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    Summary
    EudraCT Number:2018-000226-58
    Sponsor's Protocol Code Number:A3921120
    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:2018-05-09
    Trial 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 number2018-000226-58
    A.3Full title of the trial
    A Phase 3, Randomized, Double Blind, Placebo Controlled, Study Of The Efficacy And Safety Of Tofacitinib In Subjects With Active Ankylosing Spondylitis (AS)
    Estudio en fase III, aleatorizado, doble ciego, controlado con placebo, sobre la eficacia y la seguridad de tofacitinib en pacientes con espondilitis anquilosante (EA) activa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Study Of The Efficacy And Safety Of Tofacitinib In Patients With Active Ankylosing Spondylitis (AS)
    Estudio en fase III sobre la eficacia y seguridad de Tofacitinib en pacientes con espondilitis anquilosante (EA) activa
    A.4.1Sponsor's protocol code numberA3921120
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34 91 490 99 00
    B.5.5Fax number+1 303 7391119
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Xeljanz
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
    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 nameTofacitinib 5 mg
    D.3.2Product code CP-690,550
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTofacitinib
    D.3.9.1CAS number 540737-29-9
    D.3.9.2Current sponsor codeCP-690,550-10
    D.3.9.3Other descriptive nameTOFACITINIB CITRATE
    D.3.9.4EV Substance CodeSUB33105
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    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
    Type of chronic inflammatory arthritis involving the spine and/or sacroiliac joints.
    Tipo de artritis inflamatoria crónica que afecta la columna vertebral y / o las articulaciones sacroilíacas.
    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 20.0
    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 compare the efficacy of tofacitinib 5 mg BID versus placebo on the ASAS20 response rate at Week 16 in subjects with active AS that have had an inadequate response to previous treatment.
    Comparar la eficacia de tofacitinib 5 mg dos veces al día frente a placebo en la tasa de respuesta en la escala de puntuación 20 artículos de la espondilitis anquilosante (ASAS20) en la Semana 16 en pacientes con EA activa que hayan presentado una respuesta inadecuada al tratamiento previo.
    E.2.2Secondary objectives of the trial
    • To compare the safety and tolerability of tofacitinib 5 mg BID versus placebo in subjects with active AS that have had an inadequate response to previous treatment.
    • To compare the efficacy of tofacitinib 5 mg BID versus placebo at all time points in subjects with active AS that have had an inadequate response to previous treatment
    • To measure the effect of tofacitinib 5 mg BID on the quality of life and functional well-being at all collected time points.
    •Comparar la seguridad y tolerabilidad de tofacitinib 5 mg dos veces al día frente a placebo en pacientes con EA activa que hayan presentado una respuesta inadecuada al tratamiento previo.
    •Comparar la eficacia de tofacitinib 5 mg dos veces al día frente a placebo en todos los puntos temporales en pacientes con EA activa que hayan presentado una respuesta inadecuada al tratamiento previo.
    •Medir el efecto de tofacitinib 5 mg dos veces al día sobre la calidad de vida y el bienestar funcional en todos los puntos temporales de recogida.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
    2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    3. Subject is at least 18 years old (20 years old for subjects in Taiwan) at the screening visit.
    4. The subject has a diagnosis of AS based on the Modified New York Criteria for Ankylosing Spondylitis (1984).
    5. The subject must have a radiograph of the SI joints (AP Pelvis) documenting diagnosis of AS. Previous radiographs (up to 2 years old) can be used if they are accepted by the central reader. Otherwise, a new radiograph will be obtained at the Screening visit.
    6. Subject has active AS Screening and Baseline (Day 1) visits defined as:
    • BASDAI score of ≥4; and
    • Back pain score (BASDAI Question 2) of ≥4.
    7. Subject has active disease despite nonsteroidal anti-inflammatory drug (NSAID) therapy or is intolerant to NSAIDs
    8. Subjects who are designated as TNFi-IR must have received at least 1, but not more than 2 approved TNF inhibiting biologic agent that was administered in accordance with its labeling recommendations and was inadequately effective after the minimum treatment times listed below and/or not tolerated after one or more doses.
    • At least 3 months of adalimumab treatment;
    • At least 3 months of etanercept treatment;
    • At least 4 infusions of infliximab;
    • At least 3 injections of golimumab;
    • At least 3 months of certolizumab treatment.
    Intolerance is defined as having experienced a treatment-related AE (eg, infusion/injection reactions, infections, laboratory test changes, etc)
    9. Subjects may be receiving the following csDMARDs at the time of the screening visit. These medications should be continued throughout the entire study and doses should remain unchanged. Any other DMARDs require discussion prior to enrollment with the sponsor for washout timeframe.
    • Methotrexate (MTX): Maximum dose of 20 mg/week. Minimum duration of therapy 4 months and dose stable for 4 weeks prior to first dose of investigational product. Subjects on MTX should be on an adequate and stable dose of folate supplementation per local standards/regulatory approval (eg, not less than 5 mg weekly based on folic acid, unless such doses would violate the local label guidelines or standard of care) for at least 4 weeks prior to the first dose of investigational product. Subject must not have had previous serious toxicity while on MTX and not be expected to require evaluation for possible methotrexate toxicity (eg, require a liver biopsy for methotrexate toxicity) during the study;
    • Sulfasalazine (Azulfidine®, Salazpyrin®): Maximum dose of 3 gm/day. Minimum duration of therapy 2 months and dose stable for 4 weeks prior to first dose of investigational product.
    10. Subjects who are already taking oral corticosteroids (not injectables) may participate in the study:
    • Oral corticosteroids: Subjects who are already receiving oral corticosteroids must be on a stable dose of ≤10 mg/day of prednisone or equivalent for 4 weeks prior to the first dose of investigational product;
    • Injected (eg, intraarticular, intramuscular, epidural or intravenous) corticosteroids must be discontinued 4 weeks prior to the first dose of investigational product;
    • Topical and intra-rectal corticosteroids will be allowed during the study.
    11. Subject has discontinued all disallowed concomitant medication for the required time prior to the first dose of investigational product.
    12. Subjects who are receiving any investigational or marketed treatment for AS, arthritis or back pain not mentioned elsewhere must have that treatment discontinued for 4 weeks or 5 half-lives, whichever is longer.
    13. Subjects receiving non-prohibited concomitant medications for any reason must be willing to stay on a stable regimen (doses and frequency) as defined in the protocol.
    14. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB)
    15. Women of childbearing potential must test negative for pregnancy prior to enrollment in this study.
    16. Female subjects of non-childbearing potential must meet at least 1 of the following criteria:
    • Achieved post-menopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with/and have a central laboratory confirmation of serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
    • Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    • Have medically confirmed ovarian failure.
    All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
    1.Constancia de un formulario de consentimiento informado firmado y fechado personalmente que indique que se ha informado al paciente (o a un representante legal) de todos los aspectos pertinentes del estudio. 2.Voluntad y capacidad de cumplir las visitas programadas, el plan de tratamiento, los análisis de laboratorio y otros procedimientos del estudio.
    3.El paciente tiene al menos 18 años de edad (20 años para pacientes de Taiwán) en la visita de selección. 4.El paciente tiene un diagnóstico de EA basado en los criterios modificados de Nueva York para la espondilitis anquilosante (1984).5.El paciente debe presentar un diagnóstico de EA confirmado mediante radiografía de las articulaciones sacroilíacas (imagen anteroposterior de la pelvis). Las radiografías anteriores (hasta un máximo de 2 años de antigüedad) pueden utilizarse si las acepta el evaluador central. De lo contrario, se obtendrá una nueva radiografía en la visita de selección.6.El paciente presenta EA activa en las visitas de selección y de inicio (Día 1) definida como: puntuación BASDAI ≥4; y puntuación del dolor de espalda (pregunta 2 del BASDAI) ≥4. 