Rheumatoid Arthritis MedDRA version: 20.0 Level: LLT Classification code 10003268 Term: Arthritis rheumatoid System Organ Class: 100000004859
Conditions
Sponsors
Joint Research & Development Office (QMUL)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients will be recruited with active RA: 1. 2010 ACR / EULAR Rheumatoid Arthritis classification criteria for a diagnosis of RA * 2. Patient with DMARD failure eligible for anti-TNF-a therapy as per UK NICE guidelines ** 3. Patients must have a minimum of 3 swollen joints - the joint selected for biopsy and a minimum of 2 from the 28 joint count set, as assessed at biopsy visit 4. Selected joint for biopsy must be minimum grade 2 synovial thickening, as assessed at the biopsy visit 5. 18 years of age and over 6. Patients must be capable of giving informed consent and the consent must be obtained prior to any screening procedures 7. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures *The ACR/EULAR classification for a diagnosis of RA could have been at any time in the patient’s disease history; the score does not need to be 6 or more at screening. ** According to the National Institute for Health and Care Excellence (NICE) guidelines (TA 130), the TNF-a inhibitors are recommended as options for the treatment of adults who have both of the following characteristics: 1. Active RA as measured by DAS28>5.1 confirmed on at least two occasions, 1 month apart. 2. Have undergone trials of two DMARDs, including MTX (unless contraindicated). A trial of a DMARD is defined as being normally of 6 months, with 2 months at standard dose, unless significant toxicity has limited the dose or duration of treatment. 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 219 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 219
Exclusion criteria
Exclusion criteria: Patients will be excluded if they have any contraindication to Etanercept, Rituximab or Tocilizumab therapy: 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 an effective method of contraception (recommend double contraception) throughout the trial and beyond the end of trial treatment for the duration as defined in the relevant SmPC or IB; 12 months for Rituximab, at least 3 weeks for Etanercept, and at least 3 months for Tocilizumab. 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, any anti-TNF, Tocilizumab, or any biologic for 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 (e.g. patients on anti-coagulants may not be suitable). However, assessment of suitability for the biopsy procedure will be a local clinical decision. 24. Patients currently recruited to other clinical 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. 26. For patients potentially eligible for MRI any of the following conditions: Pacemakers and/or other non-removable metal objects, diagnosis of claustrophobia or a history of anxiety or claustrophobia during previous ?MRI scanning, abnormal creatinine/protein ratio at screening that precludes administration of MRI contrast ?medium (e.g. gadolinium) in accordance with local guidelines , previous allergic reactions to MRI contrast medium (e.g. gadolinium) The PI reserves the right to exclude patients
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 DMARD therapy, with a B cell poor synovial pathotype, Rituximab is inferior to Tocilizumab and Etanercept (treated together for analysis) 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? For the B-cell-rich synovial pathotypes, we aim to compare the treatment effects of Rituximab to the other two treatment options (Tocilizumab and Etanercept, treated together for analysis). Finally, we aim to examine the interaction between treatments and B-cell status (rich and poor). ;Primary end point(s): The primary end point will assess the difference in the ACR 20 response between Rituximab and other treatments (Tocilizumab and Etanercept therapy treated together for analysis) at 16 weeks from baseline in the B-cell poor pathotype sub-group. ;Timepoint(s) of evaluation of this end point: 16 weeks | — |
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 ACR20 response. 2. For the B-cell-rich synovial pathotype sub-group, we aim to compare the treatment effects of Rituximab to the other two treatment options (Tocilizumab and Etanercept, treated together for analysis) 3. To examine the interaction between treatments and B-cell status (rich and poor). ;Timepoint(s) of evaluation of this end point: 48 weeks. | — |
Countries
United Kingdom
Outcome results
None listed