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    Summary
    EudraCT Number:2011-001555-37
    Sponsor's Protocol Code Number:CC-10004-AS-001
    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:2012-05-28
    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 number2011-001555-37
    A.3Full title of the trial
    A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of apremilast (CC-10004) in the treatment of active ankylosing spondylitis
    Estudio fase 3, multicéntrico, aleatorizado, doble ciego, controlado con placebo, de grupos paralelos para evaluar la eficacia y la seguridad de Apremilast (CC-10004) en el tratamiento de espondilitis anquilosante activa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 study to evaluate safety and effectiveness of oral Apremilast (CC-10004) in patients with ankylosing spondylitis
    Estudio fase 3 para evaluar la seguridad y la eficacia de Apremilast (CC-10004) por vía oral en pacientes con espondilitis anquilosante
    A.4.1Sponsor's protocol code numberCC-10004-AS-001
    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 SponsorCelgene Corporation
    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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9900 W. 109th street, suite 300, building 70
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18882601599
    B.5.5Fax number+19134513459
    B.5.6E-mailClinicalTrialDisclosure@celgene.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameApremilast
    D.3.2Product code CC-10004
    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 INNApremilast
    D.3.9.1CAS number 608141-41-9
    D.3.9.2Current sponsor codeCC-10004
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameApremilast
    D.3.2Product code CC-10004
    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 INNApremilast
    D.3.9.1CAS number 608141-41-9
    D.3.9.2Current sponsor codeCC-10004
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameApremilast
    D.3.2Product code CC-10004
    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 INNApremilast
    D.3.9.1CAS number 608141-41-9
    D.3.9.2Current sponsor codeCC-10004
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Ankylosing spondylitis (AS)
    Espondilitis Anquilosante (EA)
    E.1.1.1Medical condition in easily understood language
    Ankylosing spondylitis
    Espondilitis Anquilosante
    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 PT
    E.1.2Classification code 10002556
    E.1.2Term Ankylosing spondylitis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of apremilast 30 mg twice a day (BID), compared with placebo, in the reduction of signs and symptoms in subjects with active AS at 16 weeks of treatment
    Evaluar la eficacia de apremilast 30 mg dos veces al día (2 v/día), en comparación con placebo, para reducir los signos y síntomas en sujetos con EA activa al cabo de 16 semanas de tratamiento.
    E.2.2Secondary objectives of the trial
    - To evaluate the efficacy of apremilast 30 mg BID, compared with placebo, in the reduction of signs and symptoms, improvement in physical function and range of motion in subjects with active AS at 24 weeks of treatment.
    - To evaluate the efficacy of apremilast 20 mg BID, compared with placebo, in the reduction of signs and symptoms, improvement in physical function and range of motion in subjects with active AS at 24 weeks of treatment.
    - To evaluate the efficacy of two doses of apremilast (30 mg BID and 20 mg BID) on AS lesions in the cervical and lumbar spine as assessed by radiographs in subjects with active AS at 104 Weeks and 260 Weeks of treatment.
    - Evaluar la eficacia de apremilast 30 mg dos veces al día, en comparación con placebo, para reducir los signos y síntomas, mejorar la función física y la amplitud de movimiento en sujetos con EA activa al cabo de 24 semanas de tratamiento.
    - Evaluar la eficacia de apremilast 20 mg dos veces al día, en comparación con placebo, para reducir los signos y síntomas, mejorar la función física y la amplitud de movimiento en sujetos con EA activa al cabo de 24 semanas de tratamiento.
    - Evaluar la eficacia de dos dosis de apremilast (30 y 20 mg dos veces al día) sobre las lesiones de EA en la columna cervical y lumbar, evaluadas mediante radiografías, en sujetos con EA activa al cabo de 104 y 260 semanas de tratamiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Males or females, > or = 18 years of age at the time of signing the informed consent document.
    2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
    3. Able to adhere to the study visit schedule and other protocol requirements.
    4. Must have a documented diagnosis of ankylosing spondylitis as defined by low back pain and stiffness, which improves with exercise, but is not relieved by rest for more than 3 months prior to screening. At the completion of screening procedures, a documented diagnosis of definite active AS, as defined by the modified New York criteria (1984) whereby both criteria, at least 1 radiographic criterion and at least 1 clinical criterion, must be met:
    a.Radiographic criteria (at least 1), documented by the central reader before the subject is randomized
    b. Clinical criteria (at least 1), documented in physical examination
    5. Must have symptoms of active axial disease at screening and baseline (at time of randomization), as determined by a BASDAI NRS score of > or = 4 and a total back pain NRS score > or = 4.
    6. Must be receiving treatment on an outpatient basis.
    7. Must be in good health (except for AS) as judged by the Investigator, based on medical history, physical examination, 12-lead ECG, chest radiograph, clinical laboratories and urinalysis.
    8. Must agree to maintain the same stable dose of medication (or lack of medication) taken for AS prior to randomization through Week 24 of the study as described below. Change in medication may be allowed for safety reasons.
    a. Analgesics must be stable for at least 14 days prior to Day 0
    b. Disease-modifying anti-rheumatic drugs (DMARDs) must have been taken for at least 16 weeks and must be stable for at least 28 days prior to Day 0
    c. Corticosteroids must be stable for at least 28 days prior to Day 0.
    9. Must meet the following laboratory criteria at screening:
    a. White blood cell count >or= 3000/mm3 (>or= 3.0 x 109/L) and < 14,000/mm3 (< 14 x 109/L)
    b. Platelet count > or = 100,000/microL (>or= 100 x 109/L)
    c. Serum creatinine <or= 1.5 mg/dL (<or= 132.6 micromol/L)
    d. AST (SGOT) and ALT (SGPT) <or= 2 x upper limit of normal (ULN). If initial test shows ALT or AST > 2 times the ULN, one repeat test is allowed during the screening period.
    e. Total bilirubin <or= 2 mg/dL (<or= 34 micromol/L). If initial test result is > 2 mg/dL, one repeat test is allowed during the screening period.
    f. Hemoglobin > or = 9 g/dL (>or= 5.6 mmol/L)
    g. Hemoglobin A1c <or= 9.0%
    h. Negative for hepatitis B surface antigen
    i. Negative for hepatitis C antibody
    10. Females of childbearing potential (FCBP) must have a negative pregnancy test at Screening and Baseline. While on investigational product and for at least 28 days after taking the last dose of investigational product, FCBP who engage in activity in which conception is possible must use one of the approved contraception options described below:
    Option 1: Any one of the following highly effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner?s vasectomy;
    OR
    Option 2: Male or female condom (latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]; PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide.
    11. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on investigational product and for at least 28 days after the last dose of investigational product.
    1.Varones o mujeres, con una edad mínima de 18 años en el momento de firmar el documento de consentimiento informado.
    2.Comprensión y firma voluntaria del documento de consentimiento informado antes de que se realice ninguna evaluación o procedimiento relacionado con el estudio.
    3.Capacidad de cumplir el calendario de visitas del estudio y los demás requisitos del protocolo.
    4.Diagnóstico documentado de espondilitis anquilosante, definida por lumbalgia y rigidez que mejoran con el ejercicio, pero que no se alivian con el reposo, durante más de 3 meses antes de la selección. A la conclusión de los procedimientos de selección, diagnóstico documentado de EA confirmada, según lo definido por los criterios de Nueva York modificados (1984), según los cuales han de cumplirse ambos criterios, al menos 1 criterio radiológico y al menos 1 criterio clínico:
    a.Criterios radiológicos (al menos 1), documentados por el evaluador central antes de la aleatorización del sujeto.
    b.Criterios clínicos (al menos 1), documentados en la exploración física.
    5.Presencia de síntomas de afectación axial activa en la selección y el momento basal (en el momento de la aleatorización), según lo determinado por una puntuación BASDAI > ó = 4 y una puntuación en la EVN de dolor de espalda total > o = 4.
    6.Recepción del tratamiento en régimen ambulatorio.
    7.Presencia de un buen estado de salud (excepto por la EA) según el criterio del investigador, basándose en la historia clínica, la exploración física, el ECG de 12 derivaciones, la radiografía de tórax, las pruebas analíticas y el análisis de orina.
    8.Compromiso de mantener la misma dosis estable de medicación (o ausencia de medicación) tomada para la EA antes de la aleatorización hasta la semana 24 del estudio tal como se describe a continuación. Se permitirán modificaciones de la medicación por motivos de seguridad.
    a.Los analgésicos deberán permanecer estables durante al menos 14 días antes del día 0.
    b.Los fármacos antirreumáticos modificadores de la enfermedad (FARME) deben haberse tomado durante al menos 16 semanas y deberán permanecer estables durante al menos 28 días antes del día 0.
    c.Los corticoides deberán permanecer estables durante al menos 28 días antes del día 0.
    9.Deberán cumplirse los criterios analíticos siguientes en la visita de selección:
    a.Recuento de leucocitos > ó = 3000/mm3 (> ó = 3,0 x 109/l) y < 14.000/mm 3 (< 14 x 109/l).
    b.Recuento de plaquetas > ó = 100.000 /µl (> ó = 100 x 109/l).
    c.Creatinina sérica < ó = 1,5 mg/dl (< ó = 132,6 µmol/l).
    d.AST (SGOT) y ALT (SGPT) < ó = 2 veces el límite superior de la normalidad (LSN). Si el resultado del análisis inicial de ALT o AST es > 2 veces el LSN, podrá repetirse el análisis una vez durante el período de selección.
    e.Bilirrubina total < ó = 2,0 mg/dl (< ó = 34 ?mol/l). Si el resultado del análisis inicial es > 2 mg/dl, podrá repetirse el análisis una vez durante el período de selección.
    f.Hemoglobina > ó = 9,0 g/dl ((> ó = 5,6 mmol/l).
    g.Hemoglobina A1c < ó = 9,0 %.
    h.Negatividad para el antígeno de superficie del virus de la hepatitis B.
    i.Negatividad para anticuerpos frente al virus de la hepatitis C.
    10.Las mujeres en edad fértil (MEF) deberán tener un resultado negativo en una prueba de embarazo realizada en las visitas de selección y basal. Mientras reciban el PEI y durante al menos 28 días después de tomar la última dosis del PEI, las MEF que mantengan relaciones sexuales con riesgo de embarazo deberán utilizar una de las opciones anticonceptivas aprobadas que se describen a continuación:
    Opción 1: Cualquiera de los siguientes métodos muy eficaces: anticonceptivos hormonales (orales, inyección, implante, parche transdérmico, anillo vaginal), dispositivo intrauterino (DIU), ligadura de trompas o vasectomía de la pareja. O
    Opción 2: Preservativo masculino o femenino (preservativo de látex o preservativo sin látex NO fabricado con membrana natural [animal] [por ejemplo, de poliuretano] MÁS un método de barrera adicional: (a) diafragma con espermicida; (b) capuchón cervical con espermicida o (c) esponja anticonceptiva con espermicida.
    11.Los varones (incluso si se han sometido a una vasectomía) que mantengan relaciones sexuales con riesgo de embarazo deberán utilizar anticonceptivos de barrera (preservativo masculino de látex o sin látex que NO esté fabricado con membranas naturales [animales], por ejemplo, de poliuretano) mientras reciban el PEI y durante al menos 28 días después de tomar la última dosis del PEI.
    E.4Principal exclusion criteria
    1. Major surgery (including spinal surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
    2. Autoimmune diseases such as, but not limited to: systemic lupus erythematosus, mixed connective tissue disease, multiple sclerosis, or scleroderma.
    3. Prior history of, or current, inflammatory joint disease other than AS (eg, rheumatoid arthritis, gout, reactive arthritis, psoriatic arthritis, Lyme disease).
    4. Uncontrolled, severe psoriasis (defined as Body Surface Area > 10%) or active inflammatory bowel disease (Crohn's disease or ulcerative colitis) based on an unequivocal positive calprotectin stool test defined by the local or central lab reference values.
    5. Uncontrolled uveitis at the time of randomization. Asymptomatic, concurrently treated and controlled uveitis is acceptable at randomization, as long as the treatment is limited to topical ophthalmic therapy and/or intra-ocular injections of corticosteroids. Subjects are allowed to be initiated with these therapies during screening, continue on them through randomization and tapered off or discontinue these therapies while on study as medically appropriate. Systemic treatment for uveitis is not allowed, and would result in discontinuation from the study.
    6. Prior treatment with a TNF blocker or any biologic treatment for AS.
    7. If discontinuing treatment of DMARD, then adequate washout is required prior to randomization.
    8. Treatment with any investigational agent within four weeks (or five half-lives of the investigational drug, whichever is longer) of screening.
    9. Intra-articular or parenteral corticosteroids are not allowed within 6 weeks prior to randomization.
    10. Any previous treatment with alkylating agents such as cyclophosphamide or chlorambucil, or with total lymphoid irradiation.
    11. Pregnant women or nursing (breast-feeding) mothers.
    12. Evidence of serious, poorly controlled concomitant cardiovascular, nervous system, pulmonary (including severe chronic obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus as defined by HbA1c > 9.0%) or gastrointestinal (GI) disease.
    13. Poorly controlled disease states, such as asthma, where flares are commonly treated with oral or parenteral corticosteroids.
    14. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, histoplasmosis, coccidiomycosis, but excluding onychomycosis) or any major episode of infection requiring hospitalization or treatment with IV or oral antibiotics within 4 weeks of screening.
    15. History of positive test for, or any clinical suspicion of human immunodeficiency virus (HIV), or congenital or acquired immunodeficiency (eg, common variable immunodeficiency disease).
    16. History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured).
    17. History of alcohol, drug or chemical abuse within the 6 months prior to screening.
    18. Any significant medical condition or laboratory abnormality that in the Investigator's opinion would cause the subject not to be clinically appropriate for the study.
    19. Prior history of suicide attempt at any time in the subject's life time prior to screening or randomization, or major psychiatric illness requiring hospitalization within the last 3 years.
    20. A score of > 0 or a check mark on any column other than ?Not at all? on Question 9 of the PHQ-9 questionnaire at screening or prior to randomization.
    21. Any chronic pain condition not due to AS (eg, fibromyalgia) that in the Investigator's opinion would interfere significantly with the efficacy evaluations, including the pain, entheses and joint assessments.
    1. Intervención de cirugía mayor (incluida la cirugía raquídea) en las 8 semanas previas a la selección o intervención de cirugía mayor programada en los 6 meses siguientes a la aleatorización.
    2. Enfermedades autoinmunitarias, entre otras: lupus eritematoso sistémico, enfermedad mixta del tejido conjuntivo, esclerosis múltiple o esclerodermia.
    3. Antecedentes o presencia de una artropatía inflamatoria distinta de la EA. (por ejemplo, artritis reumatoide, gota, artritis reactiva, artritis psoriásica o enfermedad de Lyme).
    4. Psoriasis grave no controlada (definida como una superficie corporal > 10 %) o enfermedad intestinal inflamatoria activa (enfermedad de Crohn o colitis ulcerosa) basándose en un resultado positivo inequívoco del análisis fecal de calprotectina, definido según los valores de referencia del laboratorio local o central.
    5. Uveítis no controlada en el momento de la aleatorización. La presencia de una uveítis asintomática, tratada y controlada simultáneamente, será aceptable en la aleatorización, siempre que el tratamiento se limite a terapia oftálmica tópica o a inyecciones intraoculares de corticoides. Se permite que los sujetos empiecen con estos tratamientos durante la selección, sigan con ellos hasta la aleatorización y los disminuyan gradualmente o suspendan durante el estudio según esté médicamente indicado. No se permite el tratamiento sistémico para la uveítis, lo cual daría lugar a la retirada del estudio.
    6. Tratamiento previo con un antagonista del TNF o cualquier tratamiento biológico para la EA.
    7. En caso de suspender un tratamiento con FARME, se exigirá un período de lavado adecuado antes de la aleatorización (véase la hoja separada de Lista de períodos de lavado de FARME).
    8. Tratamiento con cualquier fármaco en investigación en las cuatro semanas (o cinco semividas del fármaco en investigación, lo que suponga más tiempo) previas a la visita de selección.
    9. No se permite administrar corticoides intraarticulares o parenterales durante las 6 semanas previas a la aleatorización.
    10. Cualquier tratamiento previo con agentes alquilantes, como ciclofosfamida o clorambucilo, o con irradiación linfática total.
    11. Mujeres embarazadas o madres lactantes.
    12. Signos de enfermedad cardiovascular, neurológica, pulmonar (incluida la enfermedad pulmonar obstructiva crónica grave), renal, hepática, endocrina (incluida la diabetes mellitus no controlada definida por un valor de HbA1c > 9,0 %) o digestiva concomitante, grave y mal controlada.
    13. Enfermedades mal controladas, como asma, en las que las exacerbaciones suelan tratarse con corticoides orales o parenterales.
    14. Antecedentes o presencia activa de infecciones bacterianas, virales, micóticas, micobacterianas o de otra naturaleza (por ejemplo, tuberculosis y enfermedad micobacteriana atípica, hepatitis B y C, herpes zóster, histoplasmosis y coccidiomicosis, excepto las onicomicosis) recurrentes o cualquier episodio importante de infección que requiera hospitalización o tratamiento con antibióticos intravenosos u orales en las 4 semanas previas a la selección.
    15. Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH), o cualquier sospecha clínica de la misma, o de inmunodeficiencia congénita o adquirida (por ejemplo, inmunodeficiencia variable común).
    16. Antecedentes de cáncer, incluidos tumores sólidos y neoplasias malignas hematológicas (excepto el carcinoma basocelular de piel extirpado y curado).
    17. Antecedentes de alcoholismo u otras toxicomanías en los 6 meses previos a la selección.
    18. Cualquier proceso médico o anomalía analítica importante que, en opinión del investigador, pueda hacer que el sujeto no sea clínicamente adecuado para participar en el estudio.
    19. Antecedentes de intento de suicidio en cualquier momento de la vida del sujeto antes de la selección o aleatorización o de enfermedad psiquiátrica importante con necesidad de hospitalización en los 3 años precedentes.
    20. Puntuación > 0 o marca en cualquier columna distinta de ?Nada en absoluto? en la pregunta 9 del cuestionario PHQ 9 en la selección o antes de la aleatorización.
    21. Cualquier proceso doloroso crónico no debido a la EA (por ejemplo, fibromialgia) que, en opinión del investigador, pueda interferir significativamente en las evaluaciones de la eficacia, incluidas las evaluaciones del dolor, entesis y articulaciones.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects who achieve an ASAS 20. The ASAS is the Assessment of SpondyloArthritis international Society
    Proporción de sujetos que logren una respuesta ASAS 20. ASAS es el acrónimo de Assessment of SpondyloArthritis international Society
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 16
    Semana 16
    E.5.2Secondary end point(s)
    ?Change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 24
    ?Change from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 24
    ?Proportion of subjects achieving an ASAS 20 at Week 24
    ?Change from baseline in the physical component score of the Medical Outcome Study Short Form 36-Item Health Survey (SF-36) scale at Week 24
    ?Change from baseline in Bath Ankylosing Spondylitis Metrology Index -Linear (BASMI-Linear) at Week 24
    ?Change from baseline in the radiographic score using the modified Stoke Ankylosing Spondylitis Spine Score (m-SASSS) at Week 104 (Year 2) and Week 260 (Year 5) by treatment group (20 mg BID, 30 mg BID, Placebo/30 mg BID, 20 mg BID/30 mg BID)
    ?Variación con respecto al momento basal del Índice funcional en la EA de Bath (BASFI) en la semana 24.
    ?Variación con respecto al momento basal del Índice de actividad de la enfermedad en la espondilitis anquilosante de Bath (BASDAI) en la semana 24.
    ?Proporción de sujetos que logren una respuesta ASAS 20 en la semana 24.
    ?Variación con respecto al momento basal de la puntuación en el componente físico del Cuestionario abreviado de salud de 36 apartados del Medical Outcome Study (SF 36) en la semana 24.
    ?Variación con respecto al momento basal del Índice de metrología en la espondilitis anquilosante de Bath?lineal (BASMI lineal) en la semana 24.
    ?Variación con respecto al momento basal de la puntuación radiológica de la Puntuación raquídea de espondilitis anquilosante de Stoke modificada (m SASSS) en las semanas 104 (año 2) y 260 (año 5) según el grupo de tratamiento (20 mg dos veces al día, 30 mg dos veces al día, placebo/30 mg dos veces al día, 20 mg dos veces al BID/30 mg dos veces al día).
    E.5.2.1Timepoint(s) of evaluation of this end point
    See above
    Véase la información arriba
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA61
    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
    Austria
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Netherlands
    Poland
    Romania
    Russian Federation
    Slovakia
    South Africa
    Spain
    Sweden
    United Kingdom
    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
    See protocol
    Ver protocolo
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months1
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 411
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 456
    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)
    See Protocol
    Ver protocolo
    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 Decision2012-07-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-07-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-25
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