Title: Early detection of neovascular age-related macular degeneration
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Design: Multi-centre prospective cohort diagnostic accuracy study with 3 year follow-up Setting: Secondary care, ophthalmology outpatient departments Target population: Patients with newly diagnosed neovascular age related macular degeneration (nAMD) in one eye and an unaffected second eye (study eye) Inclusion criteria: Newly diagnosed (within last 3 months) with nAMD in one eye and an unaffected second eye confirmed by fundus fluorescein angiogram (FFA); about to commence or recently commenced anti VEGF therapy in the first eye; age 50-95. Exclusion criteria: patients with a history of nAMD in both eyes; nAMD detected in the study eye at baseline screening visit; presenting visual acuity worse than 73 letters in the study eye and/or retinal pathology which can confound subsequent assessments (eg. diabetic retinopathy, macular hole); not undergoing regular monitoring in standard of care; patients who cannot give informed consent; unable to undergo a FFA test Health technologies being assessed: The diagnostic technologies (tests) to be assessed are: (1) an evaluation of the fundus (a view of the retina through the dilated pupil using biomicroscopy or photography); (2) subjective change in vision in the unaffected eye, determined by questioning the patient; (3) visual acuity – measured using a sight chart; (4) Amsler test - a simple subjective test consisting of straight lines on a piece of paper that may appear distorted in patients with retinal disease; (5) optical coherence tomography (OCT) - an imaging technique providing high resolution, cross-sectional, imaging of the retina. All of the five comparator tests are routinely used in NHS outpatient clinics. Patients will be tested using all these technologies on their study eye at each treatment and/or monitoring visit for the affected eye. A positive test on one or more technologies will trigger an additional reference standard test (FFA) to confirm or rule out the presence of nAMD. The FFA scan involves injecting a dye into the circulation and taking photos of the back of the eye to look for signs of damage. In addition, FFA will be carried out in all patients in the study at baseline, 18 and 36 months. Primary outcome: The primary diagnostic performance outcomes will be the sensitivity and specificity of comparator tests on detection of nAMD in the study eye in a monitoring setting. The primary economic outcome will be the incremental costs (to the health service) per quality adjusted life year (QALY) gained. Secondary outcomes: Secondary diagnostic performance outcomes will include diagnostic odds ratio, likelihood ratio, proportion of indeterminate tests. The performance of combinations of tests will be evaluated. Other outcomes: time gain of early detection; visual acuity at diagnosis, the development of a risk calculator based upon baseline characteristics, establishment of a well-characterised cohort of clinical data for future research and biobank. Developing an optimal monitoring regime: A decision analytic model will be developed to determine the optimal monitoring strategy for patients with nAMD in one eye, in terms of clinical and cost effectiveness. Alternative monitoring strategies will be superimposed on top of a natural history model of disease progression, and risk of developing nAMD, using the sensitivity/specificity estimates obtained for alternative tests used within alternative monitoring strategies (obtained from analysis of the prospective cohort). To inform model parameters we will use a combination of primary analysis of the observed cohort as well as further data available from the literature. The analysis will capture cumulative health and social care costs, visual acuity outcomes, and quality adjusted life years. Data collection: The standard of care in the NHS for patients with nAMD is regular assessment and treatment (which is monthly for the first 3 months after diagnosis and then bimonthly during year 1. Review intervals may be extended beyond 2 months if the disease is thought to have become quiescent in years 2 and 3.) Standardised case report forms will be populated with data from clinic visits that are extracted by study staff. For participants who complete the study without nAMD detected during the study period, an FFA will be performed at 18 months and at the final exit visit. Sample size: Under the primary analysis, diagnostic accuracy allowing for repeated monitoring assessments will be compared between comparator tests. Disease status will be final status as defined by the reference standard upon completing monitoring. A positive comparator test result will be defined as any positive result during the monitoring period on the respective test. At 2-sided 5% significance level and 90% power, a paired difference of 15% (80% to 65%) in sensitivity will require 491 participants (560 allowing a 12% loss due indeterminate/missing data, including patients lost to follow-up) given a cumulative incidence of 28% at 3 years. This calculation assumes a disagreement in sensitivity between tests of 0.30. A smaller difference in specificity will be identifiable (7%; 94% to 87%). Project timetable: Study duration 63 months. Pre-funding – Ethics approval; Month 1 - First steering group meeting; Month 1 – 6 Study set-up, authorizations and protocol finalized; Month 4 – 8 Centre recruitment, recruit local staff; Month 4 –19 Recruit patients (staggering centre start up); Month 55 - Final patient follow-up; Month 55-59 Data cleaning and preliminary analyses; Month 59-63 Final analyses and reporting.

Lay abstract: “Wet” or neovascular age-related macular degeneration (nAMD) is a leading cause of sight loss in older people, due to the development of leaky and fragile blood vessels in the macula (the region of the retina responsible for detailed eyesight). The seepage of fluid from these vessels causes distortion of eyesight and destruction of the delicate retinal tissues leading to permanent sight loss. At its onset, symptoms may be absent or subtle depending on the part of the macula affected. Distortion in one eye can be ignored by the brain when the other eye compensates leading to late presentation when irreversible destruction of the retina has occurred. Since 2008, drugs have been available to stop leakage into the macula in nAMD. The effects of the drugs which are given as injections into the eye that last for two month and therefore patients are seen usually every 8 weeks. At each visit there is an assessment to check if more treatment is required. It is usual practice to monitor the unaffected eye of these persons because many will develop the same condition. While the treatments are good at stopping decline of eyesight, restoration of normal sight is rare owing to pre-existing retinal damage. Therefore detection of nAMD at a stage when damage to the retina is not permanent with prompt initiation of treatment could result in much better preservation of sight. Thus it is important to identify tests that will detect nAMD in its earliest stage. Our study aims to find out the best test or tests and the how often patients should be tested to reliably detect the start of nAMD with high specificity and sensitivity. We are evaluating five diagnostic tests which are easily performed and routinely carried out in the NHS secondary care setting and which fall into two groups; functional and morphological. The functional tests are (a) visual acuity – measuring vision using a sight chart (b) Amsler test – - a simple subjective test consisting of straight lines on a piece of paper that may appear distorted in patients with retinal disease, and (c) self-reported quality of sight in the unaffected eye. The morphological tests are (d) examination to detect any signs of nAMD in the fundus (the back of the eye) and (e) optical coherence tomography (OCT) – a non-invasive imaging scan of the retinal tissue. We will enrol patients attending eye clinics in NHS hospitals across the UK who have a recent diagnosis of nAMD in one eye only. We believe we need to enrol 560 patients to be able to accurately measure the sensitivity and specificity of the tests and the difference between them. We will obtain information on the health of the unaffected eye from the regular examinations conducted in NHS clinics during follow up. We know that some one quarter of patients will develop nAMD in the second eye within 3 years of the first eye. We will compare the results of our five tests against the “gold standard” which is a fundus fluorescein angiogram (FFA). FFA involves injecting a dye into the blood stream and taking pictures of the fundus (the back of the eye) with a special camera to diagnose and locate the leaking blood vessels. FFA carries a small yet finite risk of death due to severe allergic response to the dye (anaphylaxis), requires expensive equipment and specialist resources and is not suitable as a screening tool. Therefore FFA is usually performed in secondary care in specialist hospital settings with access to resuscitation. We will collect test results (positive or negative) from each patient at each routine eye care appointment over a 3 year period. A positive test will trigger a FFA to confirm whether the patient does have nAMD. Those patients who do not develop nAMD in the study eye during the study will have a FFA at 3 years from enrolment. From this information we will calculate the sensitivity and specificity of each assessment to diagnose nAMD. We will use this data to create a model to determine the best test and time-frame for early detection of nAMD. The demonstration and validation of one or combinations of the above tests to rapidly, robustly, and non-invasively detect the onset of nAMD will be of benefit to patients and providers of health care. We have a multidisciplinary research team of clinicians, statisticians, health service researchers and economists and will draw upon the expertise of acknowledged experts in the management of age-related macular degeneration and consumers.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EYE