Treatment of severe Diabetic macular oedema with Anti-vascular endothelial growth factor (anti-VEGF) monotherapy versus treatment with Anti-VEGF followed by subthreshold Micropulse lasEr when the thickness of the central retina goes below 400 microns (DAME): a pragmatic randomised equivalence trial

Research question: In patients who were treated with anti-vascular endothelial growth factor (anti-VEGF) therapy after presenting with diabetic macular oedema (DMO) with central retinal thickness (CRT) of 400µm or more, is the application of subthreshold micropulse laser (SML) after their CRT goes below 400µm equivalent to continuing with anti-VEGF monotherapy? Background: DMO causes sight loss in people living with diabetes. Currently, severe DMO (with CRT of 400µm or more, measured using optical coherence tomography) is treated with anti-VEGFs for months or years until it clears. In many, DMO returns when anti-VEGFs are stopped requiring their re-initiation. Anti-VEGFs are expensive, require frequent treatment/follow-up and have risks including endophthalmitis, which could cause blindness. Injections are associated with patient anxiety, and fear of injections is one of the most common reasons for discontinuation of anti-VEGFs. SML has been shown to be clinically effective and cost-effective to treat DMO with CRT<400µm with no side effects(1-3). Aim: To determine clinical and cost-effectiveness, safety, patient experience and acceptability of combined anti-VEGF+SML, with the SML applied after CRT goes below 400µm following anti-VEGFs, compared with anti-VEGF monotherapy, for patients who presented with severe DMO. Methods, Design: Pragmatic, allocation-concealed, single-masked (outcome assessors) multicentre, randomised, equivalence trial. Setting: At least 20 sites across UK. Target population: Adults with type 1 or 2 diabetes and DMO, of any age, gender, ethnicity, religion, sexual orientation, or socioeconomic status who presented with CRT of 400µm or more and in whom treatment with an anti-VEGF is initiated. Health technology assessed: Anti-VEGF+SML, with SML treatment commenced any time during the first year of anti-VEGF treatment but only once CRT is <400µm. Comparator (control): Anti-VEGF monotherapy (current standard care). Primary outcome: Change in BCVA in the study eye from randomisation to month 24 (equivalence margin +/- 5 ETDRS letters). Secondary outcomes: At 24 months: CRT in study eye; health- and vision-related quality of life; health and social care service use; non-health care costs; adverse events; number of treatments used (anti-VEGF injections, SML sessions); number/proportion of people receiving “rescue” treatment; number of rescue treatments received; number/proportion of people discontinuing treatment (with reasons), losing (with reasons) or gaining >5 or more, >10 or more and >15 ETDRS or more letters, with <300µm CRT, and with no DMO; patient experience and acceptability. Sample size: DAME is powered to demonstrate equivalence of treatment strategies for the primary outcome. Based on two one-sided t-tests at the 2.5% significance level, a 10-letter standard deviation (SD) and an equivalence margin of +/- 5 ETDRS letters (a difference of 5 or fewer letters is not considered clinically meaningful [4-7]), 210 participants would be required to be 90% sure the 95% confidence interval will exclude a difference in means of more than 5 ETDRS letters. Allowing for 20% dropout, we will require 264 participants. Timelines: Set-up: 6 months (m); recruitment:18m; follow-up:24m; analysis/write-up:6m. Anticipated impact and dissemination: DAME could change the way in which DMO is treated and benefit patients and the NHS. Results will be widely disseminated with the help of the patient and public involvement (PPI) Group.