Condition category
Musculoskeletal Diseases
Date applied
22/08/2013
Date assigned
22/08/2013
Last edited
03/12/2013
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

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.

When is study starting and how long is it expected to run for?
The study commenced in February 2013 and recruitment will be over a period of 2 years.

Who is funding the study?
The National Institute for Health Research (NIHR), UK.

Who is the main contact?
Chief Investigator: Professor Costantino Pitzalis at c.pitzalis@qmul.ac.uk; Tel: 020 7882 8191 (PA: 8192)
Trial Manager: Laura White at l.white@qmul.ac.uk ; Tel: 020 7882 2111

Trial website

http://www.r4ra-nihr.whri.qmul.ac.uk/

Contact information

Type

Scientific

Primary contact

Miss Laura White

ORCID ID

Contact details

Clinical Trials Centre 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
+44 (0)20 7882 2111
l.white@qmul.ac.uk

Additional identifiers

EudraCT number

2012-002535-28

ClinicalTrials.gov number

Protocol/serial number

14524

Study information

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)

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

12/WA/0307; First MREC approval date 21/11/2012

Study design

Randomised; Interventional; Design type: Not specified

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

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

Phase

Not Specified

Drug names

Rituximab and Tocilizumab

Primary outcome measures

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 trial start date

12/02/2013

Overall trial end date

01/12/2016

Reason abandoned

Eligibility

Participant 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 type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 128; UK Sample Size: 128

Participant 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

12/02/2013

Recruitment end date

01/12/2016

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Clinical Trials Centre Manager
LONDON
EC1M 6BQ
United Kingdom

Sponsor information

Organisation

Queen Mary University of London (UK)

Sponsor details

Joint Research Management Office (JRMO)
Queen Mary Innovation Centre
Lower Ground Floor
5 Walden Street
London
E1 2EF
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

NIHR Efficacy and Mechanism Evaluation; Grant Codes: 11/100/76

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes