Ultrasound Guided Synovial Biopsy to determine treatment response to Rituxumab versus Tocilizumab
| ISRCTN | ISRCTN97443826 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN97443826 |
| EudraCT/CTIS number | 2012-002535-28 |
| Secondary identifying numbers | 14524 |
- Submission date
- 22/08/2013
- Registration date
- 22/08/2013
- Last edited
- 25/01/2021
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Musculoskeletal Diseases
Plain English Summary
Background and study aims
Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis and the diagnosis can have devastating consequences for those affected both medically, with severe joint pain, fatigue and a shortened life span, and socially with a diagnosis frequently resulting in unemployment, depression and social isolation. Although new types of treatment termed biological therapies have revolutionized the outlook for patients with RA, approximately only 30% of patients respond completely to these treatments, with a further 30% responding partially and 40% having no response. At present guidance from the UK government body NIHCE (National Institute for Health and Clinical Excellence) states that all RA patients should be treated initially with a type of biologic drug called tumour necrosis factor inhibitors (TNFi) and when/if patients fail on these drugs either due to lack of effect or side effects they should be switched over to a different biologic medication called rituximab. Whether rituximab is the correct choice of drug at this stage is presently unknown, indeed there are a number of different biologic drugs, all licensed to treat RA, which could be used at this stage instead of rituximab, including a medication called tocilizumab. Again neither rituximab nor tocilizumab work for all patients who have failed treatment with TNFi and at present it is impossible to predict which patients will respond to which drug. Such a situation is very frustrating for both doctors and patients as cycling through ineffective drugs can leave patients with months or years of suffering, biologic therapies can have serious side effects and furthermore they are very expensive treatments, costing upwards of approximately £8,000 per year. The main aim of the study is to find out whether the patterns and absence/presence of B-cells within the joint can predict the response, resistance and the likelihood of reversion in people who receive Rituximab versus those who receive another drug, Tocilizumab. The ultimate aim is to provide a tailored approach to treatment decisions in patients at this stage of their disease, in order to maximise their potential to respond to therapy.
Who can participate?
Individuals who are over 18 years old, have rheumatoid arthritis and have failed other drug therapies (DMARDS or anti-TNF) can take part in this study.
What does the study involve?
Willing indiciduals will be invited for a screening visit. If they are entered into the study, they will then undergo an ultrasound-guided biopsy procedure. A needle is placed into the joints under ultrasound guidance in a germ-free environment and a number of samples are taken form the lining of the joint. These samples are then taken to the laboratory and used for the research purposes. Local anaesthetic is used to numb the skin and joint so as to minimise any discomfort. The participants are then randomly allocated (this is a process where a computer randomly allocates an individual to a treatment; the doctors do not decide) to receive Rituximab or Tocilizumab. Both of these drugs are already licensed and widely used to treat RA. Following treatment, participants are followed up monthly in order to assess response to treatment. They will have x-rays and ultrasound tests taken at certain time points during the study. At 16 weeks, participants will be invited to have a second biopsy, at which point patients will be switched to the other treatment if they have not responded to the first allocated treatment; i.e. patients who received Rituximab will receive Tocilizumab and vice-versa.
What are the possible benefits and risks of participating?
There are no specific advantages to you as the patient, however future patients may benefit from the research by allowing a more tailored approach to their treatment. Blood samples are obtained by inserting a needle into a vein and can cause discomfort and may result in bruising, clotting, or rarely, infection. Both discomfort and bruising should disappear in a few days. The synovial biopsy is a well-tolerated procedure. The majority of patients have no adverse reaction to the procedure but there are a number of possible complications such as infection of the joint or skin, bleeding, pain and rarely nerve or tendon damage (less than 1in 10,000). The drugs used in this study are the same medications that would be prescribed on the NHS for treatment of RA. However, as with any medication, there are always associated risks and patients should discuss these risks with their study doctor.
Where is the study run from?
The study is already underway at Queen Mary University of London / Barts Health Trust and will run in other sites in the UK, Belgium, Italy, Portugal, and Spain.
When is the study starting and how long is it expected to run for?
December 2012 to July 2019
Who is funding the study?
The National Institute for Health Research (NIHR), UK.
Who is the main contact?
1. Chief Investigator: Professor Costantino Pitzalis
c.pitzalis@qmul.ac.uk
+44 (0)20 7882 8191 (PA: 8192)
2. Trial Manager: Joanna Peel
emrclinicaltrials@qmul.ac.uk
+44 (0)20 7882 3497
Contact information
Scientific
EMR Clinical Trials Manager
Centre for Experimental Medicine and Rheumatology
2nd Floor, John Vane Science Centre
William Harvey Research Institute
Barts and the London School of Medicine and Dentistry
Charterhouse Square
London
EC1M 6BQ
United Kingdom
| Phone | +44 (0)20 7882 3497 |
|---|---|
| emrclinicaltrials@qmul.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Not specified |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | A randomised, open labelled study in anti-TNFa inadequate responders to investigate the mechanisms for response - Resistance to Rituximab versus Tocilizumab in RA (R4-RA) |
| Study acronym | R4-RA |
| Study hypothesis | Despite the advent of biological agents to treat Rheumatoid Arthritis (RA), inducing and sustaining remission is still carried out on a trial and error basis. Following DMARD and anti-TNF failure, current National Institute of Clinical Excellence (NICE) guidelines recommend the B-cell depleting agent Rituximab, followed by a switch to other biologics such as IL-6 blockade through Tocilizumab. There are few head to head trials of biologic agents and therefore limited scientific rationale behind the choices made by clinicians in the treatment of the disease. B-cells play an important role in RA both as autoantibody producing cells, antigen presenting cells and through the expression of proinflammatory cytokines. Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen expressed by B-cells, resulting in depletion in both the synovium and peripheral blood. The response, however, is varied, with only 60% reaching an ACR 20 response at 6 months. (1, 2). There is emerging evidence from the MRC funded Pathobiology of Early Arthritis Cohort initiative, led by QMUL, in which synovial biopsies have been taken from patients with early arthritis that there are at least three distinct histo-morphological subtypes. These are described as fibroblast (pauci-immune), lymphoid (B-cell rich, with or without germinal centre formation) and Myeloid (rich in monocytes but poor in B cells), which correspond to different transcriptomic signatures. With these subsets in mind, the overarching hypothesis of this study is whether a diagnostic synovial biopsy showing a B-cell rich / B- cell poor pathotype can predict response and define certain disease responsive / resistance subsets for patients stratification and help to rationalize drug choice. The purpose of this study is to test the hypothesis that the presence or absence of specific synovial and molecular signatures (B-cells and B-cell associated signatures), assessed through obtaining tissue from a synovial biopsy, will enrich for response / non-response to Rituximab, an B-cell depleting anti-CD20 monoclonal antibody. In addition, we will examine if clinical response is associated with inhibition of B cell-linked pathways within the synovium and dependent on local B-cell lineage depletion and whether the survival of auto-reactive B cells within protected synovial inches are responsible for re-population within the joint and subsequent disease resistance or relapse. The primary aim of this project is to show that in patients failing anti-TNF therapy, with a B cell poor pathotype, Rituximab is inferior to Tocilizumab therapy. For the B-cell rich pathotypes we aim to show non-inferiority of Rituximab compared to Tocilizumab. The response /resistance patterns seen in germinal centre pathotypes will constitute an exploratory component to the trial. |
| Ethics approval(s) | Approved 21/11/2012, Research Ethics Committee (REC) for Wales (Sixth Floor, Churchill House, 17 Churchill Way, Cardiff CF10 2TW; +44 (0)2920376829; corinne.scotte@wales.nhs.uk), ref: 12/WA/0307 |
| Condition | Topic: Musculoskeletal; Subtopic: Musculoskeletal (all Subtopics); Disease: Inflammatory Arthritis |
| Intervention | Rituximab/Tocilizumab: Following synovial biopsy and stratification patients will be randomized to receive Rituximab or Tocilizumab within each histolomorphological subtype group (1:1). Both of these drugs are already licensed and widely used to treat RA. Participants will be followed up 4 weekly in order to assess response to treatment.; US guided synovial biopsy, Patients who are enrolled into the trial will undergo an ultrasound-guided synovial biopsy at baseline and subsequently stratified into one of three distinct histolomorphological subtype groups: 1. B-cell poor, 2. B-cell rich or 3. Germinal Centre. Optional synovial biopsies will be undertaken at week 16, week 48 and week 96.; Follow Up Length: 24 month(s); Study Entry : Single Randomisation only |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Specified |
| Drug / device / biological / vaccine name(s) | Rituximab and Tocilizumab |
| Primary outcome measure | Improvement in Clinical disease Activity using Clinical disease activity index (CDAI) at 16 weeks; Timepoint(s): Improvement in Clinical disease Activity using the Clinical disease activity index (CDAI) at 16 week |
| Secondary outcome measures | Not provided at time of registration |
| Overall study start date | 03/12/2012 |
| Overall study end date | 10/07/2019 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 160; UK Sample Size: 160 |
| Total final enrolment | 164 |
| Participant inclusion criteria | Inclusion criteria as of 13/01/2017: 1. Patients who have failed anti-TNF therapy (inadequate responders – ir). Note; this includes patients who have failed anti-TNF therapy because of reactions. 2. Who are eligible for Rituximab therapy according UK NICE guidelines* 3. Patients should be receiving a stable dose Methotrexate for at least 4 weeks prior to 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 Rituximab 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 α (TNF-α) inhibitor therapy. Original inclusion criteria: Patients will be recruited with active RA: 1. Patients who have failed anti-TNF therapy (inadequate responders ir). 2. Who are eligible for Rituximab therapy according NICE guidelines 3. Patients should be receiving a stable dose Methotrexate for at least 4 weeks prior to screening. 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. Target Gender: Male & Female ; Lower Age Limit 18 years |
| Participant exclusion criteria | Exclusion criteria as of 13/01/2017: 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 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 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 Original exclusion criteria: 1. Patients will be excluded if they have any contraindication to Rituximab or Tocilizumab therapy. 2. Women who are pregnant or breast-feeding 3. 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. 4. History of or current inflammatory joint disease or autoimmune disease other than 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 baseline 7. Active infection 8. Septic arthritis within a native joint within the last 12 months 9. Sepsis of a prosthetic joint within 12 months or indefinitely if the joint remains in situ 10. Known HIV or hepatitis B/C infection 11. Latent TB infection unless they have completed adequate antibiotic prophylaxis 12. Malignancy (other than basal cell carcinoma) within the last 10 years 13. New York Heart Association (NYHA) grade 3 or 4 congestive cardiac failure 14. Demyelinating disease 15. Latex allergy or allergy to any excipients of Rituximab 16. Any other contra-indication to the study medications as detailed in their summaries of product characteristics 17. Receipt of live vaccine <4 weeks prior to first infusion 18. Surgery in 3 months prior to first infusion 19. Presence of a transplanted organ (with the exception of a corneal transplant >3 months prior to screening) 20. Known recent substance abuse (drug or alcohol) 21. Poor tolerability of venepuncture or lack of adequate venous access for required blood sampling during the study period. 22. Patients unable to tolerate synovial biopsy or in whom this is contraindicated (e.g. patients on anticoagulants such as warfarin or heparin). 23. 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. |
| Recruitment start date | 28/02/2013 |
| Recruitment end date | 12/12/2017 |
Locations
Countries of recruitment
- Belgium
- England
- Italy
- Portugal
- Spain
- United Kingdom
Study participating centres
2nd Floor, John Vane Science Centre
Charterhouse Square
London
EC1M 6BQ
United Kingdom
Brussels
1200
Belgium
Técnicas de Reumatología
Avenida Prof Egas Moniz
Lisbon
1649-035
Spain
Division of Internal Medicine
UZ Gasthuisberg
Skeletal Biology and Engineering Research Center Herestraat 49
Leuven
3000
Belgium
Novara
28100
Italy
Rheumatology Dpt.
Hospital Clinic
Carrer de Villarroel, 170
Barcelona
08036
Spain
Università di Cagliari
ss 554 Monserrato
Cagliari
09042
Italy
Reparti Speciali 4 piano
V.le Golgi 19
Pavia
27100
Italy
Sponsor information
University/education
Joint Research Management Office (JRMO)
Queen Mary Innovation Centre
Lower Ground Floor
5 Walden Street
London
E1 2EF
England
United Kingdom
"ROR" |
https://ror.org/026zzn846 |
|---|
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 21/01/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Stored in repository |
| Publication and dissemination plan | The results will be published in a high-impact peer-reviewed journal. Updated 18/01/2021: The results will be published in The Lancet. |
| IPD sharing plan | The anonymised raw data will be stored in a non-publically available repository called TranSMART (once the paper has been published). More information can be found here: http://www.matura.whri.qmul.ac.uk/TranSMART.php. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | results | 23/01/2021 | 25/01/2021 | Yes | No |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
25/01/2021: Publication reference and total final enrolment.
18/01/2021: The publication and dissemination plan was updated and the intention to publish date was changed from 31/07/2020 to 21/01/2021.
04/06/2020: The following changes have been made:
1. The trial participating centres "Cliniques Universitaires Saint Luc", "Centro Hospitalar Lisboa Norte, E.P.E.", "UZ/KU Leuven", "AOU Maggiore della Carità, Novara", "Hospital Clínic Provincial de Barcelona", "Azienda Ospedaliero Universitaria (AOU) di Cagliari", and "Scuola di Specializzazione in Reumatologia Università di Pavia" have been added and the trial participating centre "Clinical Trials Centre Manager" has been changed to "Queen Mary University of London".
2. The ethics approval has been updated.
29/05/2020: The following changes have been made:
1. The countries of recruitment "Belgium", "Italy", "Portugal", and "Spain" have been added.
2. The overall trial end date has been changed from 31/05/2019 to 10/07/2019.
3. The intention to publish date has been changed from 31/05/2020 to 31/07/2020.
4. The scientific contact has been updated.
5. The plain English summary has been updated to reflect the changes above.
04/02/2019: The following changes were made to the trial record:
1. The contact details were updated.
2. The target number of participants was changed from 128 to 160.
3. Publication and dissemination plan and IPD sharing statement added.
07/02/2018: The recruitment end date has been changed from 01/12/2017 to 12/12/2017.
17/01/2017: The overall trial dates have been updated from 12/02/2013 - 01/12/2016 to 03/12/2012 - 31/05/2019 and the recruitment dates have been updated from 12/02/2013 - 01/12/2016 to 28/02/2013 - 01/12/2017.
13/01/2017: The inclusion and exclusion criteria have been updated.
