Personalized treatment supported by automated quantitative fluid analysis in active neovascular age-related macular degeneration (nAMD)—a phase III, prospective, multicentre, randomized study: design and methods

www.nature.com/eye ARTICLE OPEN Personalized treatment supported by automated quantitative fluid analysis in active neovascular age-related macular degeneration (nAMD)—a phase III, prospective, multicentre, randomized study: design and methods Leonard M. Coulibaly1, Stefan Sacu1, Philipp Fuchs1, Hrvoje Bogunovic ✉ Gregor S. Reiter 2 and Ursula Schmidt-Erfurth 1,2 2 , Georg Faustmann2, Christian Unterrainer3, 1234567890();,: © The Author(s) 2022 INTRODUCTION: In neovascular age-related macular degeneration (nAMD) the exact amount of fluid and its location on optical coherence tomography (OCT) have been defined as crucial biomarkers for disease activity and therapeutic decisions. Yet in the absence of quantitative evaluation tools, real-world care outcomes are disappointing. Artificial intelligence (AI) offers a practical option for clinicians to enhance point-of-care management by analysing OCT volumes in a short time. In this protocol we present the prospective implementation of an AI-algorithm providing automated real-time fluid quantifications in a clinical real-world setting. METHODS: This is a prospective, multicentre, randomized (1:1) and double masked phase III clinical trial. Two-hundred-ninety patients with active nAMD will be randomized between a study arm using AI-supported fluid quantifications and another arm using conventional qualitative assessments, i.e. state-of-the-art disease management. The primary outcome is defined as the mean number of injections over 1 year. Change in BCVA is defined as a secondary outcome. DISCUSSION: Automated measurement of fluid volumes in all retinal compartments such as intraretinal fluid (IRF), and subretinal fluid (SRF) will serve as an objective tool for clinical investigators on which to base retreatment decisions. Compared to qualitative fluid assessment, retreatment decisions will be plausible and less prone to error or large variability. The underlying hypothesis is that fluid should be treated, while residual persistent or stable amounts of fluid may not benefit from further therapy. Reducing injection numbers without diminishing the visual benefit will increase overall patient safety and relieve the burden for healthcare providers. TRIAL-REGISTRATION: EudraCT-Number: 2019-003133-42 Eye; https://doi.org/10.1038/s41433-022-02154-8 BACKGROUND Nearly 196 million people worldwide are estimated to be affected by age-related macular degeneration (AMD). With a growing proportion of the elderly population worldwide, AMD is projected to affect up to 288 million people by 2040 [1]. Optimization of AMD treatment is crucial in the fight against visual impairment and severe, irreversible vision loss. From a clinical point of view AMD can be classified into three stages: early, intermediate and late stage [2]. Neovascular AMD (nAMD), caused by macular neovascularization, rapidly affects central vision and, if left untreated, leads to fibrotic scarring and irreversible loss of visual function [3]. The treatment of nAMD was revolutionized by the introduction of anti-vascular endothelial growth factor (anti-VEGF) leading to a substantial initial restoring of visual acuity (VA) [4]. Anti-VEGF has therefore become the gold-standard treating nAMD [5]. Due to the chronic progressive nature of the disease, frequent retreatments are necessary in order to achieve stabilization of VA. A high frequency of intravitreal injections comes with a recurrent risk for complicated sight-threatening adverse events like endophthalmitis, intraocular inflammations or rhegmatogenous retinal detachment [6]. Furthermore, anti-VEGF administration requires a substantial logistical and financial effort from healthcare systems and caregivers, as treatment visits are accompanied by regular follow-up examinations [7, 8]. Thus, the attempt to minimize the number of retreatments without compromising therapy-benefits. Several different therapy strategies have been proposed to individualize the treatment with anti-VEGF. The objective of these different models is to find a balance between frequent intravitreal injections, disease progression and restoration of VA while minimizing the risk of under- or overtreatment. 1 Vienna Clinical Trial Centre (VTC), Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria. 2Christian Doppler Laboratory for Ophthalmic Image Analysis, Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria. 3RetInSight, Vienna, Austria. ✉email: Received: 20 December 2021 Revised: 15 June 2022 Accepted: 16 June 2022 L.M. Coulibaly et al. 2 Fig. 1 Consort study diagram. Flow chart outlining patient enrolment and randomization. Disease activity encouraging retreatment decisions in more individual treatment regimens are determined by vision loss and predefined morphologic disease biomarkers. Spectral-domain optical coherence tomography (SD-OCT) has been established as the leading diagnostic tool in everyday clinical routine to determine disease activity due to its ability to non-invasively visualize the retinal compartments and their respective pathological changes in a three-dimensional manner [9]. Exudative processes, pathognomonic in nAMD, like neovascular leakage comes with related fluid accumulations inside the retina as IRF and/or underneath the retina as SRF or underneath the pigment epithelium as pigment epithelial detachment (PED) which can be observed in OCT-imaging as reliable indicators of disease activity [10]. Still, real-world therapy effectiveness for nAMD has been underwhelming in comparison to the vision gains achieved in clinical trials [11]. To minimize the risk for over- or undertreatment reliable and measurable imaging biomarkers in retreatment decisions need to be established in a precise and reproducible manner [12]. Recent studies found distinct structure-function correlations for specific exudative processes in nAMD. IRF has been consistently associated with severe and irreversible vision loss [13]. The role of SRF seems more ambiguous. Its presence in the juxtafoveal location is associated with negative effects on VA [14], but might be tolerable to some degree without sacrificing therapy benefits [15]. Nonetheless these findings underline the importance of fluid volumes in the pathophysiological process of nAMD and therefore the need for a more precise quantitative assessment of exudative processes. The mere qualitative fluid assessment as present or absent is lacking the important dimension of volumes [15, 16]. Even more so it is prone to error as the CATT and FLUID trials have both shown recurrent differing interpretations of macular fluid between reading centres and ophthalmologists, especially regarding the detection of IRF. Until recently, a precise qualitative fluid assessment was associated with an immense effort by the healthcare system as segmentation of macular fluid was done manually by human graders. With an increasing number of patients, it is unrealistic to manuall (...truncated)