Title: OpticAl Coherence TomograpHy Angiography for the dEtection of Neovascular Age-related Macular Degeneration: a Comprehensive Diagnostic Accuracy Study - the ATHENA study
Funder: Department of Health and Social Care

Abstract: Age-related Macular Degeneration (AMD) is the most frequent cause of blindness in the UK. Nearly 200 people lose sight daily from the severe form of this condition (neovascular AMD, nAMD). Effective treatments exist but depend on early detection of the disease. _x000D_ Eye specialists use several different devices to take images of the retina, a light-sensitive layer at the back of the eye which allows us to see. These images alone, or in different combinations, help eye specialists detect nAMD. We can now detect nAMD early thanks to a technology called Optical Coherence Tomography (OCT). This technology is safe, comfortable and quick for the patient and provides the results within seconds. _x000D_ OCT alone, however, is often not enough to make the diagnosis with certainty and so a further test called Fluorescein Angiography (FA) is done. This test requires an injection of a fluorescein dye in the arm of the patient and then images are taken over several minutes. The procedure is invasive and unpleasant due to prolonged exposure to bright lights, and it can also have minor side effects such as nausea. A new technology has recently become available called Optical Coherence Tomography Angiography (OCTA). This technology can potentially offer the same information as FA and help confirm the diagnosis of nAMD. OCTA however, unlike FA, is quick, comfortable and does not require a dye injection. If it would be possible to replace FA with OCTA, as an additional test to OCT for detecting nAMD, this would have significant benefits for patients and eye units. Because OCTA is a relatively new technology, however, there is not enough evidence yet that it works as well as FA, either alone or in combination with OCT, for the detection of nAMD._x000D_ In this study we want to assess the role of OCTA for the detection of nAMD. We will approach patients referred to hospital eye units with a suspicion of nAMD who have an OCT. If the OCT shows signs of nAMD we will invite the patients to take part in this study. If they agree to take part, each patient will have two more tests: OCTA and FA. We will ask the eye specialists who offer care to these patients to look at the tests and decide whether there is nAMD and how confident they are of this diagnosis. In half of the cases, chosen by chance, the eye specialists will base their diagnosis on OCT and OCTA. In the other half they will base their diagnosis on OCT and FA. We will compare the two approaches to see how well they are able to detect nAMD. We will focus our research on how eye specialists assess these tests as we want the results of our study to be of value to the NHS in real life._x000D_ We will also transfer all the images to specialist research centres in the UK (the Reading Centres) where they will be assessed by expert readers, separately from each other. This will help us make a high quality assessment of how good each of these tests alone is at detecting nAMD. We will finally assess the costs of investing in this new technology (OCTA) to help the NHS decide whether this would be good value for money._x000D_ In designing this research we have asked the opinions of our patients who agreed this is a significant research question for them. FA is unpleasant and often leads to delays in starting treatment. Our patient contributors confirmed they would be keen to see a quick, safe and convenient alternative to FA, provided there is good evidence it works as well as the existing tests.

Lay abstract: Background:_x000D_ Age-related Macular Degeneration (AMD) is the most frequent cause of blindness in the UK. Nearly 200 people aged 55 years or above in the UK lose sight daily from the severe form of this condition (neovascular AMD, nAMD). Early detection of nAMD is associated with improved visual outcomes and quality of life. The diagnosis of this condition is based on the interpretation of multiple imaging tests, including Fluorescein Angiography (FA) which is invasive and not patient friendly. Non-invasive imaging modalities commonly used for nAMD detection, such as Optical Coherence Tomography (OCT), are not always specific requiring further confirmation with other tests such as FA. Optical Coherence Tomography-Angiography (OCTA) is a more recent technology already available in many NHS Trusts; it is non-invasive, fast and has the potential to replace FA. However, to date there is only a small body of moderate quality evidence to suggest OCTA is sufficiently accurate for the detection of nAMD. _x000D_ Aim:_x000D_ To perfom a comprehensive assessment of the diagnostic accuracy of OCTA and FA both alone and in combination with OCT for the detection of nAMD in patients with a positive or suspicious OCT. _x000D_ Primary Objective:_x000D_ To assess whether the sensitivity and specificity of OCTA in patients with a positive or suspicious OCT is non-inferior to that of FA for the detection of nAMD as interpreted by clinicians. _x000D_ Secondary objectives:_x000D_ 1. To assess the diagnostic accuracy of OCTA alone and FA alone as interpreted by Reading Centre expert graders for the detection of nAMD in patients with a positive or suspicious OCT._x000D_ 2. To assess the positive predictive value (PPV) of OCT for the detection of nAMD in all patients presenting with suspicion of nAMD._x000D_ 3. To assess intra- and inter-rater agreement in the detection of nAMD on OCTA and FA as assessed by Reading Centre graders._x000D_ 4. To develop and validate criteria for the OCTA-based diagnosis of nAMD._x000D_ 5. To estimate the incremental cost per true positive detected and incremental cost per correct diagnosis for nAMD. _x000D_ Methods:_x000D_ Study Design: Non-inferiority, prospective, randomised diagnostic accuracy study with an internal pilot to confirm feasibility of the recruitment plan._x000D_ Patient Population: Patients presenting with suspicion of nAMD in secondary care opthalmology units in the first or second eye._x000D_ Setting: Recruitment will take place in 20 hospital-based eye units. Of those 6 will be involved in the pilot study and all sites will be involved in the main study. _x000D_ Analysis Plan: Each patient with a positive or suspicious OCT for nAMD will undergo both OCTA and FA and will be allocated to either the OCTA or the FA arm of the study. The allocation indicates which image will be used by the recruiting clinician to produce a first clinical diagnosis of nAMD. The two arms will be compared for non-inferiority. A second clinical diagnosis will be produced for each case by the same clinician based on review of both OCTA and FA. A masked review of OCTA alone and FA alone by expert Reading Centre graders will also be conducted. _x000D_ Reference Standard: To provide the reference standard we will use all available imaging information from multi-modal imaging (except OCTA to minimise incorporation bias) with clinical vignette describing patient symptoms. _x000D_ Timelines: _x000D_ 1) Development phase: 6 months_x000D_ 2) Internal Pilot: 6 months_x000D_ 3) Main study: 18 months_x000D_ 4) Data analysis and reporting of results: 6 months

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