test results for fungal or other infections required by regional guidelines prior to start of biologic drugs (eg, ? D glucan test for Japan) within 3 months prior to randomization;
    14.Major systemic infections (eg, positive for hepatitis B surface antigen [HBsAg], hepatitis B core antigen [HBcAg], hepatitis C virus [HCV], or human immunodeficiency virus [HIV]);
    15.Class III or IV congestive heart failure (as defined by the New York Heart Association criteria) (New York Heart Association, 1994);
    16.Presence of significant comorbid medical condition(s), including, but not limited to:
    a.uncontrolled diabetes mellitus (hemoglogin A1c [HgbA1c] ? 8% within the past 3 months or history of diabetic ketoacidosis or hypoglycemic reactions requiring hospitalization within the past 12 months);
    b.uncontrolled hypertension (systolic blood pressure > 160 mmHg and diastolic blood pressure > 100 mmHg) within the past 3 months;
    c.severe kidney disease requiring hemodialysis or peritoneal dialysis;
    d.advanced liver disease such as hepatitis or liver cirrhosis;
    e.severe congestive heart failure or history of ejection fraction ? 30%;
    f.severe lung disease requiring home oxygen; or
    g.active unstable angina requiring daily treatment with nitrates or other medications; or
    17.Presence of any other major medical or psychiatric illness that in the opinion of the Investigator would put the subject at increased risk or affect the ability to participate in the study;
    18.Known or suspected sensitivity or allergic reactions to latex or latex-containing products;
    19.History of MTX associated clinically significant toxicity such as interstitial lung disease or persistently elevated transaminases; or
    20.Women who are pregnant or nursing.
    21. Men whose partners may become pregnant (do not agree to use contraception or who are not post-menopausal) or who may breastfeed during the study. (Japan only specific exclusion).
    1.Uso de glucocorticoides parenterales en las 4 semanas previas al inicio del screening o glucocorticoides intraarticulares en las 4 semanas previas a la randomización (Atención: se podrá incluir [randomizar] el estudio a los pacientes que precisen inyecciones articulares al inicio del periodo de screening para mantener la movilidad siempre que hayan transcurrido 4 semanas desde las inyecciones, se inyecten 2 articulaciones como máximo y que las articulaciones inyectadas no se incluyan en los recuentos de articulaciones durante el screening empleados para determinar la elegibilidad para el estudio);
    2.Uso de glucocorticoides orales, o cambio en la dosis en las 2 semanas previas al inicio del screening (Atención: para que los pacientes sean elegibles, la dosis de prednisona ? 10 mg al día [o glucocorticoide equivalente] deberá permanecer estable durante el screening y ha de preverse que se mantendrá estable durante la Parte 1 del estudio;
    3. Uso de más de 1 AINE o uso de un único AINE pero a una dosis superior a la dosis diaria recomendada para ese AINE;
    4.Tratamiento previo con algún biofármaco para cualquier indicación (incluidos, entre otros, tocilizumab, certolizumab pegol, etanercept, adalimumab, anakinra, abatecept, infliximab, rituximab y golimumab.
    5.Participación en un ensayo con un medicamento o producto sanitario en fase de investigación en los 30 días previos a la randomización o en un periodo igual a 5 veces la semivida del fármaco en investigación, lo que sea mayor;
    6.AR de clase funcional IV según la clasificación revisada de1991del ACR, es decir, capacidad limitada de realizar las actividades habituales de cuidado personal, trabajo y ocio (véase el Anexo C);
    7.Diagnóstico de otra enfermedad reumática, enfermedad autoinmunitaria, enfermedad del tejido conjuntivo o enfermedad por inmunodeficiencia
    8.Antecedentes de alcohol o drogadicción en los 2 años previos al screening;
    9.Cifra de leucocitos < 4000 células/mm3, cifra de linfocitos < 1000 células/mm3, cifra de plaquetas ? 125 000 células/mm3, creatinina sérica ? 2 mg/dl (177 µmol/l), alanina-transaminasa o aspartato-transaminasa ? 2,0 × el límite superior de la normalidad del intervalo de referencia o hemoglobina ? 8.5 g/dl en el screening;
    10.Antecedentes o presencia de una neoplasia maligna (excepto carcinoma cutáneo basocelular o epidermoide no metastásico o carcinoma in situ del cuello uterino tratados de manera satisfactoria);
    11.Presencia de tuberculosis (TB) según resultado positivo en una prueba en sangre; a los pacientes que den positivo en la prueba QuantiFERON-TB Gold se les podrán volver a realizar los exámenes de screening solo después de que el médico de atención primaria los haya evaluado y haya determinado de forma concluyente que no tiene TB y que, por lo demás, son elegibles;
    12.Anomalías en una radiografía de tórax realizada en los 6 meses previos a la randomización que muestren procesos patológicos activos en el pulmón aparte de AR
    13.Antecedentes de resultados positivos para infecciones fúngicas o de otro tipo según lo exigido por las directrices regionales antes del inicio del tratamiento con biofármacos en los 3 meses previos a la randomización;
    14.Infecciones sistémicas graves
    15.Insuficiencia cardiaca congestiva de clase III o IV definida según los criterios de la New York Heart Association;
    16.Presencia de cualquier enfermedad concurrente significativa, como:
    a.Diabetes mellitus no controlada (hemoglobina glucosilada [HgbA1c] ? 8 % en los últimos 3 meses o antecedentes de cetoacidosis diabética o reacciones hipoglucémicas que hayan requerido hospitalización en los últimos 12 meses);
    b.hipertensión no controlada (presión arterial sistólica > 160 mm Hg y presión arterial diastólica > 100 mm Hg) en los últimos 3 meses;
    c.nefropatía grave que requiere hemodiálisis o diálisis peritoneal;
    d.hepatopatía avanzada como hepatitis o cirrosis hepática;
    e.insuficiencia cardíaca congestiva grave o antecedentes de fracción de eyección ? 30 %;
    f.neumopatía grave que requiera oxigenoterapia domiciliaria; o
    g.angina inestable activa que requiera tratamiento diario con nitratos u otros fármacos; o
    17.Existencia de cualquier otra dolencia médica o trastorno psiquiátrico graves que, a juicio del Investigador, pudiera aumentar el riesgo del paciente o afectar a la capacidad para participar en el estudio;
    18.Sensibilidad conocida o pendiente de confirmación o reacciones alérgicas al látex o a productos que contengan látex;
    19.Antecedentes de toxicidad clínicamente significativa asociada a MTX, como enfermedad pulmonar intersticial o elevación persistente de las transaminasas; o
    20.Mujeres embarazadas o lactantes.
    21. Parejas de pacinetes varones que puedan quedarse embarazadas (que no consientan en usar métodos anticonceptivos o que no sean postmenopausicas) o que puedan ser lactantes durante el estudio. (Criterio de exclusion específico para Japón).
    E.5 End points
    E.5.1Primary end point(s)
    1. The primary efficacy endpoint in Part 1 will be the percentage of subjects who achieve 20% improvement according to American College of Rheumatology Criteria (ACR20) at Week 24 compared to Baseline (initiation of treatment). Subjects will be considered an ACR20 responder if: compared to Baseline (Day 0), they achieve: 20% decrease in swollen joint counts (SJC), 20% decrease in tender joint counts (TJC), and 20% improvement in 3 of the following 5 measures
    ? C-reactive protein (CRP);
    ? Health Assessment Questionnaire ? Disability Index (HAQ DI);
    ? Subjects pain assessment using a visual analoguie scale (VAS);
    ? Subject global assessment of disease activity (SGA);
    ? Physicians global assessmetn of disease activity (PGA).

    2.The primary response duration endpoint will be the percentage of subjects who maintain ACR20 response from week 24 (durable effect) or who have a continued improvement in response (ACR50 response, ACR70 response) and DAS28-CRP(4) to < 3.2(low disease activity) and < 2.6 (remission) assessed at weeks 28. 36 and 48
    Parte 1:
    el criterio principal de valoración de la eficacia será el porcentaje de pacientes que alcanzan una respuesta ACR20 en la semana 24 (antes de la administración) en comparación con el periodo basal (inicio del tratamiento). Se considerará que los pacientes tienen una respuesta ACR20 si, con respecto al periodo basal (día 0), consiguen: una reducción del 20 % en el RAT, una reducción del 20 % en el RAD y una mejoría en 3 de las 5 determinaciones siguientes:
    ? PCR
    ? Cuestionario Health Assessment Questionnaire ? Disability Index (HAQ DI)
    ? Valoración del dolor por el paciente utilizando una escala visual analógica (EV)
    ? Valoración global de la actividad de la enfermedad por el paciente (SGA) (con una EVA)
    ? Valoración global de la actividad de la enfermedad por el médico (PGA) (con una EVA)

    Parte 2:
    el criterio principal de valoración de la duración de la respuesta en la Parte 2 será el porcentaje de pacientes que mantienen una respuesta ACR20 desde la semana 24 (efecto duradero) o que tienen una mejoría continuada en la respuesta (respuesta ACR50, respuesta ACR70) e índice DAS28-PCR(4) < 3,2 (actividad baja de la enfermedad) y < 2,6 (remisión) evaluados en las semanas 28, 36 y 48.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. From baseline - Day 0 to week 24
    2. Part 1 - weeks 0, 4, 8, 12, 18, and 24 and for Part 2 - weeks 28, 36, and 48.
    1. Desde la visita basal- día 0 hasta la semana 24
    2. Parte 1- semanas 0, 4, 8, 12, 18 y 24 y para la parte 2- semanas 28, 36 y 48
    E.5.2Secondary end point(s)
    The secondary efficacy variables will include
    1. ACR20 at Weeks 4, 8, 12, and 18;
    2. The average percent improvement from Baseline (Day 0) in individual ACR response criteria: TJC, SJC, HAQ-DI;
    3. Subject?s pain assessment (subject?s pain-VAS), SGA, PGA and CRP at Weeks 4, 8, 12, 18 and 24;
    4. 50% and 70% improvement according to American College of Rheumatology criteria (ACR50 and ACR70, respectively) and DAS28-CRP(4) < 3.2. ;
    5. Remission rate (defined as DAS28 CRP(4) < 2.6 on all subsequent visits after DAS28 CRP(4) < 2.6 is achieved).
    Las variables secundarias de eficacia incluirán la respuesta ACR20 en las semanas 4, 8, 12 y 18; el porcentaje medio de mejoría respecto al periodo basal (día 0) en los criterios individuales de respuesta del ACR: RAD, RAT, HAQ-DI, valoración del dolor por el paciente (dolor del paciente, EVA), SGA, PGA y PCR en las semanas 4, 8, 12, 18 y 24; la mejoría del 50 % y del 70 % según los criterios del American College of Rheumatology (ACR50 y ACR70, respectivamente) y DAS28-PCR(4) ? 3,2 en las semanas 4, 8, 12, 18 y 24; y la tasa de remisión (definida como DAS28-PCR[4] < 2,6 en todas las visitas posteriores a que se alcance DAS28 PCR(4) < 2,6).
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Weeks 4, 8, 12 and 18
    2. From Basline
    3. Weeks 4, 8, 12, 18, and 24
    4. Weeks 4, 8, 12, 18, and 24
    5. At all subsequent study visists after required DAS28 CRP(4) is reached
    1. Semanas 4, 8, 12 y 18
    2. Desde la visita basal
    3. Semanas 4, 8, 12 y 18
    4. Semanas 4, 8, 12 y 18
    5. en todas las siguientes visitas del estudio después de que se alcance DAS28 PCR(4)
    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 No
    E.6.11Pharmacogenomic No
    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 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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA46
    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
    Belarus
    Brazil
    France
    Germany
    Hungary
    Israel
    Italy
    Japan
    Poland
    Russian Federation
    South Africa
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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: 334
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 166
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 84
    F.4.2.2In the whole clinical trial 500
    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)
    The sponsor expect to conduct an open label safety extension study for subjects who complete Part 2 of the study
    El Promotor espera realizar un estudio de extension en abierto para los pacientes que completen la parte 2 del estudio
    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 Decision2014-10-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-04-27
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