Title: Optimal utilisation of biologic drugs in Behçet's Disease: a randomised controlled trial of infliximab vs alpha interferon, with genotyping and metabolomic profiling, towards a stratified medicines approach to treatment.
Funder: Department of Health and Social Care

Abstract: Behçet’s Disease (BD), an autoinflammatory multi system condition of unclear aetiology, can lead to blindness, stroke and death. It is very rare in the UK, causing high levels of disability and premature mortality and a phenotype that differs subtly from Mediterranean countries, where it is more prevalent. First line therapy with glucocorticoids and immunosuppressants, have limited efficacy and can cause significant comorbidity. Biologic drugs, typically infliximab (IFX) or alpha interferon (aIFN), are used when standard drugs have failed, enhancing outcomes - although neither is effective in all patients. The evidence base informing choice a biologic for BD is poor: almost all reports are non-randomised open-label series with attendant potential bias and from countries where BD is more prevalent. No prospective randomised controlled studies have directly compared IFX with aIFN in BD and no biomarkers allowing targeted therapy have been identified. In 2012 three National Centres of Excellence for BD were established to provide a clinical service for the estimated 500 patients with BD in England, creating a national cohort. The Centres hold funding for biologics when standard drugs have failed and have observed differences in responses to biologics from those reported elsewhere. This proposal brings together an international collaboration of experts in BD, medical statistics and personalised medicines from 2 countries, 6 Universities, 5 NHS Trusts with the UK BD Association, to evaluate IFX versus aIFN in BD patients in the UK and investigate the role of potential biomarkers to inform a future stratified medicines approach for therapy and further understand disease mechanisms. A pragmatic Bayesian approach has been taken to maximise the information gained from a very rare disease. The study will be a prospective randomised parallel group single masked trial of IFX versus aIFN in 100 patients with refractory active BD in 5 UK Centres, following standard of care, over 48 months. With the enthusiasm of the BD Patients Association and activity already in the UK Centres, we estimate accrual of 34 patients/yr. Assessments of efficacy will be by validated composite (Behçet’s Disease Activity Index, BDAI) and individual organ-specific instruments at 3 and 6 months. The primary outcome is BDAI score at 3 months, when non-responders will swap biologic, providing additional opportunity to determine an effect. Safety will be measured in parallel. In addition, blood will be taken for genotyping to measure the effect of SNPs around the IFNL3 gene (associated with enhanced response to aIFN in hepatitis virus infections) and urine saved to determine the metabolomics profile (associated with response to IFX in rheumatoid arthritis), further investigating the underlying mechanisms in BD. The potential of these as biomarkers for stratification of biologic therapy will be validated separately, with samples from BD patients in other countries, provided by our international collaborators. This study will generate the evidence base to inform choice of biologic therapy in BD, facilitating a stratified medicine approach, reducing major organ damage and minimising co-morbidity from excess glucocorticoid use. As this study follows the normal standard of care for BD in the UK Centres, with biologic drug funded, the costs are minimised. Indeed the total NHS support & treatment costs is calculated to provide savings of £298,920 to the NHS during its course.

Lay abstract: Behçet’s Disease (BD) is a very rare condition that affects many different organs and can cause blindness, stroke and death. The cause is not fully known. Standard therapy of steroids and oral immunosuppressants, is of limited effectiveness and often associated with unacceptable side effects. The biologic drugs infliximab (IFX) and alpha interferon (aIFN) are used with considerable success when standard drugs are not effective. However, they are very expensive (IFX costs £20,000/yr and aIFN £4,000/yr), are not always effective and have a poor evidence base. Trials informing their use have been uncontrolled, often retrospective series with high potential for bias, performed in countries where BD is more prevalent such as Turkey, and where there are subtly different manifestations of the disease and response to therapy than the UK. No trials have directly compared IFX with aIFN and no tests are able to predict clinical response. Choice of biologic is therefore based predominantly on physician preference and might represent a considerable waste of NHS resources. In 2012 three National Centres of Excellence for BD were established to deliver care for the approximate 500 patients with this condition and fund provision of biologic drugs when standard drugs had proven ineffective. This study brings together experts in BD, medical statistics, trial design and personalised medicines from UK and France with the UK BD Patients’ Association, in a new collaboration, uniquely able to address this. A pragmatically designed randomised prospective clinical trial will follow the UK BD standard of care pathway and compare IFX versus aIFN in a head to head study for six months, determining effectiveness by validated BD composite activity score and evaluation of individual effected organs undertaken by consultants who are masked to therapy. Samples of blood will also be taken for genotyping, to measure differences in the IFNL3 gene and urine, to measure the metabolomics profile. These biomarkers have been shown, in hepatitis infection and rheumatoid arthritis, to correlate with response to aIFN and IFX respectively. Positive results from biomarkers in this study will be, separately, tested further for validity on samples from BD patients from other countries, provided by our international collaborators. The information from this trial will provide an enhanced and robust evidence base, from which a more rational choice of biologic for BD can be made, facilitating a personalised medicines approach for the future and providing new information on the inflammatory mechanisms underlying the disease. Optimising high cost drug therapy will also deliver better value for money to the NHS. Funding is required for clinical trials management, coordination, database preparation, statistical advice/analysis and clinician time in recruitment, ensuring appropriate governance standards, timely recruitment and effective analysis and dissemination of results. The patients’ association requires modest funding for advertisement and non-clinical support of patients in the trial. However, the biologic drugs are funded by the Behçet’s Centres, reducing significantly the cost of the trial. This study will provide savings to the NHS of £298,920 during its 48 month course.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;INFLAMMATORY AND IMMUNE SYSTEM