L-dopa for neovascular (wet) age-related macular degeneration (AMD)? Can it reduce the need for anti-VEGF injections?: L-dopa in wet AMD: A Randomised Controlled Trial: LAMDARCT

Research question: What is the effectiveness and cost-effectiveness of oral L-DOPA supplementation in patients being treated for wet AMD? Background: Age-related macular degeneration (AMD) of the eye typically affects people’s central vision in their 50s/60s, making everyday activities difficult. Wet AMD is characterised by invasion of new blood vessels into the macula, leading to fluid accumulation and haemorrhages/atrophy/scarring. This process is driven by overproduction of vascular endothelial growth factor (VEGF). Current treatment for wet AMD relies on intravitreal anti-VEGF injections every 4-12 weeks and may be required for years. The benefits of safely decreasing the frequency of injections will lead to a reduced burden on patients and the opportunity to reallocate health system costs. Recent evidence from cohorts of patients with Parkinson’s disease showed that L-DOPA treatment reduces the incidence of wet AMD. In addition, ingested L-DOPA (in the form of Carbidopa-L-DOPA ) seem to reduce the frequency of anti-VEGF injection. Aims and objectives: The specific objectives are to evaluate the effects of 24 months of L-DOPA in people newly diagnosed with wet AMD on: 1) Number of anti-VEGF injections 2) Distance and near visual acuity (VA) 3) Health-related and visual-related quality of life 4) Safety 5) Anatomical retinal findings indicative of disease activity and 6) Costs and cost-effectiveness. We will conduct mechanistic evaluations using additional imaging modalities and biomarkers from tears and blood. Methods: The study will be a prospective, randomised, pragmatic, multicentre, placebo-controlled clinical trial undertaken in an NHS setting. Eligible patients with newly diagnosed wet AMD will be randomised 2:1 to receive 100mg L-DOPA+25mg carbidopa or placebo twice a day (morning and evening), in addition to the standard of care antiVEGF injections. The trial duration will be 24 months. POPULATION: People newly diagnosed with wet AMD INTERVENTION: 100mg L-DOPA plus 25mg carbidopa (known as Co-careldopa) twice a day COMPARATOR: Placebo tablets also twice a day OUTCOME: Co-primary outcomes: number of antiVEGF injections required over 2 years and best corrected distance visual acuity (BCdVA) Other important outcomes will be safety, quality of life, and cost-effectiveness. SAMPLE SIZE: 360 patients. STATISTICAL ANALYSIS: A reduction in the number of injections will be compared using a t-test with secondary analysis using multiple linear regression. We will test for non-inferiority in BCdVA using ANCOVA adjusting for baseline BCdVA using a non-inferiority margin of 5 letters. HEALTH ECONOMIC EVALUATION: A within-trial cost-utility analysis will estimate the cost effectiveness of L-DOPA+carbidopa compared with placebo. An NHS and personal social services perspective will be used. Timelines for delivery: The study will last 54 months. Setting up: 9m; recruitment: 15m, site opening will be staggered, with up to 20 sites participating. The average recruitment rate/site will be 1-2 patients/month; follow-up: 24m; data analysis: 4m; report writing: 2m. Anticipated impact and dissemination: A reduced number of injections will benefit patients and the NHS. Results will be shared with professionals and researchers through publication in high impact, open access journals and presentation at conferences. Dissemination to patients (participants and charities), service providers and policy makers in the UK will be prioritised.