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      Longitudinal Higher-Order OCT Assessment of Quantitative Fluid Dynamics and the Total Retinal Fluid Index in Neovascular AMD

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          Abstract

          Purpose

          The purpose of this study was to evaluate the feasibility of assessing quantitative longitudinal fluid dynamics and total retinal fluid indices (TRFIs) with higher-order optical coherence tomography (OCT) for neovascular age-related macular degeneration (nAMD).

          Methods

          A post hoc image analysis study was performed using the phase II OSPREY clinical trial comparing brolucizumab and aflibercept in nAMD. Higher-order OCT analysis using a machine learning−enabled fluid feature extraction platform was used to segment intraretinal fluid (IRF) and subretinal fluid (SRF) volumetric components. TRFI, the proportion of fluid volume against total retinal volume, was calculated. Longitudinal fluid metrics were evaluated for the following groups: all subjects (i.e. treatment agnostic), brolucizumab, and aflibercept.

          Results

          Mean IRF and SRF volumes were significantly reduced from baseline at each timepoint for all groups. Fluid feature extraction allowed high-resolution assessment of quantitative fluid burden. A greater proportion of brolucizumab participants achieved true zero and minimal fluid (total fluid volume between 0.0001 and 0.001mm 3) versus aflibercept participants at week 40. True zero fluid during q12 brolucizumab dosing was achieved in 36.6% to 38.5%, similar to the 25.6% to 38.5% during the corresponding q8 aflibercept cycles. TRFI was significantly reduced from baseline in all groups.

          Conclusions

          Higher-order OCT analysis demonstrates the feasibility of fluid feature extraction and longitudinal volumetric fluid burden and TRFI characterization in nAMD, supporting a unique opportunity for fluid burden assessment and the impact on outcomes.

          Translational Relevance

          Detection and characterization of disease activity is vital for optimal treatment of nAMD. Longitudinal assessment of fluid dynamics and the TRFI provide important proof of concept for future automated tools in characterizing disease activity.

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          Most cited references28

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          HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration

          Two similarly designed phase 3 trials (HAWK and HARRIER) compared brolucizumab, a single-chain antibody fragment that inhibits vascular endothelial growth factor-A, with aflibercept to treat neovascular age-related macular degeneration (nAMD).
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            Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol.

            To compare the efficacy and safety of bevacizumab versus ranibizumab when administered according to a treat-and-extend protocol for the treatment of neovascular age-related macular degeneration (AMD).
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              Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.

              To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD). A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. Patients aged ≥ 50 years with subfoveal wet AMD. Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥ 15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data. At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥ 15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was -172.0 μm, -161.2 μm, -163.3 μm, and -172.4 μm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD. Proprietary or commercial disclosure may be found after the references. Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Transl Vis Sci Technol
                Transl Vis Sci Technol
                tvst
                TVST
                Translational Vision Science & Technology
                The Association for Research in Vision and Ophthalmology
                2164-2591
                25 March 2021
                March 2021
                : 10
                : 3
                : 29
                Affiliations
                [1 ]The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cleveland Clinic, Cleveland, OH, USA
                [2 ]Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
                [3 ]Formerly Novartis Pharmaceuticals, East Hanover, NJ, USA
                [4 ]Novartis Pharmaceuticals, East Hanover, NJ, USA
                [5 ]Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
                Author notes
                [* ] Correspondence: Justis P. Ehlers, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue/i32, Cleveland, OH 44195, USA. e-mail: ehlersj@ 123456ccf.org
                Article
                TVST-20-2981
                10.1167/tvst.10.3.29
                7995350
                7bbd9378-6de6-4359-ad8d-06b517258732
                Copyright 2021 The Authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 17 January 2021
                : 24 August 2020
                Page count
                Pages: 12
                Categories
                Article
                Article

                optical coherence tomography (oct),fluid feature extraction,retinal fluid index,wet age-related macular degeneration (amd)

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