7.El paciente presenta enfermedad activa a pesar de recibir tratamiento con fármacos antiinflamatorios no esteroideos (AINE) o es intolerante a los mismos. Esto se define de la siguiente manera: El paciente debe haber sufrido al menos un total de 2 acontecimientos de respuesta clínica inadecuada (periodo de administración mínimo de 4 semanas ) o haber presentado intolerancia a al menos 2 AINE diferentes administrados por vía oral. La intolerancia se define como haber interrumpido el tratamiento con AINE debido a un acontecimiento adverso relacionado (p. ej., reacción alérgica, signos o síntomas gastrointestinales, hipertensión arterial, etc.).8.Los pacientes que no presenten una respuesta adecuada a inhibidores del FNT deben haber recibido como mínimo 1 y como máximo 2 biofármaco(s) inhibidor(es) del FNT aprobado(s), administrado(s) de acuerdo con las recomendaciones de su ficha técnica y que no demostrara(n) la eficacia adecuada tras el periodo de tratamiento mínimo que se indica a continuación y/o no fuera(n) tolerado(s) por el paciente tras una o más dosis:•al menos 3 meses de tratamiento con adalimumab;•al menos 3 meses de tratamiento con etanercept;•al menos 4 infusiones de infliximab;•al menos 3 inyecciones de golimumab;•al menos 3 meses de tratamiento con certolizumab. La intolerancia se define como aparición de AA relacionados con el tratamiento (p. ej., reacciones a la infusión/inyección, infecciones, alteraciones en las pruebas analíticas, etc.).9.Los pacientes pueden estar recibiendo los siguientes FARME sintéticos convencionales en el momento de la visita de selección. Deben mantenerse estas medicaciones durante todo el estudio y las dosis deben permanecer invariables. Cualquier otro FARME requiere una discusión con el promotor antes de la inclusión para el periodo de reposo farmacológico.•Metotrexato (MTX): dosis máxima de 20 mg/semana. Duración mínima del tratamiento de 4 meses y dosis estable durante 4 semanas antes de la primera dosis del producto en investigación. Los pacientes que tomen MTX deben recibir una dosis adecuada y estable de un suplemento de folatos según las normas locales/aprobación de las autoridades reguladoras (p. ej., no menos de 5 mg semanales de ácido fólico, a menos que dichas dosis infrinjan las directrices de la ficha técnica local o el tratamiento estándar) durante al menos 4 semanas antes de la primera dosis del producto en investigación. Los pacientes no pueden haber presentado anteriormente toxicidad grave mientras recibían MTX y no debe esperarse que se requiera una evaluación de una posible toxicidad por metotrexato (p. ej., necesidad de una biopsia hepática para evaluar la toxicidad por metotrexato) durante el estudio;•Sulfasalazina (Azulfidine®, Salazpyrin®): dosis máxima de 3 g/día. Duración mínima del tratamiento de 2 meses y dosis estable durante 4 semanas antes de la primera dosis del producto en investigación.10. Los pacientes que ya estén tomando corticoesteroides orales (no inyectables) pueden participar en el estudio:•corticoesteroides orales: los pacientes que ya estén recibiendo corticoesteroides orales deben recibir una dosis estable de ≤10 mg/día de prednisona o un equivalente durante 4 semanas antes de la primera dosis del producto en investigación;•en el caso de los corticoesteroides inyectables (p. ej., intraarticular, intramuscular, epidural o intravenoso) se debe suspender el uso 4 semanas antes de la primera dosis del producto en investigación;•se permitirán los corticoesteroides tópicos y endorrectales durante el estudio.11.El paciente ha dejado de tomar definitivamente toda la medicación concomitante no permitida durante el tiempo requerido antes de recibir la primera dosis del producto en investigación.
    (Continua en Resumen del Protocolo criterios de inclusión; puntos 12 al 16).
    E.4Principal exclusion criteria
    1. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.
    2. Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry and/or during study participation (excluding noninterventional follow-up during the screening period).
    3. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
    4. History of known or suspected complete ankylosis of the spine. This can be determined/confirmed at the time of the SI radiograph by the central reader.
    5. Subjects receiving any other conventional synthetic or biological DMARDs (other than those allowed), thalidomide (including previous use) and other prohibited concomitant medications.
    6. Subjects that have been exposed to biological DMARDs other than TNF inhibitors.
    7. Blood dyscrasias at screening or within 3 months prior to the first dose of investigational product including confirmed:
    • Hemoglobin <10 g/dL;
    • Absolute white blood cell count (WBC) <3.0 x 10^9/L (<3000 mm3);
    • Absolute neutrophil count (ANC) <1.5 x 10^9/L (<1500 mm3);
    • Absolute lymphocyte count <1.0 x 10^9/L (<1000/mm3);
    • Platelet count <100 x 10^9/L (<100,000/mm3).
    8. Estimated Creatinine Clearance <40 mL/min based on Cockcroft Gault equation at Screening visit.
    9. Total bilirubin, AST or ALT more than 1.5 times the upper limit of normal (ULN) at screening visit.
    One re-testing of a laboratory-acceptable specimen (eg, appropriately labeled, within stability parameters, not hemolyzed, appropriate type (tube and reagent) and volume) is allowed of any above parameters if the abnormal lab(s) was an uncharacteristic result(s). Documentation in the source of the typical results to allow a repeat lab is required.
    Re-test must be completed within the screening period.
    10. History of any other autoimmune rheumatic disease.
    11. History of an infected joint prosthesis at any time, with the prosthesis still in situ.
    12. History of any lymphoproliferative disorder, such as Epstein Barr Virus related lymphoproliferative disease (EBV-LPD), history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease.
    13. History of recurrent (more than one episode) herpes zoster or disseminated/multi-dermatomal (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
    14. History of infection requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator, within the 3 months prior to the first dose of investigational product.
    15. History of infection requiring antimicrobial therapy within 2 weeks prior to the first dose of investigational product.
    16. Any prior treatment with non-B cell specific lymphocyte depleting agents/therapies (eg, alemtuzamab, efalizumab), alkylating agents (eg, cyclophosphamide or chlorambucil), or total lymphoid irradiation.
    17. Any subject who has been vaccinated with live or attenuated vaccines within the 6 weeks prior to the first dose of investigational product or is to be vaccinated with these vaccines at any time during treatment or within 6 weeks after last dose of investigational product.
    18. A subject with any condition possibly affecting oral drug absorption, eg, gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass. Procedures such as gastric banding, that simply divide the stomach into separate chambers, are NOT exclusionary.
    19. A subject that is considered at risk for GI perforation by the investigator or Sponsor.
    20. History of alcohol or drug abuse unless in full remission for greater than 6 months prior to first dose of investigational product. Subjects currently using marijuana.
    21. Screening 12-lead electrocardiogram (ECG) that demonstrates clinically relevant abnormalities which may affect subject safety (eg, pattern of acute myocardial infarction, acute ischemia or serious arrhythmia) or interpretation of study results (eg, continuously paced ventricular rhythm or complete left bundle branch block).
    22. A subject with a known immunodeficiency disorder or a first degree relative with a hereditary immunodeficiency.
    Please see section 4.2 of protocol for further exclusion criteria
    1.Pacientes que sean miembros del personal del centro de investigación directamente implicados en la realización del estudio, así como sus familiares; miembros del personal del centro supervisados de alguna otra manera por el investigador o pacientes que sean empleados de Pfizer, incluidos los miembros de su familia, y que estén directamente implicados en la realización del estudio.
    2.Participación en otros estudios con fármaco(s) en investigación en las 4 semanas anteriores a la entrada en el estudio y/o durante la participación en el estudio (excepto seguimiento sin intervención durante la fase de selección).
    3.Otras enfermedades o alteraciones psiquiátricas, agudas o crónicas, incluidos los pensamientos o comportamientos suicidas recientes (en el último año) o activos, o anomalías de laboratorio que puedan aumentar el riesgo asociado a la participación en el estudio o a la administración del producto en investigación, o que puedan interferir con la interpretación de los resultados del estudio y, a juicio del investigador, hagan que el paciente no sea apto para incorporarse al estudio.
    4.Sospecha o antecedentes confirmados de anquilosis completa de la columna vertebral. Esto puede determinarlo/confirmarlo el evaluador central en el momento de la radiografía de las articulaciones sacroilíacas. 5.Pacientes que reciban otros FARME convencionales sintéticos o biológicos (distintos a los permitidos), talidomida (incluido el uso previo) y otra medicación concomitante prohibida.
