Title: What is the clinical and cost-effectiveness of using a goal-directed allopurinol-based treat-to-target protocol in people with recurrent gout attacks?
Funder: Department of Health and Social Care

Abstract: Question: What is the clinical and cost effectiveness of a goal-directed allopurinol-based treat-to-target protocol in people with recurrent gout attacks?_x000D_ _x000D_ Background: Gout is a direct consequence of hyperuricemia, and there is indirect evidence that lowering serum urate to <360 µmol/L slowly dissolves the deposited urate crystals and has the potential to provide freedom from future attacks. However, gout manifests with episodes of acute arthritis in the early stages, and, there is absence of direct randomised controlled trial data that such goal-driven urate lowering treatment (ULT), with target serum urate <360 µmol/L prevents gout attacks in a cost-effective manner compared to treating when symptoms worsen. This lack of evidence results in poor gout management and has culminated in discordant recommendations from primary care and Rheumatology gout treatment guidelines. Thus, a study comparing treat-to-target serum urate vs. treat only if symptoms worsen is urgently needed._x000D_ _x000D_ Aims and objectives: The objectives of this study are to evaluate the effects of allopurinol-based treat-to-target ULT on the number of gout attacks (primary outcome),gout attack severity, serum urate, quality of life, renal function, adverse events, comorbidities, and mortality. We will also examine the cost-effectiveness, acceptability and adherence with such treatment. _x000D_ Additionally, we will assess the consent rate (primary outcome), attrition, quality of outcome data, delivery of treat-to-target ULT, and preliminary estimate of efficacy of the intervention in a 1-year internal pilot._x000D_ _x000D_ Methods:_x000D_ Study design: Multi-centre pragmatic RCT with internal pilot and post-RCT follow-up. _x000D_ Setting: Primary care _x000D_ Study duration: 80 months_x000D_ Participants: People with recurrent gout attacks (at least 1 attack in previous 12 months), older than 18 years in age. _x000D_ _x000D_ Study groups:_x000D_ Group A - allopurinol-based treat-to-target ULT_x000D_ Group B - usual GP care_x000D_ Intervention delivery: general practice nurses _x000D_ _x000D_ Randomisation: 1:1 individual randomisation stratified by region._x000D_ _x000D_ Study participation: Each participant in the study for 4 years, 2 years each in the RCT and long-term extension respectively. _x000D_ _x000D_ Timeline for delivery: Month 2-submit ethical approval; month 4-database built; month 5-sites identified and questionnaire mail-out begins; month 6-8: screen and recruit to internal pilot; month 20: 1-yr visit of last participant in internal pilot; month 20-21: review internal pilot results against feasibility criteria; month 22: questionnaire mail-out restarts; month 28: last participant recruited in study; month 52: final visit of last participant and database lock; month 56: statistical analysis complete, study report; month 68: main study results and health-economics paper published; month 76: 2-year post-RCT data collection ends; month 80: complete long-term data analysis._x000D_ _x000D_ Impact and dissemination: The results of this study will transform the management of gout in the UK and worldwide. The trial will be disseminated to research, clinical, commissioning, and patient communities. We will publish the results in peer-reviewed journals and present at scientific meetings. We will disseminate findings through publications in Pulse, newsletters to Royal College of General Practitioners, British Society for Rheumatology, British Geriatrics Society. We will engage with NICE, NHS England, Clinical Commissioning Groups to bring about a new NICE guideline for management of gout.

Lay abstract: Gout is a common form of arthritis that affects one in forty people in the UK. It results from high level of uric acid in the body which forms urate crystals inside the joints. From time to time, these crystals shake loose from their deposits and cause severe joint pain and swelling. These flares usually last for one to two weeks. Flares are treated with anti-inflammatory tablets such as ibuprofen. However, anti-inflammatory tablets do not dissolve the urate crystals. Other tablets such as allopurinol can lower the uric acid level to below a target level, and slowly dissolve the crystals. These are safe treatments that have been used for many years. However, whether their long-term use reduces the number of gout flares is unknown._x000D_ _x000D_ We will carry out a study to find out if the long-term use of tablets such as allopurinol reduces the number of gout flares and improves wellbeing. We will also find out if this treatment is cost-effective for the NHS._x000D_ _x000D_ Study process: General practitioners (GPs) will identify people who have gout and send them information and an invitation to join the study. People interested in taking part in the study will be asked to contact the research team._x000D_ _x000D_ We need 466 adults with gout to take part in this study, and each person will be in the study for four years._x000D_ _x000D_ People taking part in the study will receive either of the following two treatments by random allocation for the first two years:_x000D_ _x000D_ Group-A: allopurinol with gradual dose increase aimed at reducing blood uric acid to below target level, or _x000D_ _x000D_ Group-B: usual gout care from the GP including the option to start allopurinol depending on symptoms._x000D_ _x000D_ People in Group-A will need an average of three to four visits in order to adjust the dose of allopurinol to reduce uric acid level sufficiently to allow the urate crystals to dissolve. _x000D_ _x000D_ In addition to the visits to increase the dose of allopurinol in Group-A, there will be three other visits for people taking part in the study. These visits will occur at study start, and annually for two years. Information on health and wellbeing, and medication use will be collected. The blood pressure, height, weight, kidney function and uric acid level will be measured at these visits. People taking part in the study will be requested to record details of each gout flare they experience while participating in the study. _x000D_ _x000D_ The main outcome of the study is the number and severity of gout flares within the first two years of treatment. This and the other information collected will be compared between the groups. The cost of treatment and overall wellbeing will be used to find out if this treatment is cost-effective for the NHS._x000D_ _x000D_ After the first two years, participants will continue taking urate lowering treatment such as allopurinol as prescribed by their GP. They will be requested to continue to provide information about gout flares for a further two years. Information about other illnesses, hospital admissions and medications prescribed will be collected from their GP. The information collected will be compared between the groups._x000D_ _x000D_ Patient and public involvement: This study was developed in partnership with people with gout. Two people with gout will be involved in managing this study as part of the research team._x000D_ _x000D_ Study impact: The results of this study will be publicised to doctors, nurses, people with gout, the general public and to the UK government. If this study shows encouraging results, we will engage with the National Institute for Health and Care Excellence (NICE) to develop a new national guideline for the management of gout. We believe that such guidelines will improve the treatment of gout in the UK and worldwide.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL