A multicentre double-masked randomised non-inferiority clinical trial comparing the clinical and cost-effectiveness of intravitreal ranibizumab (Lucentis), aflibercept (Eylea) and bevacizumab (Avastin) for Macular Oedema due to Central Retinal Vein Occlusion (acronym: LEAVO)

DESIGN: This application proposes a two year multicentre double masked pragmatic randomised controlled non-inferiority trial in macula oedema (MO) due to central retinal vein occlusion (CRVO). One eye only of participants will be randomized to bevacizumab (Avastin) vs aflibercept (Eylea) vs ranibizumab (Lucentis) (1:1:1). SETTING: Approximately 40 Ophthalmology centres in England and Wales with expertise in retinal disorders and a proven track record in effectiveness research. TARGET POPULATION: Adults (18+) with a clinical diagnosis of MO due to CRVO within the last 12 months confirmed by subsequent fluorescein angiographic review. HEALTH TECHNOLOGIES BEING ASSESSED: Investigational treatments: Bevacizumab (Avastin, Roche) [1.25mg / 50µl](Royal Liverpool) and Aflibercept (Eylea, Bayer) [2.0mg/50µl]. Standard care: Ranibizumab (Lucentis, Novartis) [0.5mg/50µl], all administered by intravitreal injection. PROTOCOL: All patients will be screened with BCVA, clinical exam, colour fundus photography, optical coherence tomography (OCT) and fluorescein angiography. EQ5D with ‘bolt ons’, VFQ 25 and resource use questionnaires will be completed at baseline. VA, clinical examination and OCT will be repeated at each visit and all tests and questionnaires at exit visit. Milestone visits at which key research data is collected will be fixed at baseline, weeks 12, 24, 52, 76 and 100. After mandated administration of treatment in all arms at baseline, 4, 8, and 12 weeks, further PRN intervention will be at 4 weekly intervals until week 24 and 4 to 8 weekly intervals thereafter until study exit and will be based on pre-defined MO retreatment criteria . There will be flexibility around the 4-8 weekly treatment only visits after week 24. OUTCOMES: The primary outcome will be change in ETDRS best corrected visual acuity letter score from baseline to 100 weeks: difference in means between bevacizumab versus ranibizumab arm and between the aflibercept versus ranibizumab arm. Secondary outcomes will include additional BCVA outcomes, differences in OCT central macular thickness and volume, changes from baseline in health related questionnaires, use of resources and adverse events. The central analysis of cost effectiveness will be mean incremental cost per QALY. SAMPLE SIZE: Bevacizumab and aflibercept are defined to be substantially inferior to ranibizumab if the primary outcome (mean change in ETDRS BCVA letter score) is worse by a margin of five letters (standard deviation= 14.3), [CRUISE study]. The null hypothesis, that bevacizumab and aflibercept are substantially inferior, will be rejected if the 95% confidence interval for the difference in treatment means lies wholly above the five letter inferiority margin. Assuming equal efficacy, there will be 80% power to reject the null hypothesis and declare non inferiority with 153 patients analysed per arm. Using nQuery Advisor 4.0 software, allowing for 15% missing data, 459 patients will be randomized. PROJECT TIMETABLE AND RECRUITMENT RATE: Proposed start date: 1st June 2014. Set up phase will be months 0-5, recruitment phase months 5-24, follow up phases months 8-48, analysis and reporting phase, months 49-53. UPDATE:The LEAVO study recruited its first patient in December 2014 and the last patient (n=463) was recruited on December 16th 2016. The study has 100 weeks of follow-up for each patient and last patient last visit will therefore occur in November 2018 and the primary outcome results of the study will be published in April 2019. As of 1st June 2018, of 463 patients recruited, 300 had successfully exited the trial at 100 weeks. The study therefore remains on track to complete as anticipated.