E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to severely active Rheumatoid Arthritis that has had an inadequate response or intolerance to conventional DMARD therapy including at least one TNF inhibitor |
Artritis Reumatoide moderada o intensamente activa que hayan presentado una respuesta insuficiente o intolerancia al tratamiento con FARME convencionales, incluido al menos un inhibidor del TNF. |
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E.1.1.1 | Medical condition in easily understood language |
Rheumatoid Arthritis |
Artritis Reumatoide |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10039075 |
E.1.2 | Term | Rheumatoid arthritis and associated conditions |
E.1.2 | System Organ Class | 100000004870 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
To show similarity of BI 695500 to MabThera and Rituxan and of Rituxan to MabThera with respect to PK (three-way PK similarity) |
Demostrar la semejanza de BI 695500 con MabThera® y Rituxan® y de Rituxan® con MabThera® con respecto a la Farmacocinética (semejanza farmacocinética de tres vías). |
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E.2.2 | Secondary objectives of the trial |
Evaluation of efficacy, safety and tolerability of BI 695500 and Rituxan/MabThera. |
Evaluar la eficacia, seguridad y tolerabilidad de BI 695500 y Rituxan/MabThera |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Must give written informed consent and be willing to follow the protocol. 2. Male or female participants, between 18 and 80 years of age, who have a diagnosis of moderately to severely active RA for at least 6 months as defined by at least six swollen joints (66 joint count) and at least eight tender joints (68 joint count) at Screening and Baseline (Day 1), and either an erythrocyte sedimentation rate (ESR) of > 28 mm/hour OR a CRP level > 1.0 mg/dL (normal: < 0.4 mg/dL) at Screening. Patients must have had an inadequate response or intolerance to conventional DMARD therapy including at least one TNF inhibitor. 3. Positive for RF and/or anti-CCP antibodies. 4. Current treatment for RA on an outpatient basis: (a) Must be currently receiving and tolerating oral or parenteral MTX therapy at a dose of 15-25 mg per week (dose may be as low as 10 mg per week if the patient is unable to tolerate a higher dose) for at least 12 weeks immediately prior to Day 1. The dose should be stable for at least 4 weeks prior to Day 1 until Week 24. For further inclusion criteria see protocol. |
1. Debe dar su consentimiento informado por escrito y estar dispuesto a cumplir el protocolo. 2. Participantes de ambos sexos, de 18 a 80 años de edad, que tengan un diagnóstico de AR modera o intensamente activa durante al menos 6 meses, definida por un mínimo de seis articulaciones inflamadas (evaluación de 66 articulaciones) y al menos ocho articulaciones dolorosas (evaluación de 68 articulaciones) en las visitas de selección y basal (día 1), y una velocidad de sedimentación globular (VSG) > 28 mm/h O una concentración de PCR > 1,0 mg/dl (normal: < 0,4 mg/dl) en la selección. Los pacientes deben haber presentado una respuesta insuficiente o intolerancia al tratamiento con FARME convencionales, incluido al menos un inhibidor del TNF. 3. Positividad para el FR y/o anticuerpos anti-CCP. 4. Tratamiento actual para la AR en régimen ambulatorio: (a) Los pacientes deben estar recibiendo actualmente y tolerar un tratamiento con metotrexato (MTX) oral o parenteral en una dosis de 15-25 mg por semana (la dosis puede ser de solo 10 mg por semana si el paciente no tolera una dosis más alta) durante al menos las 12 semanas previas al día 1. La dosis debe haberse mantenido estable durante al menos las 4 semanas previas al día 1 y hasta la semana 24. Para más Criterios de Inclusión ver Protocolo. |
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E.4 | Principal exclusion criteria |
1. ACR functional Class IV or wheelchair/bed bound. 2. Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus infection. 3. History of positive purified protein derivative test (positive tuberculosis [TB] test) without treatment for TB infection or chemoprophylaxis for TB exposure. 4. Known coronary artery disease or significant cardiac arrhythmias or severe congestive heart failure (New York Heart Association classes III or IV), or interstitial lung disease observed on chest X-ray. 5. History of IgE-mediated or non-IgE-mediated hypersensitivity or known anaphylaxis to mouse proteins or a history of hypersensitivity to antibody therapy. 6. History of cancer including solid tumors, hematologic malignancies, and carcinoma in situ (except participants with previous resected and cured basal or squamous cell carcinoma, treated cervical dysplasia, or treated in situ Grade I cervical cancer within 5 years prior to the Screening Visit). 7. History of inflamed pancreas or current peptic ulcer disease. 8. Receipt of a live/attenuated vaccine within 12 weeks prior to the Screening Visit. 9. Any condition or treatment (including biologic therapies) that, in the opinion of the investigator, may place the patient at unacceptable risk during the trial. 10. Pregnancy or breast feeding. For women of childbearing potential, a positive serum pregnancy test at the Screening Visit and/or a positive urine pregnancy test at Baseline (Day 1). 11. History of, or current, inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (e.g., systemic lupus erythematosus, inflammatory bowel disease, pulmonary fibrosis, or Felty's syndrome, scleroderma, inflammatory myopathy, mixed connective tissue disease, or any overlap syndrome). Secondary Sjögren's syndrome or secondary limited cutaneous vasculitis with RA is permitted. 12. Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16. 13. Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to the Screening Visit or planned within 24 weeks of the Screening Visit. 14. Lack of peripheral venous access. 15. Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders which, in the investigator's opinion, would preclude patient participation. 16. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV anti-infectives within 4 weeks of the Screening Visit or completion of oral anti-infectives within 2 weeks of the Screening Visit. For exclusion criteria 17. - 30. see protocol. |