    6.Pacientes expuestos a FARME biológicos distintos a los inhibidores del FNT. 7.Discrasias sanguíneas en la selección o en los 3 meses anteriores a la primera dosis del producto en investigación, incluida la confirmación de:•hemoglobina <10 g/dl;•recuento absoluto de leucocitos (RAL) <3,0 × 109/l (<3000/mm3);• recuento absoluto de neutrófilos (RAN) <1,5 × 109/l (<1500/mm3);•recuento absoluto de linfocitos <1,0 × 109/l (<1000/mm3);•recuento de plaquetas <100 × 109/l (<100 000/mm3).8. Aclaramiento de creatinina estimado <40 ml/min basado en la ecuación Cockcroft-Gault en la visita de selección. 9.Bilirrubina total, AST o ALT >1,5 veces el límite superior de la normalidad (LSN) en la visita de selección.Se permitirá repetir la prueba realizada a una muestra aceptable en laboratorio (p. ej., adecuadamente etiquetada, dentro de los parámetros de estabilidad, no hemolizada, del tipo [tubo y reactivo] y volumen apropiado) en relación con todos los parámetros citados anteriormente si los resultados anómalos de los análisis son inesperados. Se requiere la documentación en el archivo original de los resultados típicos para permitir que se repita el análisis. La repetición del análisis debe completarse dentro de la fase de selección.10.Antecedentes de cualquier otra enfermedad reumática autoinmunitaria. 11.Antecedentes de una prótesis articular infectada en cualquier momento, con la prótesis todavía colocada.12.Antecedentes de cualquier trastorno linfoproliferativo, como el síndrome linfoproliferativo asociado al virus de Epstein-Barr (SLP-VEB), antecedentes de linfoma, leucemia o signos y síntomas indicativos de una enfermedad linfática actual.13.Antecedentes de herpes zóster recurrente (más de un episodio), de herpes zoster diseminado/multidermatómico (un solo episodio) o de herpes simple diseminado (un solo episodio).14.Antecedentes de infección que requiriese hospitalización o tratamiento antibiótico parenteral, o que en cualquier caso sea considerada clínicamente significativa por el investigador, en los 3 meses anteriores a la primera dosis del producto en investigación.15.Antecedentes de infección que requiriese tratamiento con antibióticos en las 2 semanas anteriores a la primera dosis del producto en investigación.
    16.Pacientes que hayan recibido previamente tratamientos/agentes linfocitopénicos no específicos de células B (p. ej., alemtuzumab o efalizumab), agentes alquilantes (p. ej., ciclofosfamida o clorambucilo) o irradiación linfática total.17.Pacientes que hayan sido inoculados con vacunas atenuadas o vivas en las 6 semanas anteriores a la primera dosis del producto en investigación, o que deban recibir dichas vacunas en cualquier momento durante el tratamiento o en las 6 semanas posteriores a la última dosis del producto en investigación.18.Pacientes con cualquier trastorno que pueda afectar a la absorción oral de los fármacos (p. ej., gastrectomía, gastroenteropatía diabética clínicamente significativa o determinados tipos de cirugía bariátrica, como la derivación gástrica). Los procedimientos tales como los cerclajes gástricos, que simplemente dividen el estómago en cámaras separadas, NO son motivo de exclusión.19.Pacientes que el investigador o promotor considere que presentan riesgo de perforación gastrointestinal.
    (Continua en Resumen del Protocolo criterios de exclusión; puntos 20 al 28).
    E.5 End points
    E.5.1Primary end point(s)
    • ASAS20 response at 16 weeks.
    Respuesta ASAS 20 en 16 semanas
    E.5.1.1Timepoint(s) of evaluation of this end point
    16 weeks
    16 semanas
    E.5.2Secondary end point(s)
    • Incidence and severity of Adverse Events (AE).
    • Clinical laboratory tests, vital signs, physical examination and 12-lead ECG parameters.
    • ASAS40 response at all time points.
    • ASAS20 response at all other time points.
    • ASAS 5/6 response at all time points.
    • Ankylosing Spondylitis Disease Activity Score using C-Reactive Protein (ASDASCRP) at all time points.
    • hsCRP.
    • ASDAS clinically important improvement, ASDAS major improvement and ASDAS inactive disease at all time points.
    • Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at all time points.
    • BASDAI50 response at all time points
    • Bath Ankylosing Spondylitis Functional Index (BASFI) at all time points.
    • Bath Ankylosing Spondylitis Metrology Index (BASMI) at all time points.
    • Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) at all time points collected.
    • Extra-articular Involvement (Specific Medical History and peripheral articular involvement [as assessed by swollen joint count]) at all time points collected.
    • Spinal mobility at all time points collected.
    • ASAS partial remission criteria at all time points.
    • Short-Form-36 Health Survey (SF-36) Version 2, Acute at all time points collected.
    • EuroQol EQ-5D Health State Profile (EQ-5D) and Your own health state today (EQ-VAS), at all time points collected.
    • Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) at all time points.
    • Ankylosing Spondylitis Quality of Life (ASQoL) at all time points collected.
    • Work Productivity and Activity Impairment (WPAI) Questionnaire: Spondyloarthritis at all time points collected
    • AS HealthCare Resource Utilization Questionnaire (AS-HCRU) at all time points collected.
    Incidencia y severidad de los Efectos Adversos;Pruebas de laboratorio clínico, signos vitales, examen físico y parámetros de ECG de 12 derivaciones;respuesta ASAS20 en todos los puntos temporales;respuesta ASAS20 en otros puntos temporales;respuesta ASAS 5/6 en todos los puntos temporales;Índice de la actividad de la espondilitis anquilosante utilizando Proteina C reactiva en todos los puntos temporales;Alta sensibilidad a la proteina-C reactiva;mejora clínicamente importante de la puntuación de la actividad de la enfermedad de espondilitis anquilosante en todos los puntos temporales;Índice de Bath de actividad de la espondilitis anquilosante (BASDAI) en todos los puntos temporales;Respuesta BASDAI50 en todos los puntos temporales;índice funcional de Bath de la espondilitis anquilosante (BASFI) en todos los puntos temporales; Indice metrologico de la espondilitis anquilosante (BASMI) en todos los puntos temporales;Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) en todos los puntos temporales;Participación extra articular (historia médica específica y afectación articular periférica [evaluada mediante recuento de articulaciones inflamadas]) en todos los puntos temporales;movilidad espinal en todos los puntos temporales;criterios de remisión parcial en la Evaluación de la espondilitis anquilosante en todos los puntos temporales;cuestionario de salud abreviado de 36 preguntas, versión 2 (SF-36-v2), en todos los puntos temporales; cuestionario del estado de salud EuroQol-5D (EQ 5D) y cuestionario sobre su estado de salud hoy (EVA del EQ) en todos los puntos temporales;evaluación funcional del tratamiento de enfermedades crónicas - Escala de fatiga (FACIT F) en todos los puntos temporales;cuestionario sobre la calidad de vida en la espondilosis anquilosante (ASQoL), en todos los puntos temporales;cuestionario sobre el deterioro de la actividad y la productividad laboral (WPAI): espondiloartritis en todos los puntos temporales;cuestionario sobre la utilización de recursos sanitarios de la EA (AS HCRU) en todos los puntos temporales
    E.5.2.1Timepoint(s) of evaluation of this end point
    At all timepoints. Please refer to the protocol for additional details
    En todos los puntos temporalis. por favor, refieranse al Protocolo para detalles adicionales
    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 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 No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Fase de tratamiento abierto desde semana 16 a semana 48
    Open label treatment phase from Week 16 - 48
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    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
    Belgium
    Bulgaria
    Canada
    China
    Czech Republic
    France
    Germany
    Hungary
    Israel
    Korea, Republic of
    Poland
    Russian Federation
    Slovakia
    Spain
    Taiwan
    Turkey
    Ukraine
    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
    End of trial in a Member State of the EU is defined as the time at which it is deemed that a sufficient number of subjects have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
    El final del ensayo en un Estado Miembro de la UE se define como el momento en el que se considera que se ha reclutado a un número suficiente de pacientes y estos han finalizado el estudio según lo declarado en el CTA presentado para la Agencia y para el CEIC del Estado Miembro. Un reclutamiento inferior al número previsto en el CTA por parte de un Estado miembro no es un motivo de terminación prematura, pero se considera una conclusión normal del estudio en ese Estado miembro.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days14
    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: 228
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 240
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Ninguno
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-28
    P. End of Trial
    P.End of Trial StatusCompleted
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