Eccentric Viewing Training for Age-Related Macular Disease: Results of a Randomized Controlled Trial (the EFFECT Study).

Purpose: Eccentric viewing training for macular disease has been performed for > 40 years, but no large studies including control groups have assessed the benefits of this training. The EFFECT (Eccentric Fixation From Enhanced Clinical Training) study is a large randomized controlled trial of 2 types of eccentric viewing training. Design: Randomized controlled trial. Participants: Two hundred adults with age-related macular disease. Methods: Participants were randomized to either of the following: (1) a control group; (2) a group receiving supervised reading support; (3) a group receiving 3 sessions of training to optimize the use of their own preferred retinal locus; or (4) a group receiving 3 sessions of biofeedback training of a theoretically optimal trained retinal locus. All participants received standard low-vision rehabilitation. Main Outcome Measures: The primary outcome was patient-reported visual task ability measured on the Activity Inventory instrument at goal level. Secondary outcomes included reading performance and fixation stability. Results: There was no difference between groups on change in task ability (F(3,174) = 1.48, P = 0.22) or on any of the secondary outcome measures. Visual acuity and contrast sensitivity fell in all groups, suggesting that disease progression outweighed any benefit of training. Conclusions: Eccentric viewing training did not systematically improve task ability, reading performance, or fixation stability in this study. Our results do not support the routine use of eccentric viewing training for people with progressing age-related macular disease, although this training may help people with end-stage disease. Rehabilitation of an inherently progressive condition is challenging. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Test-Retest Variability and Discriminatory Power of Measurements From Microperimetry and Dark Adaptation Assessment in People With Intermediate Age-Related Macular Degeneration - A MACUSTAR Study Report.

Purpose: The purpose of this study was to assess test-retest variability and discriminatory power of measures from macular integrity assessment (S-MAIA) and AdaptDx. Methods: This is a cross-sectional study of 167 people with intermediate age-related macular degeneration (iAMD), no AMD (controls; n = 54), early AMD (n = 28), and late AMD (n = 41), recruited across 18 European ophthalmology centers. Repeat measures of mesopic and scotopic S-MAIA average (mean) threshold (MMAT decibels [dB] and SMAT [dB]) and rod intercept time (RIT [mins]) at 2 visits 14 (±7) days apart were recorded. Repeat measures were assessed by Bland-Altman analysis, intra-class correlation coefficients (ICCs) and variability ratios. Secondary analysis assessed the area under the receiver operating characteristic curves (AUC) to determine the ability to distinguish people as having no AMD, early AMD, or iAMD. Results: Data were available for 128, 131, and 103 iAMD participants for the mesopic and scotopic S-MAIA and AdaptDx, respectively. MMAT and SMAT demonstrate similar test-retest variability in iAMD (95% confidence interval [CI] ICC of 0.79-0.89 and 0.78-0.89, respectively). ICCs were worse in RIT (95% CI ICC = 0.55-0.77). All tests had equivalent AUCs (approximately 70%) distinguishing between subjects with iAMD and controls, whereas early AMD was indistinguishable from iAMD on all measures (AUC = <55%). A learning effect was not seen in these assessments under the operating procedures used. Conclusions: MMAT, SMAT, and RIT have adequate test-retest variability and are all moderately good at separating people with iAMD from controls. Translational Relevance: Expected levels of test-retest variability and discriminatory power of the AdaptDx and MAIA devices in a clinical study setting must be considered when designing future trials for people with AMD.

Repeatability and Discriminatory Power of Chart-Based Visual Function Tests in Individuals With Age-Related Macular Degeneration: A MACUSTAR Study Report.

Importance: There is a need for validated clinical end points that are reliably able to quantify potential therapeutic effects of future treatments targeting age-related macular degeneration (AMD) before the onset of serious visual impairment. Objective: To assess the reliability and discriminatory power of 5 simple chart-based visual function (VF) tests as potential measures for clinical trial end points with regulatory and patient-access intention in intermediate AMD (iAMD). Design, Setting, and Participants: This international noninterventional study took place at 18 tertiary ophthalmology departments across Europe. Participants were recruited between April 2018 and March 2020 and were identified during routine clinical review. Participants with no AMD and early AMD were recruited from hospital staff, friends, and family of participants with AMD and via referrals from community ophthalmologists and optometrists. The repeatability and discriminatory power of 5 simple chart-based assessments of VF (best-corrected visual acuity [BCVA], low-luminance visual acuity [LLVA], Moorfields Acuity Test [MAT], Pelli-Robson Contrast Sensitivity [CS], and International Reading Speed Test [IReST]) were assessed in a repeated-measures design. VF assessments were performed on day 0 and day 14. Participants with early AMD, iAMD, late AMD, and no AMD were recruited. Main Outcomes and Measures: Intraclass correlation coefficients (ICCs) and Bland-Altman 95% limits of agreement (LoA) were computed to assess repeatability. Area under the receiver operating characteristic curves (AUCs) determined the discriminatory ability of all measures to classify individuals as having no AMD or iAMD and to differentiate iAMD from its neighboring disease states. Results: A total of 301 participants (mean [SD] age, 71 [7] years; 187 female participants [62.1%]) were included in the study. Thirty-four participants (11.3%) had early AMD, 168 (55.8%) had iAMD, 43 (14.3%) had late AMD, and 56 (18.6%) had no AMD. ICCs for all VF measures ranged between 0.88 and 0.96 when all participants were considered, indicating good to excellent repeatability. All measures displayed excellent discrimination between iAMD and late AMD (AUC, 0.92-0.99). Early AMD was indistinguishable from iAMD on all measures (AUC, 0.54-0.64). CS afforded the best discrimination between no AMD and iAMD (AUC, 0.77). Under the same conditions, BCVA, LLVA, and MAT were fair discriminators (AUC, 0.69-0.71), and IReST had poor discrimination (AUC, 0.57-0.61). Conclusions and Relevance: BCVA, LLVA, MAT, CS, and IReST had adequate repeatability in this multicenter, multiexaminer setting but limited power to discriminate between no AMD and iAMD. The prognostic power of these variables to predict conversion from iAMD to late AMD is being examined in the ongoing longitudinal part of the MACUSTAR study.

Lockdown low vision assessment: an audit of 500 telephone-based modified low vision consultations.

PURPOSE: Non-urgent face-to-face outpatient ophthalmology appointments were suspended in the United Kingdom in March 2020, due to the COVID-19 outbreak. In common with other centres, Moorfields Eye Hospital NHS Foundation Trust (London) offered modified telephone consultations to new and follow-up patients in the low vision clinic. Here we assess the success of this telephone service. METHODS: Data were collected for 500 consecutive telephone low vision appointments. Successful completion of the assessment and clinical outcomes (low vision aids prescribed, onward referral) were recorded. RESULTS: Telephone assessments were completed for 364 people (72.8%). The most common reasons for non-completion were either no answer to the telephone call (75 people, 15%), or the patient declining assessment (20 people, 4%). There was no association between age and the likelihood of an assessment being completed. 131 new low vision aids were dispensed, 77 internal referrals were made and 15 people were referred to outside services. More than 80% of the low vision aids prescribed were useful. CONCLUSIONS: Telephone low vision assessments were completed in about three-quarters of cases. About one-quarter of consultations resulted in new low vision aids being dispensed, which were generally found useful. Telephone low vision assessments can be used successfully in a large low vision clinic, but have many limitations when compared to face-to-face assessments.

Clinical Perspectives and Trends: Microperimetry as a Trial Endpoint in Retinal Disease.

Endpoint development trials are underway across the spectrum of retinal disease. New validated endpoints are urgently required for the assessment of emerging gene therapies and in preparation for the arrival of novel therapeutics targeting the early stages of common sight-threatening conditions such as age-related macular degeneration and diabetic macular oedema. Visual function measures are likely to be key candidates in this search. Over the last 2 decades, microperimetry has been used extensively to characterise functional vision in a wide range of retinal conditions, often detecting subtle defects in retinal sensitivity that precede visual acuity loss and tracking disease progression over relatively short periods of time. Given these appealing features, microperimetry has already been adopted as an endpoint in interventional studies, including multicentre trials, on a modest scale. A review of its use to date shows a concurrent lack of consensus in test strategy and a wealth of innovative disease and treatment-specific metrics which may show promise as clinical trial endpoints. There are practical considerations to consider for its use, but these have not held back its popularity and it remains a widely used psychophysical test in research. Endpoint development trials will undoubtedly be key in understanding the validity of microperimetry as a clinical trial endpoint, but existing signs are promising.

Use of Composite End Points in Early and Intermediate Age-Related Macular Degeneration Clinical Trials: State-of-the-Art and Future Directions.

The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite end points as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite end points used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite end point categories were: combined structural and functional end points, combined structural end points, combined functional end points and combined multicategorical end points. The majority of the studies included binary composite end points. There was a lack of sensitivity analyses of different end points against accepted outcomes (i.e., progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined end points in clinical studies of early stages of AMD exists, and no surrogate end points have been accepted for AMD progression.

Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom.

Overall, approximately one-quarter of patients with genetic eye diseases will receive a molecular diagnosis. Patients with developmental eye disorders face a number of diagnostic challenges including phenotypic heterogeneity with significant asymmetry, coexisting ocular and systemic disease, limited understanding of human eye development and the associated genetic repertoire, and lack of access to next generation sequencing as regarded not to impact on patient outcomes/management with cost implications. Herein, we report our real world experience from a pediatric ocular genetics service over a 12 month period with 72 consecutive patients from 62 families, and that from a cohort of 322 patients undergoing whole genome sequencing (WGS) through the Genomics England 100,000 Genomes Project; encompassing microphthalmia, anophthalmia, ocular coloboma (MAC), anterior segment dysgenesis anomalies (ASDA), primary congenital glaucoma, congenital cataract, infantile nystagmus, and albinism. Overall molecular diagnostic rates reached 24.9% for those recruited to the 100,000 Genomes Project (73/293 families were solved), but up to 33.9% in the clinic setting (20/59 families). WGS was able to improve genetic diagnosis for MAC patients (15.7%), but not for ASDA (15.0%) and congenital cataracts (44.7%). Increased sample sizes and accurate human phenotype ontology (HPO) terms are required to improve diagnostic accuracy. The significant mixed complex ocular phenotypes distort these rates and lead to missed variants if the correct gene panel is not applied. Increased molecular diagnoses will help to explain the genotype-phenotype relationships of these developmental eye disorders. In turn, this will lead to improved integrated care pathways, understanding of disease, and future therapeutic development.

Clinical study protocol for a low-interventional study in intermediate age-related macular degeneration developing novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention-MACUSTAR.

BACKGROUND: There is an unmet need for treatment options in intermediate age-related macular degeneration (iAMD). However, for any new interventions to be tested in clinical trials, novel currently unavailable clinical endpoints need to be developed. Thus, the MACUSTAR study aims to develop and evaluate functional, structural, and patient-reported candidate endpoints for use in future iAMD trials. METHODS: The protocol describes a low-interventional clinical multicenter study employing a novel two-part design. The cross-sectional part (total duration, 1 month) and the longitudinal part (total duration, 36 months) include participants with iAMD and control groups with early/late/no AMD. The cross-sectional part's primary objective is a technical evaluation of functional, structural, and patient-reported candidate outcomes. The longitudinal part's primary objective is to assess the prognostic power of changes in functional, structural, and patient-reported outcomes for progression from iAMD to late AMD. All data will be used to support a biomarker qualification procedure by regulatory authorities. DISCUSSION: The MACUSTAR study characterizes and evaluates much needed novel functional, structural, and patient-reported endpoints for future clinical trials in iAMD and will improve our understanding of the natural history and prognostic markers of this condition. TRIAL REGISTRATION: ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017.

MACUSTAR: Development and Clinical Validation of Functional, Structural, and Patient-Reported Endpoints in Intermediate Age-Related Macular Degeneration.

