Title: 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)
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: In this study we will compare three types of drugs for people with an eye disease that often leads to poor vision. The eye disease is called central retinal vein occlusion, which leads to excess fluid at the back of the eye, called macula oedema. The back of the eye is called the retina, and is the light sensing tissue that acts like the film in a camera. The retina has two key parts. The first is the peripheral retina which gives us night and side vision and the second is the very small central macula which gives us fine distance i.e. reading a car number plate and near vision i.e. reading a book. A blood supply brings oxygen and nutrients to the retina. Blood drains from the retina into small veins which join to form the central retinal vein through which blood passes out of the eye. Unfortunately the central retinal vein can block, preventing blood from leaving the eye and resulting in a build up of back pressure within the retinal veins. The resultant leakage of clear fluid i.e. plasma out of the congested veins into the macula results in macula oedema [MO due to CRVO]. Around seven thousand patients every year in England and Wales are affected by this condition. The cause is unknown in the majority of cases, but likely factors include high blood pressure, diabetes and glaucoma. Just five years ago, no treatment was available for this problem. However recently a drug, ranibizumab, that works by tightening blood vessels to prevent them leaking reduces the fluid at the macula and improves vision. The treatment involves an injection into the eye every four weeks for one to two years. The injections improve vision in about half of the people who receive them with few side effects although they are very expensive. Aflibercept, another drug similar to ranibizumab may last longer in the eye after injection so that fewer of them are needed. It improved vision in 60% of patients with MO due to CRVO. It has just been recommended for this condition in the UK by NICE and costs a similar amount as ranibizumab, although if fewer injections are required it may be good value for money. Finally a third drug, bevacizumab, again similar to ranibizumab, is not licensed for use in the eye, but is commonly used ‘off label’ ie. a doctor may give it to a patient if he or she believes it will work and is safe. It has not been studied extensively in MO due to CRVO but has been shown to be as effective as ranibizumab for another eye condition called wet age related macular degeneration. Bevacizumab is significantly cheaper than the other two drugs but it has not been recommended for use in the NHS because there is not enough data to judge whether it works well enough and is safe. Providing it is shown to be as good as ranibizumab with no more side effects, its use in MO due to CRVO would result in very significant savings to the NHS. This study will determine whether bevacizumab and aflibercept work as well and are as safe as ranibizumab in improving vision for people affected with this condition. It will also determine whether aflibercept can be given less frequently than ranibizumab and whether therefore either it or bevacizumab would result in a significant cost saving if used in the NHS. This trial will enrol 459 patients into three groups and give each group either ranibizumab, aflibercept or bevacizumab for two years. The trial will take place in the Eye Department of approximately 40 NHS hospitals in the UK. There are six experienced Ophthalmologists overseeing the study and a very experienced Clinical Trials team, i.e. a group of scientists who specialise in running clinical trials, who will look after all aspects of the study from start to finish.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: EYE