E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Artritis reumatoide / Rheumatoid arthritis |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. Determinar la eficacia de rituximab para prevenir la progresión del deterioro articular estructural y evaluar la seguridad de rituximab en pacientes con artritis reumatoide activa que inician un tratamiento con MTX. 2. Evaluar la eficacia de rituximab para mejorar la función física de los pacientes y los signos y síntomas de la AR. 3. Investigar, mediante un modelo de análisis poblacional, la farmacocinética (FC) de rituximab en la población de pacientes con AR que se pretende estudiar y la influencia de las covariables en los parámetros FC. 4. Investigar la eficacia y la seguridad a largo plazo de la administración de ciclos adicionales de rituximab.
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E.2.2 | Secondary objectives of the trial | |
E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Capacidad y voluntad de otorgar el consentimiento informado por escrito y de cumplir los requisitos del protocolo del estudio. 2. Pacientes con artritis reumatoide de 8 semanas de duración como mínimo y de 4 años como máximo, diagnosticada de acuerdo con los criterios del American College of Rheumatology (ACR) revisados en 1987, para la clasificación de la artritis reumatoide. 3. Pacientes que no han sido tratados previamente con metotrexato y que se consideren candidatos a recibir este tratamiento. 4. Presentar un recuento de articulaciones inflamadas (SJC) 8 (recuento de 66 articulaciones) y de articulaciones dolorosas (TJC) 8 (recuento de 68 articulaciones) en las evaluaciones de selección y basal. 5. Concentración de PCR 1,2 mg/dl (12 mg/l) en la evaluación de selección 6. Edad 18-80 años. 7. Se permite el tratamiento con glucocorticoides ( 10 mg de prednisolona al día o equivalente) si la dosis se ha mantenido estable como mínimo durante las 4 semanas previas a la evaluación basal. 8. Se permite el uso de AINEs si la dosis se ha mantenido estable como mínimo durante las 2 semanas previas a la evaluación basal. 9. Los pacientes en edad fértil (tanto varones como mujeres) deben utilizar un método anticonceptivo eficaz (p. ej. anticonceptivos hormonales, parche anticonceptivo, dispositivo intrauterino, métodos de barrera) durante su participación en el estudio. 10. Los pacientes deben estar dispuestos a recibir folato por vía oral. 11. (Sólo para los pacientes con FR negativo). Los pacientes deben presentar indicios radiográficos de erosión definida, como mínimo, en una articulación, que sea atribuible a AR. 12. Pacientes que van a recibir o que están recibiendo actualmente tratamiento en régimen ambulatorio.
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E.4 | Principal exclusion criteria |
1. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (including but not limited to vasculitis, pulmonary fibrosis or Felty’s syndrome). Secondary Sjögren’s syndrome or secondary limited cutaneous vasculitis with RA is permitted. 2. Functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis. 3. History of, or current, inflammatory joint disease other than RA (including, but not limited to, gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (including, but not limited to, systemic lupus erythematosus, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or any overlap syndrome). 4. Diagnosis of juvenile idiopathic arthritis (JIA) or juvenile rheumatoid arthritis (JRA) and/or RA before age 16. 5. Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned during the study. 6. Lack of peripheral venous access. 7. Pregnancy or breast feeding. 8. Significant and/or uncontrolled cardiac or pulmonary disease (including obstructive pulmonary disease). 9. Evidence of significant concomitant disease, including but not limited to, nervous system, renal, hepatic, endocrine or gastrointestinal disorders which, in the investigator’s opinion, would preclude patient participation. 10. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection. 11. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with i.v. anti-infectives within 4 weeks of baseline or completion of oral antiinfectives within 2 weeks prior to baseline. 12. History of deep space/tissue infection (e.g. fasciitis, abscess, osteomyelitis) within 52 weeks prior to baseline. 13. History of serious recurrent or chronic infection (for screening for a chest infection a chest radiograph will be performed at screening if not performed within 12 weeks prior to screening). 14. History of cancer, including solid tumors, hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured). 15. Any neurological (congenital or acquired), vascular or systemic disorder which could affect any of the efficacy assessments, in particular, joint pain and swelling (e.g. Parkinsons disease, cerebral palsy, diabetic neuropathy). 16. Currently active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to baseline. 17.History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins. 18. Previous treatment with any approved or investigational biologic agent for RA. 19. Previous treatment with an anti-alpha 4 integrin antibody or co-stimulation modulator. 20. Concurrent treatment with any biologic agent or DMARD other than MTX. Treatment must be discontinued 14 days prior to baseline, except for the following: azathioprine for ≥ 28 days; leflunomide for ≥ 8 weeks (or ≥ 14 days after 11 days of standard cholestyramine or activated charcoal washout). 21. Previous treatment with any cell depleting therapies, including investigational agents (e.g. CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti-CD11a, anti-CD22, BLys/ BAFF, and anti-CD20). 22. Treatment with any investigational agent within 28 days of baseline or 5 half lives of the investigational drug (whichever is the longer). 23. Receipt of a live/attenuated vaccine within 28 days prior to baseline (it is recommended that a patient’s vaccination record and the need for immunization prior to receiving rituximab/placebo should be carefully investigated) 24. Intra-articular or parenteral glucocorticoids within 4 weeks prior to baseline. 25. Intolerance or contraindications to i.v. glucocorticoids. 26. Positive serum human chorionic gonadotropin (hCG) measured prior to the first rituximab infusion. 27. Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBsAb) or hepatitis C serology. 28. Hemoglobin < 8.0 g/dL. 29. Concentrations of serum IgG and/or IgM below 5.0 and 0.40 mg/mL, respectively. 30. Absolute neutrophil count (ANC) < 1.5 × 103/µL. 31. AST or ALT > 2.5 times upper limit of normal. |
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E.5 End points |
E.5.1 | Primary end point(s) |
La variable principal es la variación producida, con respecto al valor de selección, en la puntuación total Sharp modificada en la semana 52, basándose en la población IDT modificada. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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
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Los pacientes recibirán la medicación en estudio durante 3 años o hasta que rituximab esté disponible en el mercado para la indicación de artritis reumatoide (lo que ocurra más tarde). Por lo tanto el final del tratamiento será definido como los 3 años requeridos, seguidos de un periodo adicional de al menos un año para hacer seguimientos de seguridad. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |