Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration: A Nonrandomized Controlled Trial.

Importance: Existing therapies to slow geographic atrophy (GA) enlargement in age-related macular degeneration (AMD) have relatively modest anatomic efficacy, require intravitreal administration, and increase the risk of neovascular AMD. Additional therapeutic approaches are desirable. Objective: To evaluate the safety and possible anatomic efficacy of oral minocycline, a microglial inhibitor, for the treatment of GA in AMD. Design, Setting, and Participants: This was a phase 2, prospective, single-arm, 45-month, nonrandomized controlled trial conducted from December 2016 to April 2023. Patients with GA from AMD in 1 or both eyes were recruited from the National Institutes of Health (Bethesda, Maryland) and Bristol Eye Hospital (Bristol, UK). Study data were analyzed from September 2022 to May 2023. Intervention: After a 9-month run-in phase, participants began oral minocycline, 100 mg, twice daily for 3 years. Main Outcomes and Measures: The primary outcome measure was the difference in rate of change of square root GA area on fundus autofluorescence between the 24-month treatment phase and 9-month run-in phase. Results: Of the 37 participants enrolled (mean [SD] age, 74.3 [7.6] years; 21 female [57%]), 36 initiated the treatment phase. Of these participants, 21 (58%) completed at least 33 months, whereas 15 discontinued treatment (8 by request, 6 for adverse events/illness, and 1 death). Mean (SE) square root GA enlargement rate in study eyes was 0.31 (0.03) mm per year during the run-in phase and 0.28 (0.02) mm per year during the treatment phase. The primary outcome measure of mean (SE) difference in enlargement rates between the 2 phases was -0.03 (0.03) mm per year (P = .39). Similarly, secondary outcome measures of GA enlargement rate showed no differences between the 2 phases. The secondary outcome measures of mean difference in rate of change between 2 phases were 0.2 letter score per month (95% CI, -0.4 to 0.9; P = .44) for visual acuity and 0.7 µm per month (-0.4 to 1.8; P = .20) for subfoveal retinal thickness. Of the 129 treatment-emergent adverse events among 32 participants, 49 (38%) were related to minocycline (with no severe or ocular events), including elevated thyrotropin level (15 participants) and skin hyperpigmentation/discoloration (8 participants). Conclusions and Relevance: In this phase 2 nonrandomized controlled trial, oral minocycline was not associated with a decrease in GA enlargement over 24 months, compared with the run-in phase. This observation was consistent across primary and secondary outcome measures. Oral minocycline at this dose is likely not associated with slower rate of enlargement of GA in AMD.

Safety and effectiveness of the fluocinolone acetonide intravitreal implant (ILUVIEN): 3-year results from the European IRISS registry study.

BACKGROUND: The ILUVIEN Registry Safety Study was a multicentre, open-label, non-randomised, observational, phase 4 study designed to assess the safety and effectiveness of the fluocinolone acetonide (FAc) implant in all indications in real-world practices in Europe. METHODS: The study included data collected prospectively and retrospectively. Patients receiving FAc implants between 2013 and 2017 were included and monitored until the last patient reached ≥3 years of follow-up. Mean intraocular pressure (IOP) data over the course of the study, along with IOP events, use of IOP-lowering therapy, mean change in visual acuity (VA) and information on supplemental therapy use were analysed post-FAc implantation. RESULTS: Six hundred and ninety-five eyes from 556 patients, with a mean±SD follow-up of 1150.5±357.36 days, were treated with a FAc implant. 96.7% of eyes had chronic diabetic macular oedema (cDMO). IOP lowering was achieved in 34.5% of eyes using topical agents and 4.3% by surgery. Seventy-three eyes (64.6% of 113 phakic) required cataract surgery during follow-up. Mean VA increased from a baseline of 52.2 letters to 57.1 letters at month 36, with improvement observed up to month 48. Supplementary therapies were given in 43.7% of eyes. When classified by length of cDMO less than or greater than the median duration those with a shorter history experienced greater VA gains than those with a longer history. CONCLUSION: This study confirms the favourable, long-term benefit-to-risk profile of the FAc implant in eyes with cDMO, with an additional benefit in patients when this therapy is administered earlier.

Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked Noninferiority Clinical Trial.

PURPOSE: To determine clinical effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) < 400 µm. DESIGN: Pragmatic, multicenter, allocation-concealed, double-masked, randomized, noninferiority trial. PARTICIPANTS: Adults with center-involved DME < 400 µm and best-corrected visual acuity (BCVA) of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. METHODS: Randomization 1:1 to 577 nm SML or SL treatment. Retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if 10 or more ETDRS letter loss occurred, CRT increased > 400 µm, or both. MAIN OUTCOME MEASURES: Primary outcome was mean change in BCVA in the study eye at 24 months (noninferiority margin 5 ETDRS letters). Secondary outcomes were mean change from baseline to month 24 in binocular BCVA; CRT and mean deviation of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL EQ-5D-5L, 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life-years (QALYs) gained; adverse effects; and number of laser and rescue treatments. RESULTS: The study recruited fully (n = 266); 87% of SML-treated and 86% of SL-treated patients had primary outcome data. Mean ± standard deviation BCVA change from baseline to month 24 was -2.43 ± 8.20 letters and -0.45 ± 6.72 letters in the SML and SL groups, respectively. Subthreshold micropulse laser therapy was deemed not only noninferior but also equivalent to SL therapy because the 95% confidence interval (CI; -3.9 to -0.04 letters) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS letters). No statistically significant difference was found in binocular BCVA (0.32 ETDRS letters; 95% CI, -0.99 to 1.64 ETDRS letters; P = 0.63); CRT (-0.64 µm; 95% CI, -14.25 to 12.98 µm; P = 0.93); mean deviation of the visual field (0.39 decibels (dB); 95% CI, -0.23 to 1.02 dB; P = 0.21); meeting driving standards (percentage point difference, 1.6%; 95% CI, -25.3% to 28.5%; P = 0.91); adverse effects (risk ratio, 0.28; 95% CI, 0.06-1.34; P = 0.11); rescue treatments (percentage point difference, -2.8%; 95% CI, -13.1% to 7.5%; P = 0.59); or EQ-5D, NEI-VFQ-25, or VisQoL scores. Number of laser treatments was higher in the SML group (0.48; 95% CI, 0.18-0.79; P = 0.002). Base-case analysis indicated no differences in costs or QALYs. CONCLUSIONS: Subthreshold micropulse laser therapy was equivalent to SL therapy, requiring slightly higher laser treatments.

Practical implementation of a q4-q16 aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration: Updated guidance from a UK expert panel.

OBJECTIVES: This report, based on guidance from a panel of UK retina specialists, introduces a revised intravitreal aflibercept (IVT-AFL) treat-and-extend (T&E) pathway for the treatment of neovascular age-related macular degeneration (nAMD). The T&E pathway incorporates the updated IVT-AFL label (April 2021) allowing flexible treatment intervals of 4 weeks to 16 weeks, after three initiation doses and a further dose after 8 weeks. Practical guidance is provided on the clinical implementation of the revised pathway, with the aim of supporting clinical decision-making to benefit patients and addressing capacity issues in nAMD services. METHODS: Three structured round-table meetings of UK retina specialists were held online on 19 May, 16 June and 13 October 2021. These meetings were organised and funded by Bayer. RESULTS: The authors revised the previously published consensus pathway to reflect the changes to the IVT-AFL label and developed guidelines for the implementation of the pathway in UK clinical practice. The guidelines include topics such as recommendations for extending patients with 2- or 4-week adjustments, extending patients to 16-week treatment intervals, managing fellow eye involvement, and reducing treatment intervals for patients with particularly active disease. CONCLUSIONS: The revised IVT-AFL T&E nAMD pathway offers guidance to clinicians seeking to increase the dosing flexibility of IVT-AFL, with 4- to 16-week treatment intervals, in line with the updated IVT-AFL label, to meet the continually evolving demands of nAMD service provision.

Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema: the DIAMONDS non-inferiority RCT.

BACKGROUND: The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm on optical coherence tomography. The DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial compared standard threshold macular laser with subthreshold micropulse laser to treat diabetic macular oedema suitable for macular laser. OBJECTIVES: Determining the clinical effectiveness, safety and cost-effectiveness of subthreshold micropulse laser compared with standard threshold macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm. DESIGN: A pragmatic, multicentre, allocation-concealed, double-masked, randomised, non-inferiority, clinical trial. SETTING: Hospital eye services in the UK. PARTICIPANTS: Adults with diabetes and centre-involving diabetic macular oedema with a central retinal subfield thickness of < 400 µm, and a visual acuity of > 24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. INTERVENTIONS: Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. MAIN OUTCOME MEASURES: The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10-2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire - 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. RESULTS: The DIAMONDS trial recruited fully (n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was -2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and -0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (-3.9 to -0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. FUTURE WORK: A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to < 400 µm following anti-vascular endothelial growth factor injections would be of value because it could reduce the number of injections and, subsequently, costs and risks and inconvenience to patients. LIMITATIONS: The majority of participants enrolled had poorly controlled diabetes. CONCLUSIONS: Subthreshold micropulse laser was equivalent to standard threshold macular laser but required a slightly higher number of laser treatments. TRIAL REGISTRATION: This trial is registered as EudraCT 2015-001940-12, ISRCTN17742985 and NCT03690050. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 50. See the NIHR Journals Library website for further project information.

The retina is a layer at the back of the eye. Its centre is called the macula and is responsible for central vision. Some people with diabetes develop diabetic macular oedema. In diabetic macular oedema fluid leaks from retinal blood vessels and builds up at the macula, resulting in sight loss. Diabetic macular oedema can be mild or severe; this can be determined measuring the thickness of the macula, which is measured in micrometres (µm). One micrometre is one thousandth of a millimetre. In mild diabetic macular oedema, the thickness of the macula increases, but is less than 400 µm. Patients with mild diabetic macular oedema can be treated with a laser and there are two laser types. The standard threshold macular laser has been available for many years. It clears the diabetic macular oedema but produces a 'burn' in the retina. The subthreshold micropulse laser is newer. It does not produce a burn but also clears the diabetic macular oedema. The lack of a burn, however, has led to doubts about whether or not this laser works as well as the standard threshold macular laser because 'no burn' was taken to mean 'less benefit'. These doubts led to our establishing the DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial, which compared these two lasers for people with mild diabetic macular oedema. A total of 266 people suitable for either laser joined the study at 16 NHS hospitals across the UK; 133 received standard threshold macular laser and 133 received subthreshold micropulse laser. The choice of laser was determined by chance. The DIAMONDS trial found that the subthreshold micropulse laser was as good as the standard threshold macular laser (i.e. 'clinically equivalent') in terms of improving people's vision, reducing macula thickness, allowing people to meet driving standards and maintaining their quality of life, both in general terms and for vision in particular. There was a small increase (less than one session on average per person) in the number of laser treatment sessions needed with subthreshold micropulse laser. The costs of both laser treatments were about the same.

The changing landscape for the management of patients with neovascular AMD: brolucizumab in clinical practice.

Untreated neovascular age-related macular degeneration (nAMD) can lead to severe and permanent visual impairment. The chronic nature of the disease can have a significant impact on patients' quality of life and an economic and time burden on medical retina (MR) services, with the care need outweighing the growth of resources that clinical services can access. The introduction of a new treatment into clinical services can be challenging, especially for services that are already under capacity constraints. Guidance for practical implementation is therefore helpful. Roundtable meetings, facilitated by Novartis UK, between a working group of MR experts with experience of leading and managing NHS retinal services in the intravitreal era were conducted between 2020 and 2021. These meetings explored various aspects and challenges of introducing a new anti-vascular endothelial growth factor (VEGF) therapy to the UK medical retina services. Provision of clear expert recommendations and practical guidance nationally, that can be adapted locally as required to support clinicians and healthcare professionals (HCPs), is valuable in supporting the introduction of a new anti-VEGF therapy within the NHS environment. The experts provide ophthalmologic HCPs with a collation of insights and recommendations to support the introduction and delivery of brolucizumab in their local service in the face of current and projected growth in demand for retina care.

Long-term Retinal Morphology and Functional Associations in Treated Neovascular Age-Related Macular Degeneration: Findings from the Inhibition of VEGF in Age-Related Choroidal Neovascularisation Trial.

PURPOSE: To describe the frequency of long-term morphologic features and their relationships with visual function in participants who exited the Inhibition of VEGF in Age-Related Choroidal Neovascularisation (IVAN; ISRCTN92166560) trial. DESIGN: Multicenter cohort study up to 7 years after enrollment. PARTICIPANTS: Patients enrolled in the IVAN trial, excluding participants who died or withdrew during the trial. METHODS: Multimodal fundus images, best-corrected visual acuity (BCVA), and low-luminance visual acuity (LLVA) were obtained for a subset of 199 participants who attended a research visit. Clinical sites (n = 20) also provided all visual acuity and clinical information from usual care records for 532 participants and submitted the most recent color, OCT, and other fundus images for 468 participants to a reading center. MAIN OUTCOME MEASURES: Assessed the following from the most recent images: intralesional macular atrophy (ILMA) within the footprint of the neovascular lesion; hyperreflective material (HRM); intraretinal fluid (IRF); subretinal fluid (SRF); pigment epithelial detachment (PED); and disorganized retinal outer layers (DROLs). Cross-sectional relationships between morphologic features and BCVA/LLVA were estimated. RESULTS: Intralesional macular atrophy was present in 31.8% of the study eyes at IVAN exit (mean follow-up, 1.96 years) and 89.5% at the most recent imaging visit (mean follow-up, 6.18 years). Hyperreflective material, IRF, SRF, PED, and DROLs were present in 78.8%, 47.7%, 7.6%, 94.5%, and 55% of the study eyes, respectively. In the subset with complete imaging data, in eyes without DROL, the BCVA was worst in the thinnest outer fovea tertile (thinnest minus middle and thickest tertiles, -19.7 and -19.5 letters, respectively), whereas in eyes with DROL, the BCVA was worst in the thickest (thinnest and middle tertiles minus thickest, 12.5 and 12.2, respectively). Regression models showed that the presence of ILMA and HRM was independently associated with BCVA (22 letters worse [95% confidence interval {CI}, -11.2 to -32.8; P < 0.001] and 9.8 letters worse [95% CI, -0.1 to -19.4; P = 0.047], respectively). Subretinal fluid and foveal PED were associated with better BCVA (5.9 letters [95% CI, -7.9 to 19.7; P = 0.399] and 6.4 letters [95% CI, -1.1 to 14.0; P = 0.094], respectively). The model with LLVA was similar. A sensitivity analysis involving the entire eligible cohort yielded similar estimates. CONCLUSIONS: Macular atrophy and HRM were common after 7 years of follow-up and strongly associated with visual outcomes.

Extended real-world experience with the ILUVIEN® (fluocinolone acetonide) implant in the United Kingdom: 3-year results from the Medisoft® audit study.

BACKGROUND: This study aimed to assess the long-term effectiveness of the 0.2 µg/day fluocinolone acetonide (FAc) implant over ≥3 years for patients with diabetic macular oedema. METHODS: A retrospective audit of pseudo-anonymised data from patients with chronic diabetic macular oedema (cDMO) and treated with the FAc implant across 14 UK clinical sites. Safety and clinical effectiveness were measured. RESULTS: Two-hundred and fifty-six eyes had ≥3 years of follow-up (mean 4.28 years), during which a mean of 1.14 FAc implants were used per eye. Mean best-recorded visual acuity (BRVA) increased from 52.6 to 56.7 letters at month 3 and remained stable thereafter; this trend was also seen in pseudophakic eyes. The proportion of patients attaining a BRVA ≥6/12 increased from 17% at baseline to 27% 1 month after FAc implant and remained stable above 30% from month 12 onwards. Eyes with no prior history of intraocular pressure (IOP)-related events required significantly less treatment-emergent IOP-lowering medication than those with a prior history of IOP events (17.9% vs. 50.0% of eyes; p < 0.001). The incidence of an IOP increase of ≥10 mmHg, use of IOP-lowering medication, laser trabeculoplasty and IOP-lowering surgery was 28.9%, 29.7%, 0.8% and 2.7%, respectively, for the whole cohort. There were significant reductions in mean central foveal thickness and macular volume (p < 0.001). CONCLUSIONS: The FAc implant was well tolerated, with predictable and manageable IOP-related events while delivering a continuous microdose of corticosteroid to eyes with cDMO, providing prolonged vision preservation and a reduced number of treatments.

Prevalence and incidence of diabetic retinopathy (DR) in the UK population of Gloucestershire.

PURPOSE: To estimate prevalence and incidence of diabetic retinopathy (DR) in a UK region by severity between 2012 and 2016 and risk factors for progression to proliferative DR (PDR). METHODS: Electronic medical records from people with diabetes (PWD) ≥18 years seen at the Gloucestershire Diabetic Eye Screening Programme (GDESP) and the hospital eye clinic were analysed (HEC). Prevalence and incidence of DR per 100 PWD (%) by calendar year, grade and diabetes type were estimated using log-linear regression. Progression to PDR and associated risk factors were estimated using parametric survival analyses. RESULTS: Across the study period, 35 873 PWD had at least one DR assessment. They were aged 66 (56-75) years (median (interquartile range)), 57% male, 5 (1-10) years since diabetes diagnosis, 93% Type 2 diabetes. Prevalence of DR decreased from 38.9% (95% CI: 38.1%, 39.8%) in 2012 to 36.6% (95% CI: 35.9%, 37.3%) in 2016 (p < 0.001). Incidence of any DR decreased from 10.9% (95% CI: 10.4%, 11.5%) in 2013 to 8.5% (95% CI: 8.1%, 9.0%) in 2016 (p < 0.001). Prevalence of PDR decreased from 3.5% (95% CI: 3.3%, 3.8%) in 2012 to 3.1% (95% CI 2.9%, 3.3%) in 2016 (p = 0.008). Incidence of PDR did not change over time. HbA1c and bilateral moderate-severe NPDR were statistically significant risk factors associated with progression to PDR. CONCLUSIONS: Incidence and prevalence of DR decreased between 2012 and 2016 in this well-characterized population of the UK.

Conversion of Central Subfield Thickness Measurements of Diabetic Macular Edema Across Cirrus and Spectralis Optical Coherence Tomography Instruments.

Purpose: Develop equations to convert Cirrus central subfield thickness (CST) to Spectralis CST equivalents and vice versa in eyes with diabetic macular edema (DME). Methods: The DRCR Retina Network Protocol O data were split randomly to train (70% sample) and validate (30% sample) conversion equations. Data from an independent study (CADME) also validated the equations. Bland-Altman 95% limits of agreement between predicted and observed values evaluated the equations. Results: Protocol O included 374 CST scan pairs from 187 eyes (107 participants). The CADME study included 150 scan pairs of 37 eyes (37 participants). Proposed conversion equations are Spectralis = 40.78 + 0.95 × Cirrus and Cirrus = 1.82 + 0.94 × Spectralis regardless of age, sex, or CST. Predicted values were within 10% of observed values in 101 (90%) of Spectralis and 99 (88%) of Cirrus scans in the validation data; and in 136 (91%) of the Spectralis and 148 (99%) of the Cirrus scans in the CADME data. Adjusting for within-eye correlations, 95% of conversions are estimated to be within 17% (95% confidence interval, 14%-21%) of CST on Spectralis and within 22% (95% confidence interval, 18%-28%) of CST on Cirrus. Conclusions: Conversion equations developed in this study allow the harmonization of CST measurements for eyes with DME using a mix of current Cirrus and Spectralis device images. Translational Relevance: The CSTs measured on Cirrus and Spectralis devices are not directly comparable owing to outer boundary segmentation differences. Converting CST values across spectral domain optical coherence tomography instruments should benefit both clinical research and standard care efforts.

Reliability of Retinal Pathology Quantification in Age-Related Macular Degeneration: Implications for Clinical Trials and Machine Learning Applications.

Purpose: To investigate the interreader agreement for grading of retinal alterations in age-related macular degeneration (AMD) using a reading center setting. Methods: In this cross-sectional case series, spectral-domain optical coherence tomography (OCT; Topcon 3D OCT, Tokyo, Japan) scans of 112 eyes of 112 patients with neovascular AMD (56 treatment naive, 56 after three anti-vascular endothelial growth factor injections) were analyzed by four independent readers. Imaging features specific for AMD were annotated using a novel custom-built annotation platform. Dice score, Bland-Altman plots, coefficients of repeatability, coefficients of variation, and intraclass correlation coefficients were assessed. Results: Loss of ellipsoid zone, pigment epithelium detachment, subretinal fluid, and drusen were the most abundant features in our cohort. Subretinal fluid, intraretinal fluid, hypertransmission, descent of the outer plexiform layer, and pigment epithelium detachment showed highest interreader agreement, while detection and measures of loss of ellipsoid zone and retinal pigment epithelium were more variable. The agreement on the size and location of the respective annotation was more consistent throughout all features. Conclusions: The interreader agreement depended on the respective OCT-based feature. A selection of reliable features might provide suitable surrogate markers for disease progression and possible treatment effects focusing on different disease stages. Translational Relevance: This might give opportunities for a more time- and cost-effective patient assessment and improved decision making as well as have implications for clinical trials and training machine learning algorithms.

Efficacy and Safety of Intravitreal Aflibercept Treat-and-Extend for Macular Edema in Central Retinal Vein Occlusion: the CENTERA Study.

PURPOSE: To evaluate the efficacy and safety of intravitreal aflibercept (IVT-AFL) treat-and-extend dosing in patients with macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: CENTERA (Evaluation of a Treat and Extend Regimen of Intravitreal Aflibercept for Macular Edema Secondary to CRVO; NCT02800642) was an open-label, Phase 4 clinical study. METHODS: Patients received 2 mg of IVT-AFL at baseline and every 4 weeks thereafter, until disease stability criteria were met (or until week 20), at which point treatment intervals were adjusted in 2-week increments based on functional and anatomic outcomes. RESULTS: From baseline to week 76, 105 patients (65.6%) (P <.0001 [test against threshold of 40%]) gained ≥15 letters; and, during the treat-and-extend phase, 72 patients (45.0%) (P = 0.8822 [test against threshold of 50%]) achieved a mean treatment interval of ≥8 weeks. A last and next planned treatment interval of ≥8 weeks was achieved by 101 patients (63.1%) and by 108 patients (67.5%), respectively. Mean ± SD best-corrected visual acuity increased from 51.9 ± 16.8 letters at baseline to 72.3 ± 18.5 letters at week 76 (mean change: +20.3 ± 19.5 letters), and central retinal thickness decreased from 759.9 ± 246.0 µm at baseline to 265.4 ± 57.9 µm at week 76 (mean change: -496.1 ± 252.4 µm). The safety profile of IVT-AFL was consistent with that of previous studies. CONCLUSIONS: Clinically meaningful improvements in functional and anatomic outcomes were achieved with IVT-AFL treat-and-extend dosing. Most patients achieved a last actual and last intended treatment interval of ≥8 weeks; therefore, treatment intervals may have been extended even further with a longer study duration.

Quantification of Key Retinal Features in Early and Late Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: We sought to develop and validate a deep learning model for segmentation of 13 features associated with neovascular and atrophic age-related macular degeneration (AMD). DESIGN: Development and validation of a deep-learning model for feature segmentation. METHODS: Data for model development were obtained from 307 optical coherence tomography volumes. Eight experienced graders manually delineated all abnormalities in 2712 B-scans. A deep neural network was trained with these data to perform voxel-level segmentation of the 13 most common abnormalities (features). For evaluation, 112 B-scans from 112 patients with a diagnosis of neovascular AMD were annotated by 4 independent observers. The main outcome measures were Dice score, intraclass correlation coefficient, and free-response receiver operating characteristic curve. RESULTS: On 11 of 13 features, the model obtained a mean Dice score of 0.63 ± 0.15, compared with 0.61 ± 0.17 for the observers. The mean intraclass correlation coefficient for the model was 0.66 ± 0.22, compared with 0.62 ± 0.21 for the observers. Two features were not evaluated quantitatively because of a lack of data. Free-response receiver operating characteristic analysis demonstrated that the model scored similar or higher sensitivity per false positives compared with the observers. CONCLUSIONS: The quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features. The quantified parameters provided by the model can be used in the current clinical routine and open possibilities for further research into treatment response outside clinical trials.

Evaluation of a New Model of Care for People with Complications of Diabetic Retinopathy: The EMERALD Study.

PURPOSE: The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent life-long follow-up, have increased hospital demands markedly. Subsequent delays in patient's evaluation and treatment are causing sight loss. Strategies to increase capacity are needed urgently. The retinopathy (EMERALD) study tested diagnostic accuracy, acceptability, and costs of a new health care pathway for people with previously treated DME or PDR. DESIGN: Prospective, multicenter, case-referent, cross-sectional, diagnostic accuracy study undertaken in 13 hospitals in the United Kingdom. PARTICIPANTS: Adults with type 1 or 2 diabetes previously successfully treated DME or PDR who, at the time of enrollment, had active or inactive disease. METHODS: A new health care pathway entailing multimodal imaging (spectral-domain OCT for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-widefield [UWF] fundus images for PDR) interpreted by trained nonmedical staff (ophthalmic graders) to detect reactivation of disease was compared with the current standard care (face-to-face examination by ophthalmologists). MAIN OUTCOME MEASURES: Primary outcome: sensitivity of the new pathway. SECONDARY OUTCOMES: specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, and with inadequate images or indeterminate findings. RESULTS: The new pathway showed sensitivity of 97% (95% confidence interval [CI], 92%-99%) and specificity of 31% (95% CI, 23%-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS images (85% [95% CI, 77%-91%] and 48% [95% CI, 41%-56%], respectively) or UWF images (83% [95% CI, 75%-89%] and 54% [95% CI, 46%-61%], respectively) were comparable. For detection of high-risk PDR, sensitivity and specificity were higher when using UWF images (87% [95% CI, 78%-93%] and 49% [95% CI, 42%-56%], respectively, for UWF versus 80% [95% CI, 69-88%] and 40% [95% CI, 34%-47%], respectively, for 7-field ETDRS images). Participants preferred ophthalmologists' assessments; in their absence, they preferred immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard of care, the new pathway could save £1390 per 100 DME visits and between £461 and £1189 per 100 PDR visits. CONCLUSIONS: The new pathway has acceptable sensitivity and would release resources. Users' suggestions should guide implementation.

Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group.

The management of diabetic retinopathy (DR) has evolved considerably over the past decade, with the availability of new technologies (diagnostic and therapeutic). As such, the existing Royal College of Ophthalmologists DR Guidelines (2013) are outdated, and to the best of our knowledge are not under revision at present. Furthermore, there are no other UK guidelines covering all available treatments, and there seems to be significant variation around the UK in the management of diabetic macular oedema (DMO). This manuscript provides a summary of reviews the pathogenesis of DR and DMO, including role of vascular endothelial growth factor (VEGF) and non-VEGF cytokines, clinical grading/classification of DMO vis a vis current terminology (of centre-involving [CI-DMO], or non-centre involving [nCI-DMO], systemic risks and their management). The excellent UK DR Screening (DRS) service has continued to evolve and remains world-leading. However, challenges remain, as there are significant variations in equipment used, and reproducible standards of DMO screening nationally. The interphase between DRS and the hospital eye service can only be strengthened with further improvements. The role of modern technology including optical coherence tomography (OCT) and wide-field imaging, and working practices including virtual clinics and their potential in increasing clinic capacity and improving patient experiences and outcomes are discussed. Similarly, potential roles of home monitoring in diabetic eyes in the future are explored. The role of pharmacological (intravitreal injections [IVT] of anti-VEGFs and steroids) and laser therapies are summarised. Generally, IVT anti-VEGF are offered as first line pharmacologic therapy. As requirements of diabetic patients in particular patient groups may vary, including pregnant women, children, and persons with learning difficulties, it is important that DR management is personalised in such particular patient groups. First choice therapy needs to be individualised in these cases and may be intravitreal steroids rather than the standard choice of anti-VEGF agents. Some of these, but not all, are discussed in this document.

Translating evidence into practice: recommendations by a UK expert panel on the use of aflibercept in diabetic macular oedema.

OBJECTIVES: This paper describes recommendations from a panel of UK retina experts on aflibercept in diabetic macular oedema (DMO). METHODS: A roundtable meeting was held in London, UK in March 2018. The meeting was sponsored by Bayer. RESULTS: Recommendations are based on clinical experience and level 1 evidence. Clinical experience supports the evidence base, reinforcing that aflibercept should be initiated with intensive proactive dosing at 2 mg every 4 weeks. Most panel members use six initial 4-weekly doses as in Protocol T, rather than five initial monthly doses as recommended in the Summary of product characteristics (SmPC). After intensive proactive dosing, patients with a good response (meet Protocol T 'improvement' criteria ≥5-letter improvement in visual acuity [VA] and/or ≥10% improvement in central subfield thickness [CST] from baseline) but who are not yet stable should continue with 4-weekly aflibercept until stability is reached. Patients with a good response and stability should initiate monitor-and-extend (not in line with SmPC). Those with a sub-optimal response (meet 'improvement' criteria but with additional concerns e.g. fluid worsening on macular volume map) should continue with 4-weekly aflibercept but additional treatments should be considered (aflibercept is not licensed for combination treatment). For patients with no response (no change, or meeting Protocol T 'worsening' criteria [≥5-letter decrease in VA and/or ≥ 10% increase in CST] from baseline), switching to a non-anti-vascular endothelial growth factor treatment should be considered. CONCLUSIONS: Clinical experience reinforces that, when using aflibercept in DMO, the licensed posology or Protocol T regimens achieve the best outcomes.

Direct Ophthalmic Healthcare Resource Use among Patients with Geographic Atrophy in a Large Cohort from the United Kingdom.

PURPOSE: To estimate the direct ophthalmic healthcare resource use in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective analysis of anonymized data derived from electronic medical records (EMRs) acquired at 10 clinical sites in the United Kingdom. PARTICIPANTS: Patients aged ≥50 years with ≥1 eye with a clinical record of GA or, for comparison, bilateral early/intermediate AMD. Four subgroups were identified: GA in both eyes (GA:GA); GA in 1 eye, choroidal neovascularization (CNV) in the fellow eye (GA:CNV); GA in 1 eye with early or intermediate AMD in the fellow eye (GA:E); and early/intermediate AMD in both eyes (E:E). METHODS: The EMRs were analyzed to derive the median number of visits over the first 2 years after diagnosis of GA or early/intermediate AMD. Clinical tests recorded at visits were used to calculate estimated costs (payer perspective) of monitoring. Analyses were restricted to patients with an initial diagnosis on or after January 1, 2011, to represent present day monitoring and costs associated with AMD. MAIN OUTCOME MEASURES: Median number of visits and estimated monitoring costs per patient (in £) over the first 2 years among patients with ≥2 years of follow-up and in the individual subgroups. Intravitreal treatment costs in the GA:CNV group were excluded. RESULTS: For all 3 GA subgroups (n = 1080), the median number of visits over the first 2 years was 5, and monitoring costs were £460.80 per patient. The GA:CNV subgroup (n = 355) had the highest number of visits (median, 15), with a cost of £1581, compared with the GA:E subgroup (n = 283; median 4 visits; cost ∼£369) and the GA:GA subgroup (n = 442; median 3 visits; cost ∼£277). Ophthalmic tests were conducted most frequently in the GA:CNV subgroup. Visits and costs in the E:E subgroup (n = 6079) were lower. CONCLUSIONS: Resource use in patients with GA varies considerably and is strongly influenced by the concomitant presence of CNV and lack of monitoring strategies for GA.

Diabetic macular oedema and diode subthreshold micropulse laser (DIAMONDS): study protocol for a randomised controlled trial.

BACKGROUND: In the UK, macular laser is the treatment of choice for people with diabetic macular oedema with central retinal subfield thickness (CST) < 400 µm, as per National Institute for Health and Care Excellence guidelines. It remains unclear whether subthreshold micropulse laser is superior and should replace standard threshold laser for the treatment of eligible patients. METHODS: DIAMONDS is a pragmatic, multicentre, allocation-concealed, randomised, equivalence, double-masked clinical trial that aims to determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser compared with standard threshold laser, for the treatment of diabetic macular oedema with CST < 400 µm. The primary outcome is the mean change in best-corrected visual acuity in the study eye from baseline to month 24 post treatment. Secondary outcomes (at 24 months) include change in binocular best corrected visual acuity; CST; mean deviation of the Humphrey 10-2 visual field; change in percentage of people meeting driving standards; European Quality of Life-5 Dimensions, National Eye Institute Visual Functioning Questionnaire-25 and VisQoL scores; incremental cost per quality-adjusted life year gained; side effects; number of laser treatments and use of additional therapies. The primary statistical analysis will be per protocol rather than intention-to-treat analysis because the latter increases type I error in non-inferiority or equivalence trials. The difference between lasers for change in best-corrected visual acuity (using 95% CI) will be compared to the permitted maximum difference of five Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear and logistic regression models will be used to compare outcomes between treatment groups. A Markov-model-based cost-utility analysis will extend beyond the trial period to estimate longer-term cost-effectiveness. DISCUSSION: This trial will determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser, when compared with standard threshold laser, for the treatment of diabetic macular oedema, the main cause of sight loss in people with diabetes mellitus. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN17742985 . Registered on 19 May 2017 (retrospectively registered).

Intralesional Macular Atrophy in Anti-Vascular Endothelial Growth Factor Therapy for Age-Related Macular Degeneration in the IVAN Trial.

PURPOSE: To report on the development and progression of macular atrophy (MA) and its relationship with morphologic and functional measures in study and fellow eyes in the Inhibition of vascular endothelial growth factor (VEGF) in Age-related Choroidal Neovascularisation trial. DESIGN: Reading center analysis of data from a randomized controlled trial. PARTICIPANTS: Participants with previously untreated neovascular age-related macular degeneration (nAMD) in the study eye. METHODS: Color, fluorescein angiography (FA) and OCT images acquired at baseline and during the 2-year follow-up were graded systematically for presence of MA. Regression models were constructed to explore relationships between MA and lesion morphology and vision measures (best-corrected distance and near acuity, reading speed and index, contrast sensitivity). MAIN OUTCOME MEASURES: Primary outcome was development of intralesional MA (≥175 µm greatest linear dimension of choroidal vessels seen on FA and/or color, aided by OCT) lying within the maximum footprint of the neovascular lesion. RESULTS: Study eye data were available for 594 of 610 participants; 57 (9.6%) showed intralesional MA at baseline. Incident intralesional MA occurred in 24.4% by the final visit and extralesional MA in only 1.54%. In fellow eyes, an established nAMD lesion was present at baseline in 248 of whom 42 (16.9%) showed intralesional MA at baseline and 32 (12.9%) developed incident intralesional MA. The odds of incident intralesional MA by final visit were lower in study eyes that had ≥50% classic CNV at baseline (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.19-0.80; P = 0.010), subretinal fluid at final visit (OR, 0.41; 95% CI, 0.25-0.76; P = 0.004), or pigment epithelial detachment at final visit (OR, 0.40; 95% CI, 0.21-0.74; P = 0.004). Secondary analyses of incident or progressed intralesional MA in study eyes supported these findings, with odds increasing if the fellow eye had baseline intralesional MA (OR, 2.43; 95% CI, 1.09-5.44; P = 0.030). No significant associations were observed between development of intralesional MA and any other morphologic or visual function measure. CONCLUSIONS: Macular atrophy frequently develops within an nAMD lesion in eyes receiving anti-VEGF therapy over 2 years. No associations between incident MA and drug or treatment frequency or visual function were detected, providing some reassurance to clinicians; however, the longer-term effects remain unknown.

Changes in intraocular pressure after intravitreal fluocinolone acetonide (ILUVIEN): real-world experience in three European countries.

AIMS: The ILUVIEN Registry Safety Study is an ongoing, multicentre, open-label, observational study collecting real-world data on the safety and effectiveness of the 0.2 µg/day fluocinolone acetonide (FAc) implant in patients treated according to the European label requirements. METHODS: Patients included in this analysis were treated for the licensed indication of chronic diabetic macular oedema (cDMO; that is, DMO that persists or recurs despite treatment). Data presented in the current analysis were collected from patient records up to 6 March 2017. Visual acuity (VA) data, including mean change in VA over time and at last observation, intraocular pressure (IOP) over the course of the study, IOP events, use of IOP-lowering therapy and cup:disc ratio were analysed. Information on additional DMO treatments post-FAc implant was also captured. RESULTS: Five hundred and sixty-three patients (593 eyes) were enrolled on the study. Mean IOP for the overall population remained within the normal range throughout follow-up and 76.7% of patients did not require IOP-lowering therapy following treatment with the FAc implant. Sixty-nine per cent of eyes did not require additional DMO treatments. Mean VA in the overall population increased from 51.9 letters at baseline to 55.6 letters at month 12, with a significant increase of 2.9 letters at last observation. Patients with short-term cDMO experienced greater VA gains than those with long-term cDMO. CONCLUSIONS: The results of this analysis are comparable with those of other studies, including the Fluocinolone Acetate for Macular Edema study. The study reinforces the good safety and effectiveness profile of FAc, and demonstrates the benefit of early FAc treatment.