Efficacy and safety of AZR-MD-001 selenium sulfide ophthalmic ointment in adults with meibomian gland dysfunction: A vehicle-controlled, randomized clinical trial.

PURPOSE: Meibomian gland dysfunction (MGD) is a chronic progressive disease with downstream effects on ocular signs and symptoms. AZR-MD-001 is a selenium sulfide ophthalmic ointment that was investigated as a potential treatment option for patients with MGD. METHODS: A Phase 2, multi-center, double-masked, parallel group study was conducted across 29 sites, with 245 patients randomized 1:1:1 to AZR-MD-001 0.5%, AZR-MD-001 1.0% or vehicle applied to the lower eyelid, twice weekly. Patients were eligible for the trial if they presented with signs and symptoms of MGD. Co-primary efficacy endpoints were the changes from baseline in number of open glands (Meibomian Glands Yielding Liquid Secretion [MGYLS] score) and patient-reported ocular surface symptoms (Ocular Surface Disease Index [OSDI] total score) at Month 3. Efficacy outcomes were captured at Day 14, Month 1.5 and Month 3. Safety and tolerability were assessed for treatment-emergent adverse events (TEAEs). RESULTS: AZR-MD-001 0.5% (n = 82 patients) treatment resulted in significant improvements in MGYLS score, with patients experiencing an average increase from baseline of 4.2 and 2.4 open glands secreting meibum for the drug and vehicle, respectively (p < 0.001) and from baseline a mean OSDI total score improvement of 7.3 and 3.8 for the drug and vehicle, respectively (p < 0.05). Most TEAEs were mild and transient, with 3 serious adverse events (SAEs) reported with AZR-MD-001 (none related to study drug). CONCLUSIONS: Co-primary endpoints were met for AZR-MD-001 0.5% at Month 3, with a statistically significant improvement in the signs and symptoms of MGD. AZR-MD-001 was safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03652051, ANZCTR Registration Number: AZ201801.

Automated Identification of Lesion Activity in Neovascular Age-Related Macular Degeneration.

PURPOSE: The objective of the study was to evaluate the accuracy of the Notal OCT Analyzer (NOA) versus that of a retina specialist (RS) in the automated detection of fluid on optical coherence tomography (OCT). DESIGN: A study of the performance of the NOA compared with the results from 3 RSs. PARTICIPANTS: A selection of 155 anonymized OCT scans (Zeiss Cirrus; Carl Zeiss Meditec, Dublin, CA) from an image repository at a single tertiary referral retina center (Belfast Health and Social Care Trust, Belfast, United Kingdom) after approval from the local data guardian of the clinical site. METHODS: One hundred fifty-five OCT cube scans were stripped of all clinical identifiers and exported. The NOA and 3 independent RSs analyzed all 128 B-scans of each cube scan for the presence of intraretinal fluid, subretinal fluid, and sub-retinal pigment epithelium fluid. The NOA also ranked individual B-scans of each volume scan for likelihood of CNV activity, which was subjected to a second grading session by the 3 RSs. MAIN OUTCOME MEASURES: The NOA's sensitivity and specificity versus the RS grading and the NOA's performance in ranking B-scans for activity. RESULTS: One hundred forty-two cube scans met the inclusion criteria for the primary analysis. On testing the RS grading versus the NOA, the accuracy was 91% (95% confidence interval [CI], ±7%), sensitivity was 92% (95% CI, ±6%), and specificity was 91% (95% CI, ±6%), meeting the primary outcome. The graders' accuracy when compared with the majority of the other graders (including a fourth grader) was 93%. On average, the 3 graders could identify fluid in 95% of scans by just reviewing a single cross-section with the highest NOA score and 99.5% of scans with fluid by viewing the top 3 cross-sections. CONCLUSIONS: Concordance between the NOA and the RS determination of lesion activity was extremely high. The level of discrepancy between the RS and the NOA results was similar to the NOA's mismatches. Our results show that automated delineation of the retinal contours combined with interpretation of disease activity is feasible and has the potential to become a powerful tool in terms of its clinical applications.

Short-Term Retinal Sensitivity and Metamorphopsia Changes following Half-Fluence Photodynamic Therapy in Central Serous Chorioretinopathy.

PURPOSE: The aim of this study was to investigate the short-term retinal sensitivity and metamorphopsia changes after half-fluence photodynamic therapy (PDT) in patients with central serous chorioretinopathy (CSC). METHODS: Patients with acute CSC and evidence of angiographic leakage and subretinal fluid on optical coherence tomography (OCT) were enrolled. Before, and 1 week (W-1) and 2 months (M-2) after PDT, all patients underwent best-corrected visual acuity, enhanced depth imaging OCT, microperimetry (MP) and preferential hyperacuity perimetry (PHP). We considered 'affected' the Early Treatment of Diabetic Retinopathy Study (ETDRS) sectors showing a mean retinal thickness greater than 350 µm on the baseline OCT thickness map. MP retinal sensitivity, PHP 'score' and retinal thickness were measured in each ETDRS 'affected sector'. Functional correlation between MP and PHP was also investigated. RESULTS: Twelve eyes of 12 patients were included. MP and PHP correlated with each other at baseline (p = 0.04) but not at W-1 (p = 0.12) and M-2 (p = 0.05). Mean MP retinal sensitivity slightly improved from 12.9 ± 5.0 dB at baseline to 14.5 ± 4.7 dB at M-2 (p = 0.2). The PHP score changed from 0.33 at baseline to 0.32 at M-2 (p = 0.3). In the ETDRS 'affected sectors', MP retinal sensitivity improved significantly from 12.9 ± 5.0 dB at baseline to 14.5 ± 4.7 dB at M-2 (p = 0.03), whereas the PHP score did not show significant changes over time. CONCLUSION: Half-fluence PDT achieved short-term improvement in the sensitivity of the retinal 'affected sectors' but did not influence metamorphopsia as measured on PHP in patients with acute CSC.

Functional characterization and multimodal imaging of treatment-naive "quiescent" choroidal neovascularization.

PURPOSE: To investigate the multimodal morphological and functional characteristics of treatment-naïve "quiescent" choroidal neovascularization (CNV) secondary to AMD. METHODS: Eleven patients with treatment-naïve "quiescent" CNV that consecutively presented over a 6-month period, underwent multimodal morphological and functional assessment (including indocyanine green angiography [ICGA], spectral-domain optical coherence tomography [SD-OCT], microperimetry, and preferential hyperacuity perimeter [PHP]). For the purpose of this study, asymptomatic previously untreated CNVs showing absence of intraretinal/subretinal exudation in two consecutive visits (at least 6 months apart) were defined as treatment-naïve "quiescent" CNV. RESULTS: Eleven eyes of 11 patients (9 females; mean age 76.5 ± 8.5 years) were included. On fluorescein angiography (FA), "quiescent" CNVs appeared as late speckled hyperfluorescent lesions lacking well-demarcated borders. Mid-late phase ICGA allowed visualizing the hyperfluorescent "quiescent" CNV network and delineating the plaque. Mean lesion area (mid-late phase ICGA) appeared larger compared with earliest previous examination performed 23.8 ± 16.0 months before (3.24 ± 2.51 mm(2) vs. 3.52 ± 2.46 mm(2), respectively; P = 0.01). SD-OCT revealed, at the site of "quiescent" CNV, an irregularly slightly elevated RPE, without hyporeflective intraretinal/subretinal fluid, showing a major axis in the horizontal plane, which was characterized by collections of moderately reflective material in the sub-RPE space and clear visualization of the hyperreflective Bruch's membrane. Hypergeometric distribution revealed a significant correlation between microperimetry and PHP with respect to locations of "affected areas" (P = 0.001). CONCLUSIONS: "Quiescent" CNVs are sub-RPE CNVs secondary to AMD, showing absence of intraretinal/subretinal exudation on repeated OCT. "Quiescent" CNVs enlarge over time and may contribute to local reduced retinal sensitivity and metamorphopsia.

Preferential hyperacuity perimeter as a functional tool for monitoring exudative age-related macular degeneration in patients treated by intravitreal ranibizumab.

PURPOSE: To analyze the response to anti vascular endothelial growth factor (VEGF) treatment for exudative age-related macular degeneration (AMD), with respect to changes in the Preferential Hyperacuity Perimeter (PHP), best-corrected visual acuity (BCVA), and spectral-domain optical coherence tomography (SD-OCT), and to investigate whether the PHP score predicts the need for reinjection. METHODS: Consecutive patients with newly diagnosed exudative AMD underwent the PHP metamorphopsia test, BCVA, and SD-OCT at five time points after initiation of ranibizumab therapy (0.05 mL/0.5 mg). At the third and sixth months, reevaluation for additional injections was done. The relationships between PHP, BCVA, and SD-OCT parameters over time as well as their ability to predict the need for reinjection were examined. RESULTS: Analysis included 17 eyes (17 patients, 70% females; mean age, 83.2 years). The mean PHP metamorphopsia test score improved from 25.6 ± 41 (baseline) to 10.7 ± 20.1 (P < 0.05) over 6 months, after a mean of 4.2 (±1.0) injections. Mean reduction in SD-OCT parameters well reflected the functional improvements as evaluated by PHP (Spearman correlation = 0.9, P < 0.05). Mean BCVA did not improve over 6 months (0.6 vs. 0.58 logMAR), and neither correlated with SD-OCT morphologic changes (Spearman correlation = 0.1, P > 0.05) nor with PHP functional changes (Spearman correlation = 0.1, P > 0.05). The PHP predicted the need for reinjection with an accuracy of 75% (sensitivity, 83 ± 12%; specificity, 67 ± 15%), whereas a combination of all the measurements (PHP, BCVA, and SD-OCT) yielded an accuracy of 87% (sensitivity, 83 ± 12%; specificity, 90 ± 10%). CONCLUSIONS: Improvement in the metamorphopsia test score after intravitreal injections of ranibizumab, as well as its ability to predict the need for retreatment, suggest that PHP may be used to monitor response to anti-VEGF therapy in patients with exudative AMD.

Toward earlier detection of choroidal neovascularization secondary to age-related macular degeneration: multicenter evaluation of a preferential hyperacuity perimeter designed as a home device.

PURPOSE: The primary purpose of this study was to evaluate the ability of a home device preferential hyperacuity perimeter to discriminate between patients with choroidal neovascularization (CNV) and intermediate age-related macular degeneration (AMD), and the secondary purpose was to investigate the dependence of sensitivity on lesion characteristics. METHODS: All participants were tested with the home device in an unsupervised mode. The first part of this work was retrospective using tests performed by patients with intermediate AMD and newly diagnosed CNV. In the second part, the classifier was prospectively challenged with tests performed by patients with intermediate AMD and newly diagnosed CNV. The dependence of sensitivity on lesion characteristics was estimated with tests performed by patients with CNV of both parts. RESULTS: In 66 eyes with CNV and 65 eyes with intermediate AMD, both sensitivity and specificity were 0.85. In the retrospective part (34 CNV and 43 intermediate AMD), sensitivity and specificity were 0.85 +/- 0.12 (95% confidence interval) and 0.84 +/- 0.11 (95% confidence interval), respectively. In the prospective part (32 CNV and 22 intermediate AMD), sensitivity and specificity were 0.84 +/- 0.13 (95% confidence interval) and 0.86 +/- 0.14 (95% confidence interval), respectively. Chi-square analysis showed no dependence of sensitivity on type (P = 0.44), location (P = 0.243), or size (P = 0.73) of the CNV lesions. CONCLUSION: A home device preferential hyperacuity perimeter has good sensitivity and specificity in discriminating between patients with newly diagnosed CNV and intermediate AMD. Sensitivity is not dependent on lesion characteristics.

Preferential Hyperacuity Perimetry to detect hydroxychloroquine retinal toxicity.

PURPOSE: To determine if Preferential Hyperacuity Perimetry (PHP) testing can detect the presence of retinal toxicity due to hydroxychloroquine (HCQ) or chloroquine administration. METHODS: Fifteen patients were divided into three groups. Five patients had confirmed HCQ or chloroquine toxicity, five patients had suspected HCQ toxicity, and five patients had history of long-term use of HCQ or chloroquine but no evidence of toxicity. All patients underwent PHP testing. RESULTS: All patients with either known or suspected toxicity based upon standardized visual field testing and/or fluorescein angiography demonstrated significant hyperacuity defects on PHP testing. None of the patients on long-term HCQ therapy, without clinical suspicion of toxicity, demonstrated a PHP hyperacuity defect. CONCLUSION: Results of this pilot study with patients with known or suspected HCQ or chloroquine toxicity suggest that PHP may be a useful adjunct for testing of patients suspicious for toxicity due to these medications. Further testing is warranted.

Results of a multicenter clinical trial to evaluate the preferential hyperacuity perimeter for detection of age-related macular degeneration.

PURPOSE: To compare the preferential hyperacuity perimeter (PHP) with an Amsler grid in detection of age-related macular degeneration (AMD). METHODS: Patients underwent refraction, visual acuity examination, PHP, Amsler grid examination, and macular photography. RESULTS: One hundred fifty patients participated in the trial. Of 19 eyes with neovascular AMD, 19 (100%) were positive on the PHP, and 10 (53%), on the Amsler grid. Of 27 eyes with geographic atrophy, 26 (96%) were positive on the PHP, and 12 (44%), on the Amsler grid. Of 20 eyes with intermediate AMD, 14 (70%) were positive on the PHP, and 4 (20%), on the Amsler grid. Of 51 eyes with early AMD, 21 (41%) were positive on the PHP, and 4 (8%), on the Amsler grid. Of 33 eyes with no AMD, 6 (18%) were positive on the PHP, and none, on the Amsler grid. Thus, 80 (68%) of 117 patients with AMD had a positive PHP, while 30 (26%) had positive results of Amsler grid examination (P < 0.001, McNemar test). CONCLUSION: The PHP had greater sensitivity, although with a relatively high rate of false-positive results for healthy individuals, than the Amsler grid in detecting AMD-related lesions.

Replacing the Amsler grid: a new method for monitoring patients with age-related macular degeneration.

PURPOSE: To investigate a method that uses hyperacuity, the Macular Computerized Psychophysical Test (MCPT), to evaluate the central macular visual field in patients with age-related macular degeneration (AMD). DESIGN: Prospective case-control study of a diagnostic test. PARTICIPANTS AND CONTROLS: One hundred eight eyes of 108 Patients with AMD and 51 eyes of 51 age-matched patients with no retinal disease. Patients with AMD included 32 (30%) patients with choroidal neovascularization (CNV), 23 (21%) with geographic atrophy (GA), 35 (32%) with AMD with high-risk characteristics (HRC), and 18 (17%) with early AMD with non-HRC. TESTING: Each subject underwent the MCPT, in which a virtual line composed of dots (white dots on a black background, maximal contrast) is flashed across different macular loci to a perifoveal radius of 7 degrees. Patients' responses were recorded and automatically analyzed using a specific algorithm developed before the onset of the study. All patients also underwent a supervised Amsler grid examination on the encounter before or after the MCPT in random order. MAIN OUTCOME MEASURES: Distortion, scotoma, or blurring perceived by the patient after a swift change of fixation was considered positive on the MCPT. Any perception of distortion, scotoma, or blurring was considered positive on the Amsler grid. RESULTS: Of the 32 patients with CNV, 30 (94%) were found positive on the MCPT and 11 (34%) were found positive on the Amsler grid. Of the 23 GA patients, 21 (91%) were found positive on the MCPT and 7 (30%) were found positive on the Amsler grid. Of the 35 HRC patients, 28 (80%) were found positive on the MCPT and 3 (9%) were found positive on the Amsler grid, and of the 18 early AMD with non-HRC patients, 8 (44%) were found positive on the MCPT and 3 (17%) were found positive on the Amsler grid. Of the 51 controls, 3 (6%) were positive on the MCPT and 1 (2%) was positive on the Amsler grid. CONCLUSIONS: The MCPT was superior to the Amsler grid in detecting AMD-related lesions in this cohort. Studies are underway to determine whether the MCPT is feasible for home monitoring to provide early detection of progression to CNV.