Rheumatoid Arthritis MedDRA version: 20.0 Level: LLT Classification code 10003268 Term: Arthritis rheumatoid System Organ Class: 100000004859
Conditions
Interventions
Trade Name: MabThera
Product Name: MabThera
Pharmaceutical Form: Concentrate for solution for infusion
Trade Name: RoActemra
Product Name: RoActemra
Pharmaceutical Form: Concentrate for solution for
Sponsors
Joint Research & Development Office (Barts and The London School of Medicine & Dentistry)
Eligibility
Sex/Gender
All
Inclusion criteria
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. 18 years of age or over 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. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 0 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
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 rheumatological inflammatory joint disease or primary 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 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 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). 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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. ;Secondary Objective: 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? ;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 his | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Patients deemed treatment failures at 16 weeks, will be switched to the other therapeutic option. Such patients will be considered a new patient starting at week 0 with treatment response assessed again at 16 weeks for primary response. Treatment difference before and after switch will be compared in B cell poor and B cell rich. 2. For the B-cell rich synovial pathotypes, we aim to show non-inferiority of Rituxumab compared to Tocilizumab. The same analysis as for the primary endpoint will be repeated. 3. Area under the curve (AUC) of mean improvement in DAS28 over time between 0 and 16 weeks and between 0 and 48 weeks 4. Percentage of patients with low disease activity (DAS28 < 3.2) at 16, 24, 36, 48, 96 weeks 5. Percentage of patients in remission (DAS28 < 2.6) at 16 and 48 weeks 6. Percentage of patients with a low clinical disease activity index score (CDAI) at 16, 48 and 96 weeks 7. Mean % change in DAS28 between baseline and 16, 48 and 96 weeks 8. Mean % change in SF-36 score 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 baseline and week 24. 14. Reduction in US 2D grey scale and power Doppler signal at baseline, 16 and 48 weeks. 15. Mean change in synovial immune cell infiltrate determined immunohistologically (C20, CD68, CD138, CD3) between baseline, 16 and 48 weeks 16. Mean change in synovial gene expression between baseline, 16 weeks and 48 weeks 17. EULAR response based on DAS28 (good and moderate responder/non-responders) Exploratory endpoint: | — |
Countries
Belgium, Italy, Netherlands, Portugal, Spain, United Kingdom
Outcome results
None listed