Title: A randomised placebo-controlled clinical trial of fenofibrate to prevent progression of non-proliferative retinopathy in diabetes (LENS: Lowering Events in Non-proliferative retinopathy in Scotland)
Funder: Department of Health and Social Care

Abstract: Background: Diabetic retinopathy (DR) is one of the commonest causes of impaired vision and blindness in people aged 30-69 yet few treatments can slow its progression. Design: Double-blinded placebo-controlled randomised trial of fenofibrate to slow progression from observable to clinically significant DR, or the need for intervention due to DR (namely retinal laser, vitrectomy or intra-vitreal injection); randomisation will follow an active two month run-in period. Literature review: Two major cardiovascular trials (FIELD and ACCORD-Lipid) which included DR as a tertiary outcome suggested that fenofibrate may slow DR progression by 30-40%. Major UK and international guidelines don't yet advocate its use however. Target population: Patients with type 1 or type 2 diabetes plus observable DR will be recruited from up to 11 Scottish health boards via the Scottish Diabetes Research Network (SDRN) patient register, the SHARE register and the Scottish Diabetic Retinopathy Screening [DRS] service which provides 6-24 monthly imaging to 250,000 patients. Inclusion/exclusion criteria: Major inclusion criteria are T1DM or T2DM; observable DR (defined here in NHS Scotland DRS grading as R2 or M1 in one/both eyes; or R1 in both eyes); and age over 18. Major exclusion criteria are gallbladder disease, pancreatitis, transaminases above 2X the upper limit of normal, eGFR below 40mL/min/m2, pregnancy, breastfeeding or previous intolerance to fibrates. Health Technology assessment: The addition of a generically available lipid-modifying medicine, fenofibrate, to standard diabetes care; no alternative therapies exist. All study drug will be mailed out by registered post. Outcomes: Pre-specified outcomes (DR grading, visual acuity, eye procedures, urine albumin: creatinine ratio, CVD events, amputation) will be collected from centrally-held electronic records using various sources (Scottish Care Information – Diabetes data; Information Service Division Scotland; Scottish DRS service) and also from questionnaires. Apart from face-to-face screening and a 2 month randomisation visit, all contact will be by phone/email/post thereafter. Health economic analysis: Data for all relevant events (in- and out-patient visits, tests and interventions for eye, renal and cardiovascular outcomes) will be valued using national unit prices. The cost difference between treatment groups will be estimated at 5 years using generalised linear regression. Incremental cost per QALY gained will be estimated for fenofibrate versus standard care. Sample size: We will randomise 1,060 patients with observable DR (over 25,000 such patients live in Scotland). The primary outcome is progression to clinically significant DR (grades 'R3', 'R4' or 'M2' in NHS Scotland DRS grading) or the need for intervention due to DR (by laser treatment, vitrectomy or intra-vitreal injection) over an intended median follow-up of 4 years. The progression rate for our selected population is 29% over 4 years, based on NHS Scotland DRS data. 1,060 participants will yield 222 events (allowing for 15% drop-out), providing 85% power at alpha 0.05 to detect a 33% reduction in the primary outcome. Timetables: The full project is expected to last 6 years. After 6 month set-up, research sites will be activated to open over months 6-18. We will use overall interim recruitment targets and health board targets to demonstrate feasibility and maintain recruitment. Average follow up will be 4 years. Patient follow up will end at 66 months, allowing 6 months of statistical and health economic analyses.

Lay abstract: A major complication of diabetes is retinopathy, when diabetes affects the small blood vessels at the back of the eye. Diabetic retinopathy is usually unnoticed early on, but it often progresses to more severe eye disease which can impair vision and even cause blindness. While eye specialists can offer treatments like laser treatment, eye injections and surgery, these treatments are only useful when retinopathy is advanced. These treatments are expensive and they often do not restore or improve sight. Strict blood sugar control can modestly slow the progression of retinopathy, but it is difficult to achieve for many patients and retinopathy often progresses even in those who achieve good blood sugar control. Therefore, simple approaches to reduce the development and progression of retinopathy are needed. Fenofibrate is a safe and well tolerated medicine that reduces cholesterol and has been shown to modestly reduce the risk of patients with diabetes having a heart attack. It is seldom used because other medicines like statins are better at preventing heart attacks, though it can be safely used with other medicines. Two cardiovascular trials suggested that fenofibrate may reduce the progression of diabetic retinopathy by over a third. Doctors are very interested in the potential use of fenofibrate to treat those with diabetic retinopathy and they are keen to see further evidence from a trial specifically designed to look at the drug’s effect on diabetic retinopathy. In Scotland, all 250,000 patients with diabetes are invited to attend retinal screening appointments once or twice a year. Photographs are taken allowing NHS professionals to identify who needs to be seen at specialist clinics for expert treatment. These photographs are taken at sites across Scotland by the Diabetic Retinopathy Screening (DRS) service. For the majority in whom retinal photographs show no eye disease or mild to moderate eye disease, a further DRS appointment is arranged in 6-24 months. In those who have developed severe eye disease, referrals are automatically made to specialist NHS eye clinics by DRS. Scotland is a world leader for electronic health data collection, especially in diabetes. Information regarding blood and urine results, hospitalisations, outpatient clinic attendances, retinal photography screening results and other information can be obtained for all patients with diabetes who have consented to participate in research studies. This provides the ideal environment to study diabetes treatments in an efficient and cost-effective way. We have designed a trial, called LENS, to test how effective fenofibrate is at slowing retinopathy's progression. About 1,000 patients with observable diabetic retinopathy will be studied. Half of the participants will be treated with fenofibrate and half with an identical dummy tablet but no participants will know which treatment they are on. The only times that participants will need to attend a research unit is at the start (for a screening visit) and again after 2 months. All study medication will be sent to participants by registered post. Information about the medicine’s effects on eye disease and other key outcomes will be collected electronically from the excellent data sources mentioned above and also from six monthly questionnaires. Participants will take part for an average of 4 years each. We will recruit patients directly from the Scottish Diabetes Research Network and SHARE registers, and the NHS Scotland's retinal screening program will also assist by providing information about the trial to patients who may be suitable to take part.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: EYE;METABOLIC AND ENDOCRINE