| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis |
| Artritis Reumatoidea |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid Arthritis |
| Artritis Reumatoidea |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003268 |
| E.1.2 | Term | Arthritis rheumatoid |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 |
The main aim of this project is to test the hypothesis that the presence or absence of specific synovial cellular and molecular signatures(B cells and B cell-associated signatures), assessed following a synovial tissue biopsy, will enrich for response / non-response to the B cell depleting anti-CD20 monoclonal antibody (mAb) Rituximab.
The primary aim of this project is to show that in patients failing anti-TNF therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab therapy. |
| . Específicamente, conocer si una biopsia sinovial diagnóstica que muestra un ?prototipo rico/pobre en células B? define unos subgrupos de enfermos respondedores/resistentes que permitan la estratificación de los pacientes y ayuden a racionalizar la selección de los fármacos biológicos. |
|
| E.2.2 | Secondary objectives of the trial |
In addition to the primary objective previously stated, we will address the following questions:
1) Can a diagnostic synovial biopsy showing a B-cell ?rich/poor pathotype? define specific disease responsive/resistant subsets for patient stratification and help rationalize biologic drug choice?
2) Is clinical response associated with inhibition of B cell-linked pathways within the synovium and dependent on local B cell lineage depletion?
3) Is survival of auto-reactive B cells within ?protected? synovial niches responsible for B-cell joint re-population and disease resistance-relapse? |
¿1) puede una muestra de la biopsia sinovial diagnóstico una b-célula "rich/poor pathotype" definir subgrupos de respondedores-resistentes para la estratificación de los pacientes y ayudar a racionalizar la elección del fármaco biológico?
¿2) está la respuesta clínica asociada a la inhibición de las vías de la célula de B- de la membrana sinovial y es dependiente del la poca producción de células B locales?
¿3) es la supervivencia de las células B auto-reactivas responsable de la repoblación conjunta de células B y resistencia-recidiva de los nichos de enfermedad sinovial ? |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients will be recruited with active RA:
1. Patients who have failed anti-TNF therapy (inadequate responders ? ir). Note: this includes patients that have failed anti-TNF therapy because of reactions.
2. Who are eligible for Rituximab therapy according NICE guidlines*
3. Patients should be receiving a stable dose Methotrexate for at least 4 weeks prior to the biopsy visit.
4. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of Rheumatoid Arthritis.
5. Over 18 years of age
6. Patient must be capable of giving informed consent
7. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures
*Reference to NICE guidelines: 1.1 Rituximuab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or intolerance of other disease-modifying anti-rheumatic drugs (DMARDS), including treatment with at least one tumour necrosis factor alpha (TNF alpha) inhibitor therapy. |
1. Que hayan fracasado a tratamientos anti-TNF (respondedores inadecuados ?RI). Esto incluye pacientes que han fracasado por toxicidad.
2. Que sean elegibles para recibir tratamiento con Rituximab según las recomendaciones del UK NICE
3. Que estén recibiendo dosis estándar de Metotrexato durante al menos las 4 semanas antes de la visita de biopsia.
4. Que cumplan los criterios 2010 ACR / EULAR de clasificación diagnóstica de la de la artritis reumatoide
5. Mayores de 18 años
6. Capaces de otorgar el consentimiento informado
7. Con voluntad y capacidad de cumplir con los procedimienos y visitas del estudio |
|
| E.4 | Principal exclusion criteria |
1.Women who are pregnant or breast-feeding
2.Women of child-bearing potential, or males whose partners are women of child-bearing potential, unwilling to use effective contraception during the study and for at least 6 months after stopping study treatment.
3.History of or current primary inflammatory joint disease or primary autoimmune disease other than RA
4. Prior exposure to Rituximab or Tocilizumab for the treatment of RA
5.Treatment with any investigational agent ? 4 weeks prior to baseline or < 5 half lives of the investigational drug
6.Intra articular or parenteral corticosteroids ? 4 weeks prior to biopsy visit (Visit 2)
7. Oral Prednisolone more than 10mg per day or equivalent ? 4 weeks prior to biopsy visit (Visit 2)
8.Active infection
9.Septic arthritis within a native joint within the last 12 months
10.Sepsis of a prosthetic joint within 12 months or indefinitely if the joint remains in situ
11.Known HIV or hepatitis B/C infection. Hepatitis B screening test must be performed at or in the preceding 3 months of screening visit.
12.Latent TB infection unless they have completed adequate antibiotic prophylaxis
13.Malignancy (other than basal cell carcinoma) within the last 10 years
14.New York Heart Association (NYHA) grade 3 or 4 congestive cardiac failure
15.Demyelinating disease
16.Latex allergy or allergy to any excipients of Rituximab or Tocilizumab
17.Any other contra-indication to the study medications as detailed in their summaries of product characteristics (SmPC) including low IgG levels at clinician's discretion
18.Receipt of live vaccine <4 weeks prior to first infusion
19. Major surgery in 3 months prior to first infusion
20.Presence of a transplanted organ (with the exception of a corneal transplant >3 months prior to screening)
21.Known recent substance abuse (drug or alcohol)
22.Poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period.
23.Patients unable to tolerate synovial biopsy or in whom this is contraindicated (e.g. patients on anti-coagulants).
24. Patients currently recruited to other clinical trial(s) involving an investigational medicinal product (except any observational follow-up periods not involving an IMP).
25. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgement of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgement of the investigator, would make the patient inappropriate for entry into this study |
1. Mujeres embarazadas o lactantes
2. Mujeres en edad fértil
3. Historia de enfermedades autoinmunes o inflamatorias diferentes de la AR.
4. Tratamiento previo con Rituximab o Tocilizumab para la AR
5. Tratamiento con medicamentos en investigación en las 4 semanas previas o 5 semividas del fármaco previas a la visita basal.
6. Uso de corticoides intraarticulares o parenterales en las 4 semanas previas a la biopsia
7. Uso de más de 10 mg/día de prednisolona oral o equivalente en las 4 semanas previas a la biopsia
8. Infección activa.
9. Artritis séptica en los últimos 12 meses..
10. Infección crónica por VIH, VHB o VHC
11. Tuberculosis latente excepto si se ha finalizado la profilaxis.
12. Cáncer en los últimos 10 años (con excepción de carcinoma basocelular)
13. Insuficiencia cardiaca grado 3 o 4 de la NYHA
14. Enfermedad desmielinizante.
15. Alergia al látex o a los excipientes de Rituximab o Tocilizumab
16. Haber recibido vacunas vivas en las últimas 4 semanas antes de la infusión
17. Pacientes en los que la biopsia está contraindicada (p.ej: en tratamiento anticoagulante) o no se tolera
18.Haber recibido alguna vacuna viva 4 semanas antes de la primera infusión
19. cirugía 3 meses antes de la primera infusión
20. la presencia de un órgano trasplantado (con la excepción de un trasplante de córnea 3 meses antes de la proyección)
21. reciente abuso de sustancias (alcohol o drogas)
22. pobre tolerabilidad de venopunción o la falta de un acceso venoso adecuado para tomar muestras de sangre necesarias durante el período de estudio.
23. pacientes incapaces de tolerar la biopsia sinovial o que presenten alguna contraindicación (por ejemplo, los pacientes con tratamiento anticoagulante).
24. los pacientes formana parte de otro ensayo clínico u otra prueba clínica que involucre a un medicamento en investigación (excepto estudios obserbacionales que no impliquen a un IMPD).
25. otra condición médica o psiquiátrica aguda o crónica severa, o anormalidad de los análisis de laboratorio, exceso de riesgo asociado a la participación en el estudio o de la administración del fármaco o que, a juicio del investigador sea inadecuada la entrada del paciente en el presente estudio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The main aim of this project is to test the hypothesis that the presence or absence of specific synovial cellular and molecular signatures (B cells and B cell-associated signatures), assessed following a synovial tissue biopsy, will enrich for response/non-response to the B cell depleting anti-CD20 monoclonal antibody (mAb) Rituximab.
Therefore, while this study can be thought of as three distinct clinical trials in separate synovial histomorphological phenotypes (1. B cell rich, 2. B cell poor and 3. Germinal centres)with each sub group randomised to Rituximab or Tocilizumab; the Primary outcome measure is the proportion of patients achieving a CDAI (Clinical disease activity index) response at 16 weeks from baseline.
The primary analysis will focus on whether there is a superiority of Tocilizumab over Rituximab in histologically defined ?B cell poor patients?. |
El objetivo principal de este proyecto es probar la hipótesis de que la presencia o ausencia de cel específicas sinoviales y moleculares (linfocitos B y asociada a la célula de B), evaluados después de una biopsia del tejido sinovial, mejorarán la respuesta/no respuesta de la célula de B- ligadas al anticuerpo monoclonal anti-CD20 Rituximab (mAb).
Por lo tanto, mientras que este estudio puede ser pensado como tres distintos ensayos clínicos en fenotipos histomorfológicos sinovial separados (1. Ricos en células b, 2. Célula de b pobre y 3. Centros germinales) con cada subgrupo al azar a Rituximab o Tocilizumab; la medida de resultado primaria es la proporción de pacientes que lograron una respuesta (índice de actividad de la enfermedad clínica) CDAI en 16 semanas desde el inicio.
El análisis primario se centrarán en si hay una superioridad de Tocilizumab sobre Rituximab en la histológia definiendo 'los pacientes pobres encélulas B'. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timepoint for evaluation of the primary end point will be at 16 weeks from baseline. |
| evaluación de end point primario: será a las 16 semanas de la visita basal |
|
| E.5.2 | Secondary end point(s) |
In addition we will also examine:
1. For the B-cell rich synovial pathotypes, we aim to show non-inferiority of Rituxumab compared to Tocilizumab.
2. Germinal Centre pathotypes will constitute an exploratory component to the trial as insufficient power will be generated to show a significant difference in clinical response between each treatment.
3. Area under the curve (AUC) of mean improvement in DAS28 over time between 0, 16 and 48 weeks.
4. Percentage of patients with low disease activity (DAS28 < 3.2) at 12, 24, 36, 48, 96 weeks
5. Percentage of patients in remission (DAS28 < 2.6) at 16 and 48 weeks
6. Percentage of patients with ACR 20, 50 and 70 response rates at 16, 48 and 96 weeks
7. Percentage of patients with a low clinical disease activity index score (CDAI)
8. Mean % change in DAS28 between baseline and 16, 48 and 96 weeks
9. Mean % change in clinical disease activity index score (CDAI) between baseline and 16, 48 and 96 weeks
10. Mean change in HAQ score between baseline and 16, 48 and 96 weeks
11. Change in Fatigue score between baseline and 16, 48 and 96 weeks
12. Serious adverse events over 12 months; the rate of serious adverse events in the 16 week period following a switch from one technology to the other will be compared
13. Mean change in erosive score by the van der Heijde/Sharp scoring system at 24 and 48 weeks.
14. Reduction in US 2D grey scale and power Doppler signal at 16, 48 and 96 weeks.
15. The effect of synovial immuno-histology on drug response rates |
Además también examinaremos:
1. para la b-célula patotipos sinovial ricos, nuestro objetivo es demostrar la no inferioridad de Rituxumab comparado con Tocilizumab.
2.el centro germinal de patotipos constituirá un componente exploratorio para mostrar una diferencia significativa en la respuesta clínica entre cada tratamiento.
3. el área bajo la curva (AUC) de mejoría media en DAS28 con el tiempo entre 0, 16 y 48 semanas.
4. porcentaje de pacientes con enfermedad baja actividad (DAS28 3.2) en 12, 24, 36, 48, 96 semanas
5. porcentaje de pacientes en remisión (DAS28 2.6) en 16 y 48 semanas
6. porcentaje de pacientes con ACR 20, 50 y 70 las tasas de respuesta en el 16, 48 y 96 semanas
7. porcentaje de pacientes con un índice de actividad de la enfermedad clínica baja puntuación (CDAI)
8. cambio en DAS28 entre la línea de fondo y 16, 48 y 96 semanas
9. cambio en el índice de actividad de la enfermedad clínica puntuación (CDAI) entre la línea de fondo y 16, 48 y 96 semanas
10. cambio en puntuación HAQ basal y 16, 48 y 96 semanas
11. cambio en la puntuación de fatiga entre la línea de fondo y 16, 48 y 96 semanas
12. efecto adverso graves durante 12 meses; se comparará la tasa de eventos adversos graves en el período de 16 semanas
13. cambio en la puntuación erosivo por la HeijdeSharp van der sistema de puntuación a las 24 y 48 semanas.
14. reducción en escala de grey 2D de Estados Unidos y la señal del Doppler en 16, 48 y 96 semanas.
15. el efecto de inmuno-histología sinovial en las tasas de respuesta de drogas |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The timepoints for evaluation of secondary end points will be up to 96 weeks from baseline. |
| Los endpoint secundarios serán en la semana 96 del estudio |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | 2 |
| 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 | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| This will be the last visit of the last patient after 24 months of follow up. |
| está prevista la última visita del último paciente después de 24 meses de seguimiento . |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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