Title: Rheumatoid Arthritis Prevention: catalysing PlatfORm Trial delivery (RAPPORT).
Funder: Medical Research Council

Abstract: Problem and Potential Rheumatoid arthritis (RA) is a common long-term condition in which the immune system causes damage to the joints, causing pain, swelling, and reduced wellbeing. Treatment is not always successful, and drugs used can cause side effects. Recent advances in our understanding of the biological processes that lead to RA have helped us understand that some people without the condition are nonetheless at increased risk of developing it in the future compared with the general population. They often have detectable abnormalities in their immune systems, and sometimes suffer with very significant pain and fatigue symptoms. Doctors have yet to understand how best to help them, but strongly suspect treatments could not only relieve their symptoms but also prevent them from going on to develop RA itself. Confirming this could have major benefits for individuals and society alike. Challenges of Prevention Studies in RA A few trials of medicines have been attempted in people at risk of RA who volunteered to receive either an active drug or a “dummy” version – without knowing which – for a limited period of time to find out if the drug delayed or prevented RA. Some preliminary results are encouraging but, partly because people at risk of RA do not attend clinics often, it has proved difficult to recruit the number of volunteers needed. Another complexity is that people’s risk of developing RA varies. Some can be said to have a relatively low risk over three years (i.e. less than 10%) whilst others’ is 80% or more. People at “high” risk may, if properly informed, be more willing than those at “low risk” to participate in studies trying out new treatments where there might be side effects – whereas “low risk” people might prefer to try a lifestyle change (such as changing their diet). Taking all this into account, there is a need for the research community and the public to come together to devise a coordinated approach to designing trials of prevention treatments. Proposed Solution In a 12-month project we will convene a team of rheumatologists, specialists in trial design and members of the public with experience of living at increased risk of RA. Together we will devise a single, collaborative “platform trial,” led from Newcastle but including colleagues from around the UK and Europe. A platform trial is one in which the effectiveness of multiple different treatments can be tested in a large group of appropriately selected participants according to agreed criteria. People at risk of RA will first be enrolled into a Europe-wide Registry to receive the best possible care and, depending on their calculated risk of RA progression (“high,” “medium,” “low”), will then be offered participation in pre-defined “arms” of the study. People in the “low risk” arm may be offered a lifestyle intervention, whereas those in the “high risk” arm may be offered a new medicine. By applying carefully controlled inclusion criteria for each “arm” and using agreed measures of effectiveness across the entire platform, it will be possible to test treatments simultaneously and efficiently to generate reliable results that can quickly be translated into new treatment guidelines for doctors looking after at-risk people. By the end of our project we plan to submit a major funding application to implement our platform trial across numerous European hospitals, bringing about a step-change in the management of RA that recognises prevention is better than cure.

Lay abstract: Our ambition is to deliver a pan-European precision medicine platform for preventative interventions in people at risk of rheumatoid arthritis (RA) – a disease of immune dysregulation in which destructive joint inflammation impairs quality of life. Current management aimed at long-term suppression of inflammation incurs unwanted effects and sustained financial cost. However, ever-advancing understanding of RA pathogenesis, during which symptoms may accompany latent autoimmunity in people at risk of the condition – together with emergent biomarkers of relevance for quantifying that risk and an array of targeted therapies – all suggest disease prevention is now within reach. Isolated trials of time-limited interventions have addressed this possibility and shown promise, but progress is hampered by recruitment challenges and inconsistent enrolment criteria. A coordinated, multicentre strategy to deliver interventional trials efficiently and responsively in suitably characterised populations of at-risk volunteers therefore remains a major unmet need. Leveraging a recently-established Europe-wide registry of people at risk of RA (European Risk RA Registry) together the UK NIHR Musculoskeletal Translational Research Collaboration (TRC), and building on an existing international network of clinician scientists in the field (RT-Cure and NORMALISE Consortia), our aim is to bring about a step-change in progress towards RA prevention by launching a platform trial whose sequential readouts accelerate new knowledge and directly inform precision medicine guidelines for the clinic. During a 12-month Accelerator Project we will first convene an international At Risk RA Precision Platform Trial Management Group (TMG) with representation from expert UK/EU units, individuals with experience of living at risk of RA and the Risk RA Registry to plan coordinated participant identification, enrolment and follow-up that builds on existing infrastructure. Having refined and achieved consensus on optimal clinical and immunological biomarkers (including cut-offs and implementation strategies) for participant stratification in a precision medicine platform, we will next design and establish a Master Protocol compatible with the range of healthcare infrastructures of countries in which it is to be deployed. Recognising challenges to delivery, this will be informed by systematic literature review and expert sponsorship, information governance and contracting teams at Newcastle Hospitals NHS Foundation Trust (NuTH). In parallel we will engage existing industry/academic partners to finalise initiator interventional arms and feasibility, supported by robust power calculations based on real-life data. Further supported by local and international PPI/E groups, our collaboration with NuTH and Newcastle Clinical Trials Unit (NCTU) paves the way for a UK-led funding application to launch our international precision medicine platform study in April 2024. Successful delivery will herald a coordinated strategy to prevent RA and, by extension, other immune-mediated inflammatory diseases (IMIDs).

Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM