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)

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.