PURPOSE: Currently, no outcome measures are clinically validated and accepted as clinical endpoints by regulatory agencies for drug development in intermediate age-related macular degeneration (iAMD). The MACUSTAR Consortium, a public-private research group funded by the European Innovative Medicines Initiative intends to close this gap. PROCEDURES: Development of study protocol and statistical analysis plan including predictive modelling of multimodal endpoints based on a review of the literature and expert consensus. RESULTS: This observational study consists of a cross-sectional and a longitudinal part. Functional outcome measures assessed under low contrast and low luminance have the potential to detect progression of visual deficit within iAMD and to late AMD. Structural outcome measures will be multimodal and investigate topographical relationships with function. Current patient-reported outcome measures (PROMs) are not acceptable to regulators and may not capture the functional deficit specific to iAMD with needed precision, justifying development of novel PROMs for iAMD. The total sample size will be n = 750, consisting mainly of subjects with iAMD (n = 600). CONCLUSIONS: As clinical endpoints currently accepted by regulators cannot detect functional loss or patient-relevant impact in iAMD, we will clinically validate novel candidate endpoints for iAMD.

A Discussion of Commercially Available Intra-ocular Telescopic Implants for Patients with Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the western world, causing significant reduction in quality of life. Despite treatment advances, the burden of visual impairment caused by AMD continues to rise. In addition to traditional low vision rehabilitation and support, optical and electronic aids, and strategies to enhance the use of peripheral vision, implantable telescopic devices have been indicated as a surgical means of enhancing vision. Here we examine the literature on commercially available telescopic devices discussing their design, mode of action, surgical procedure and published outcomes on visual acuity, quality of life, surgical complication rates and cost effectiveness data where available.Funding Article processing charges were funded by VisionCare Inc.

Patient and public preferences for health states associated with AMD.

PURPOSE: Health utility values suitable for calculating quality-adjusted life-years are increasingly used to assess the cost-effectiveness of treatments for age-related macular degeneration (AMD). In the United States, health utilities are usually derived from the patients' own valuation or modeled using visual acuity as a surrogate outcome. In the United Kingdom and throughout Europe, health utilities are derived from public valuations. Our aim was to test if utility values for health states associated with AMD elicited directly from patients were different from those calculated from public tariffs for health-related quality of life (HRQoL) questionnaires. METHODS: Generic preference-based HRQoL questionnaires (EQ-5D and SF-6D) and the time trade-off (TTO) and visual analog scale (VAS) valuation techniques were administered to a sample of UK patients with AMD (N = 60). Health utilities were calculated using standard general population tariffs for the patient EQ-5D and SF-6D health states and directly from patient TTO and VAS scores. RESULTS: Mean utilities derived from the public tariffs were significantly higher than from patients' valuation (mean [±SD], 0.613 (±0.275) for the EQ-5D and 0.628 (±0.114) for the SF-6D compared with 0.481 [±0.411] for the TTO and 56.7 [±21.8] for the VAS score; p < 0.001). The EQ-5D was not significantly different from the SF-6D (p > 0.6). Visual acuity in the better seeing eye was not associated with any utility measure (all r < 0.08; p > 0.2). CONCLUSIONS: Patient and public preferences for health states associated with AMD are different, with patients valuing their health state more severely than the public tariffs of commonly used HRQoL questionnaires. Visual acuity did not predict health utility using any measure, and therefore, care should be taken when using visual acuity as a surrogate measure for utility in health economic analyses.

The effect of low vision rehabilitation in diabetic eye disease: a randomised controlled trial protocol.

PURPOSE: Current research highlights a rising incidence of diabetes and its complications. Diabetic retinopathy is the leading cause of blindness within the working-age population of the United Kingdom. Increasing severity of retinopathy is associated with reduced visual function and participation in daily living. Only 8% of those referred to Moorfields Eye Hospital's low vision clinic have diabetic eye disease, a value less than prevalence figures for diabetes would predict. The lack of evidence for effectiveness of low vision intervention in this patient group could be responsible. Therefore, in line with CONSORT guidance, we present the methodology of the first randomised controlled trial to quantify the effect of low vision rehabilitation on people with diabetic eye disease. METHODS: One hundred participants were recruited into four retinopathy severity groups based on their diagnosis according to the English National Screening Programme Grading Protocol. Participants were randomised to either immediate intervention (1-2 weeks after enrollment) or delayed (control) intervention (3 months after enrollment). Intervention was a standard low vision assessment performed in a hospital clinic. The Activity Inventory (AI), was administered to all participants by telephone within 1 week of enrollment (before any intervention) and repeated at 3 and 6 months. RESULTS: One hundred participants (Type 1: 28, Type 2: 72; male: 62, female 38) have been recruited. Median habitual distance acuity was 0.19 logMAR (6/9, 20/30), with an interquartile range of 0.06-0.30 logMAR (6/7.5-6/12, 20/25-20/40). AI responses were scored by Rasch analysis, providing a measure of visual ability. Median baseline visual ability was 1.64 logits, with an interquartile range of 0.60-3.75 logits. Difference in mean change in visual ability between intervention groups will be assessed 3 months (primary outcome) and 6 months (secondary outcome) after enrollment. CONCLUSIONS: This is the first randomised controlled trial investigating the effectiveness of low vision rehabilitation for people with diabetic eye disease. With recruitment already complete, it is hoped this work will be the first step in guiding referral criteria for those with diabetic eye disease into the low vision service.

Fixation stability: a comparison between the Nidek MP-1 and the Rodenstock scanning laser ophthalmoscope in persons with and without diabetic maculopathy.

PURPOSE: Impaired fixation stability is associated with reduced reading speed. In previous research, fixation stability has been assessed using an infrared eye tracker or a confocal scanning laser ophthalmoscope. The new MP-1 microperimeter from Nidek Technologies (Padova, Italy) provides another option for the assessment of fixation. Here the authors compare fixation stability values measured using the MP-1 microperimeter and the Rodenstock scanning laser ophthalmoscope (SLO; Rodenstock GmbH, Munich, Germany) in persons with and without diabetic maculopathy. METHODS: Sixteen normally sighted volunteers and 21 patients with diabetic maculopathy were recruited. Fixation stability was recorded monocularly on the SLO and the MP-1 in counterbalanced order while participants fixated a red 1 degree cross. Fixation data collected from each instrument were used to calculate a bivariate contour ellipse area (BCEA) that encompassed 68% of fixation points. RESULTS: For control subjects, MP-1 BCEA values were larger than SLO by 0.25 log min arc(2), though the difference was small (10%) and of borderline significance (MP-1, 2.51 log min arc(2); SLO, 2.26 log min arc(2); P = 0.06). In patients with diabetic maculopathy there was no significant difference between MP-1 and SLO values (MP-1, 2.94 log min arc(2); SLO, 2.90 log min arc(2); P = 0.88). CONCLUSIONS: No significant difference was found in BCEA values from the SLO and MP-1 in control subjects and patients with diabetic maculopathy. The authors suggest that the similarity between BCEA values, together with the consistent and reliable operation of the MP-1, make it a useful and viable alternative to the SLO in the assessment of fixation.

Fixation stability measurement using the MP1 microperimeter.

PURPOSE: The Nidek microperimeter (MP1, Nidek Instruments, Italy) is a microperimetry device that also assesses fixation stability. The MP1 does not use the method of quantifying fixation stability by calculating a bivariate contour ellipse area (BCEA). Here we compare the MP1 fixation quantification with the BCEA technique by correlating these values to various parameters of reading known to be related to fixation stability. METHODS: Twenty-five people with age-related macular disease were assessed. Eye position was recorded using the MP1 during a fixation task. Fixation score and central 2 degrees and central 4 degrees values were obtained from the MP1. Bivariate contour ellipse area values were calculated from raw fixation data. Reading was assessed using MNREAD, Rapid Serial Visual Presentation, and European reading tests. RESULTS: Fixation data could not be collected for two observers. For the other 23 participants, the MP1 fixation scores were very poorly related to reading parameters. In contrast, there was a significant relationship between fixation stability assessed using the BCEA technique and Rapid Serial Visual Presentation reading speed (r = -0.59, P < 0.01), European reading test reading error rate (r = 0.66, P < 0.01), and MNREAD peak reading speed (r = 0.55, P < 0.05). CONCLUSION: Using the software supplied with the MP1 does not adequately quantify fixation stability in people with age-related macular disease. We recommend that the BCEA technique is used to quantify fixation stability when using the MP1 microperimeter.