1. Clase funcional IV del ACR o paciente en silla de ruedas o encamado. 2. Inmunodeficiencia primaria o secundaria (o antecedentes), por ejemplo, antecedentes de infección por el virus de la inmunodeficiencia humana. 3. Antecedentes de positividad en la prueba del derivado proteínico purificado (prueba positiva de la tuberculosis [TB]) sin tratamiento para la infección o quimioprofilaxis para la exposición a la TB. 4. Enfermedad de las arterias coronarias o insuficiencia cardíaca congestiva intensa (clases III o IV de la New York Heart Association) conocidas o enfermedad pulmonar intersticial observada en la radiografía de tórax. 5. Antecedentes de hipersensibilidad mediada por IgE o no IgE anafilaxia conocida a las proteínas de ratón o antecedentes de hipersensibilidad al tratamiento con anticuerpos. 6. Antecedentes de cáncer, lo que incluye tumores sólidos, neoplasias malignas hematológicas y carcinoma in situ (excepto carcinoma espinocelular o basocelular previamente extirpado y curado, displasia cervical tratada o cáncer de cuello uterino de grado I in situ tratado en los 5 años anteriores a la visita de selección). 7. Antecedentes de enfermedad inflamatoria del páncreas o enfermedad ulcerosa péptica actual. 8. Vacuna de microorganismos atenuados en las 12 semanas previas a la visita de selección. 9. Cualquier enfermedad o tratamiento (incluidos los tratamientos biológicos) que, en opinión del investigador, pueda poner al paciente en un riesgo inaceptable durante el ensayo. 10. Embarazo o lactancia. En las mujeres en edad fértil, una prueba de embarazo en suero positiva en la visita de selección o un prueba de embarazo en orina positiva en la visita basal (día 1). 11. Antecedentes o presencia de artropatía inflamatoria distinta de la AR (por ejemplo, gota, artritis reactiva, artritis psoriásica, espondiloartropatía seronegativa, enfermedad de Lyme) u otro trastorno autoinmunitario sistémico (por ejemplo, lupus eritematoso sistémico, enfermedad inflamatoria intestinal, fibrosis pulmonar, síndrome de Felty, esclerodermia, miopatía inflamatoria, enfermedad mixta del tejido conjuntivo o cualquier síndrome solapado). Se permite el síndrome de Sjögren secundario o una vasculitis cutánea limitada secundaria con AR. 12. Diagnóstico de artritis idiopática juvenil, también conocida como AR juvenil, o AR antes de los 16 años. 13. Cualquier intervención quirúrgica, incluida la cirugía osteoarticular/sinovectomía (incluida la artrodesis o la artroplastia) realizada en las 12 semanas anteriores a la visita de selección o programada en las 24 semanas posteriores a dicha visita. 14. Falta de acceso venoso periférico. 15. Signos de enfermedad concomitante significativa no controlada tal como trastornos del sistema nervioso, renales, hepáticos, endocrinos o digestivos que, en opinión del investigador, impidan la participación del paciente. 16. Infección activa conocida de cualquier tipo (excepto las onicomicosis) o cualquier episodio importante de infección que precise hospitalización o tratamiento con antiinfecciosos intravenosos en las 4 semanas anteriores a la visita de selección o finalización del tratamiento con antiinfecciosos orales en los 2 semanas anteriores a la visita de selección. Para Criterios de Exclusión 17-30 ver Protocolo. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoints: Primary efficacy endpoints are the change from Baseline in DAS28 at 24 weeks and the proportion of patients meeting the ACR20 response criteria at Week 24
Primary PK endpoints: ? AUC0-tz (area under the plasma concentration versus time curve from time zero to the last measurable concentration, determined after the second drug infusion) ? AUC0-? (area under the plasma concentration versus time curve from time zero to infinity, determined after the second drug infusion). |
Criterios de Valoración Principales de Eficacia: Los criterios de valoración principales de la eficacia son la variación con respecto al valor basal del DAS28 en la semana 24 y la proporción de pacientes que cumplan los criterios de respuesta ACR20 en dicha semana.
Criterios de Valoración principales de FC:
? AUC0-tz (área bajo la curva de concentración plasmática frente al tiempo desde el tiempo cero hasta la última concentración mensurable, determinada después de la segunda infusión de la medicación) ? AUC0-? (área bajo la curva de concentración plasmática frente al tiempo desde el tiempo cero hasta el infinito, determinada después de la segunda infusión de la medicación). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints: at Week 24 PK endpoints: Will be assessed after 150 patients have each completed 16 weeks in Part 1. |
Criterios de evaluación de eficacia: en la Semana 24 Criterios de evaluación FC: Se evaluarán después de que 150 pacientes hayan completado 16 semanas en la parte I |
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E.5.2 | Secondary end point(s) |
DAS28 difference in mean change and ACR20 response rate. Physical examination, vital signs (blood pressure, pulse rate, respiratory rate, body temperature), 12-lead electrocardiogram, laboratory tests, adverse events and tolerability |
Diferencia en la variación media del DAS28 y la tasa de respuestas ACR20. Examen físico, signos vitales (presión sanguinea, frecuencia de pulso,frecuencia respiratoria, temperatura corporal), electrocardiograma de 12 derivaciones, pruebas analíticas, acontecimientos adversos y tolerabilidad |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | Yes |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | Yes |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 98 |
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 | No |
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 |
Argentina |
Belgium |
Brazil |
Bulgaria |
Canada |
Chile |
Estonia |
France |
Germany |
Greece |
Guatemala |
Hungary |
Ireland |
Italy |
Mexico |
Netherlands |
New Zealand |
Norway |
Peru |
Poland |
Portugal |
Russian Federation |
Serbia |
South Africa |
Spain |
Sweden |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial 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
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LVLS or Independent data monitoring committee recommendation |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |