E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis |
Artrite Reumatóide |
|
E.1.1.1 | Medical condition in easily understood language |
Rheumatoid Arthritis |
Artrite Reumatóide |
|
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 | 20.0 |
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.
|
O objetivo principal deste projeto é testar a hipótese de que a presença ou ausência de assinaturas celulares e moleculares sinoviais específicas (células B e assinaturas associadas a células B), avaliada após uma biópsia de tecido sinovial, prediz a resposta/ não resposta ao anticorpo monoclonal depletor de células B Rituximab.
O objetivo primário deste projeto é demonstrar que em doentes com resposta inadequada à terapia anti-TNF, com patotipo sinovial pobre em células B, o Rituximab é inferior ao Tocilizumab. |
|
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?
|
Adicionalmente ao objetivo primário previamente estabelecido, iremos ainda avaliar as seguintes questões:
1) Poderá uma biópsia sinovial diagnóstica, evidenciando patotipo “rico/pobre” em células B, definir subgrupos de doença específicos de resposta/resistência para estratificar doentes e ajudar a racionalizar a escolha da terapêutica biológica?
2) Estará a resposta clínica associada à inibição das vias associadas às células B na membrana sinovial e dependente da depleção local das células de linhagem B?
3) Será a sobrevivência de células B auto-reativas dentro de nichos sinoviais "protegidos" responsável pelo reaparecimento de células B nas articulações e resistência a recidiva de doença? |
|
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 |
Serão recrutados doentes com AR ativa:
1. Doentes com falência à terapêutica anti-TNF (resposta inadequada-ir). Nota: são incluídos doentes que tenham falência à terapêutica anti-TNF devido a reações adversas.
2. Elegíveis para terapêutica com rituximab de acordo com as guidelines NICE.
3. Os doentes devem estar a receber uma dose estável de metotrexato por pelo menos 4 semanas antes da visita de biópsia.
4. Critérios de classificação do ACR/EULAR 2010 para o diagnóstico da Artrite Reumatóide.
5. Idade superior a 18 anos.
6. O doente deve ser capaz de dar o seu consentimento informado.
7. Ter disponibilidade e aceitar cumprir as visitas planeadas, planos de tratamento e exames laboratoriais e outros procedimentos do estudo. |
|
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 12 months after stopping study treatment.
3. History of or current primary inflammatory joint disease, or primary rheumatological autoimmune disease other than RA (if secondary to RA, then the patient is still eligible).
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, whichever is the longer).
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 active 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 including(e.g. patients on anti-coagulants (oral anti-platelet agents are permitted)).
24. Patients currently recruited to other clinical trial(s) involving an investigational medicinal product (except any observational follow-up periods not involving an IMP).trials.
25. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
|
1. Mulheres grávidas ou em aleitamento.
2. Mulheres em idade fértil, ou homens cujas parceiras estejam em idade fértil, que não estejam dispostos a utilizar métodos contraceptivos eficazes durante o estudo e pelo menos até 12 meses após a interrupção do tratamento.
3. História prévia ou atual, de doença reumatológica inflamatória articular ou autoimune reumatológica primária que não AR (se secundária AR, então o doente ainda é elegível )
4. Exposição anterior a Rituximab ou Tocilizumab para o tratamento da AR.
5. Tratamento com qualquer medicamento experimental ≤ 4 semanas antes da visita de “baseline” ou < 5 semi-vidas do medicamento experimental, qual deles seja o mais longo
6. Corticosteróides intra-articulares ou parentéricos ≤ 4 semanas antes da visita da biópsia (V2)
7. Prednisolona oral mais do que 10 mg dia ou equivalente inferior ou igual a 4 semanas antes da visita de biópsia (V2)
8. Infeção ativa.
9. Artrite séptica de uma articulação não intervencionada nos últimos 12 meses.
10. Sépsis de uma articulação prostésica nos últimos 12 meses ou indefinidamente se a articulação permanecer in situ.
11. HIV ou hepatite B/C activa conhecida. O teste de screening para Hepatite B deve ser efectuado até ou aos 3 meses antes da visita de screening.
12. TB latente, exceto se o doente tiver completado profilaxia antibiótica adequada.
13. Doença oncológica (exceto carcinoma de células basais) nos últimos 10 anos.
14. Insuficiência cardíaca congestiva classe 3 ou 4 pela NYHA.
15. Doença desmielinizante.
16. Alergia ao látex ou a quaisquer excipientes do Rituximab ou Tocilizumab
17. Qualquer outra contraindicação aos medicamentos experimentais conforme descrito nos RCM, incluindo diminuição dos níveis de IgG de acordo com critério clinico
18. Ter recebido uma vacina viva <4 semanas antes da primeira infusão.
19. Cirurgia major nos 3 meses antes da primeira infusão.
20. Presença de um órgão transplantado (com exceção de transplante de córnea >3 meses antes da visita de “screening”).
21. Abuso de substâncias (droga ou álcool) conhecido.
22. Baixa tolerância a punção venosa ou sem acesso venoso adequado para colheitas de sangue necessárias durante o estudo.
23. Doentes incapazes de tolerar uma biopsia sinovial ou em que esta seja contraindicada incluindo doentes com tratamento anticoagulante ( anticoagulantes orais são permitidos).
24. Doentes actualmente recrutados para outros ensaios clínicos envolvendo um medicamento experimental (excepto se observacional no período de follow up não envolvendo um IMP).
25. Outras condições médicas ou psiquiátricas severas agudas ou crónicas, ou alterações laboratoriais que impliquem, na opinião do investigador, um excessivo risco associado à participação no estudo ou à administração da medicação, ou que, na opinião do investigador, torne o doente inadequado para entrar neste estudo.
|
|
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’.
|
|
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. |
|
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 SF-36 score between baseline and 16, 48 and 96
weeks
10. Mean % change in clinical disease activity index score (CDAI) between baseline and 16, 48 and 96 weeks10.
11. Mean change in HAQ score between baseline and 16, 48 and 96 weeks
12. Change in Fatigue score between baseline and 16, 48 and 96 weeks
13. 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
14. Mean change in erosive score by the van der Heijde/Sharp scoring
system at baseline and week 24.
15. Reduction in US 2D grey scale and power Doppler signal at baseline,
16 and 48 weeks.
16. Mean change in synovial immune cell infiltrate determined
immunohistologically (C20, CD68, CD138, CD3) between baseline, 16
and 48 weeks
17. Mean change in synovial gene expression between baseline, 16
weeks and 48 weeks
Exploratory endpoint:
The association between synovial histology and ultrasound measures of
inflammation, and drug response rates, disease outcome and disability.
|
|
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. |
|
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 | No |
E.8.1.3 | Single blind | Yes |
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 | 20 |
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
|
The end of the study (data collection period) will be triggered when
the last recruited patient completes the treatment phase of the trial at
48 weeks + 30 days (post-treatment Safety Follow-up Visit/ phone
call) (Last Patient Last Visit LPLV).
|
|
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 |