Efficacy and Safety of CSF-1 (0.4% Pilocarpine Hydrochloride) in Presbyopia: Pooled Results of the NEAR Phase 3 Randomized, Clinical Trials.

PURPOSE: This study was undertaken to evaluate the safety and efficacy of CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) for use in individuals with presbyopia. METHODS: Two Phase 3 multicenter, randomized, double-masked, vehicle-controlled, parallel-group clinical trials were conducted in 35 private ophthalmology clinics in the United States from October 2020 to February 2022. Key inclusion criteria were the following: (1) age 45-64 years, (2) distance-corrected near visual acuity (DCNVA) at 40 cm ≥0.40 and ≤0.90 logarithm of the minimum angle of resolution (logMAR, approximately 20/50-20/160 Snellen) in at least 1 eye, (3) manifest refraction (MR) between -4.50 and +2.00 diopter (D) sphere in each eye with ≤2.00D difference between eyes, (4) <2.00D of cylinder MR in each eye, (5) ≤0.04 logMAR (20/20-2 or better) corrected distance visual acuity (CDVA) at 4 m in each eye. Key exclusion criteria were the following: (1) >0.14 logMAR (7 letters) improvement in post-vehicle treatment in monocular DCNVA in either eye at visit 1, (2) introcular pressure (IOP) <9 or >22 mm Hg, (3) average dark-adapted pupillometry <3.5 mm in either eye, (4) prior refractive surgery or intraocular lens (IOL) implantation. Participants applied CSF-1 or vehicle twice per day for 2 weeks. Efficacy and safety assessments were performed at several times on days 1, 8, and 15. Response was defined as ≥3-line gain in DCNVA without loss of ≥1-line in CDVA in the study eye under mesopic room lighting conditions. The primary efficacy endpoint was measured 1 hour post-dose 1 on day 8. Key secondary endpoints were 2 hours post-dose 1, and 1 and 2 hours post-dose 2, also on day 8. Safety endpoints were ocular and non-ocular treatment-related adverse events (TRAE), conjunctival redness, drop comfort, slit-lamp biomicroscopy, intraocular pressure, indirect fundoscopy, and CDVA at 4 m. FINDINGS: Six hundred thirteen participants were randomized to CSF-1 (n = 309) or vehicle (n = 304). Participants were predominantly White (80.8%) and female (62.0%), with mean age (standard deviation) of 54.7 (4.8). CSF-1 met the primary and key secondary endpoints. At the primary endpoint, 40.1% of the CSF-1 group achieved response versus 19.1% of the vehicle group (P < 0.0001). The percentage of responders was significantly greater in CSF-1 compared with vehicle at all tested times. Changes from baseline in all safety endpoints were comparable between groups. Most adverse events (AEs) were mild and transient. Neither serious nor severe AEs were reported with CSF-1. IMPLICATIONS: CSF-1, a low-dose pilocarpine ophthalmic solution, demonstrated superiority to vehicle in improving near vision in individuals with presbyopia without compromising distance vision. CSF-1 demonstrated a favorable safety profile. CLINICALTRIALS: gov identifier: NCT04599933 (NEAR-1), NCT04599972 (NEAR-2).

Visual Field Artifacts in Glaucoma With Face Mask Use During the COVID-19 Pandemic.

PURPOSE: The coronavirus (COVID-19) pandemic has changed how outpatient care is delivered in ophthalmology clinics, particularly with glaucoma care. This case series highlights the need for awareness of fogging and improper face mask fit as causes of standard automated perimetry artifacts in patients with ocular hypertension and glaucoma. CLINICAL PRESENTATIONS: Six patients with the diagnosis of ocular hypertension, glaucoma suspect, or glaucoma underwent standard automated perimetry (24-2 or 10-2 SITA, Humphrey Field Analyzer) while wearing ear-loop surgical face masks. Due to patient complaints of fogging during the testing, low test reliability, and unexpected results, the tests were repeated after taping securely the mask to the bridge of the nose. CLINICAL FINDINGS: Fogging may reduce visual field (VF) test reliability and induce artifacts that mimic glaucomatous defects. VF test reliability can be improved and artifacts minimized following mask taping. In 1 case there was worsening of VF defects after mask taping. This suggests that fogging may also disguise true VF defects. CONCLUSIONS: Fogging can result in unreliable VF testing with glaucoma-like artifacts. Secure taping of the face mask to the nose bridge may minimize this problem and reduce unnecessary additional testing and follow-up visits.

Use of Topical Steroids in Conjunctivitis: A Review of the Evidence.

PURPOSE: Conjunctivitis, or inflammation of the conjunctiva, is a common condition that can be caused by infectious (eg, bacterial or viral infections) and noninfectious (eg, allergy) etiologies. Treatment involves diagnosis of the underlying cause and use of appropriate therapies. A broad-spectrum therapy that can address multiple etiologies, and also the accompanying inflammation, would be very useful. In this review, we discuss the usefulness of topical ophthalmic corticosteroids and ophthalmic formulations that combine corticosteroids with anti-infectives/antibiotics for treating acute infectious conjunctivitis. METHODS: A review of the published literature and relevant treatment guidelines. RESULTS: Topical corticosteroids are useful in treating ocular inflammation, but most treatment guidelines recommend steroid use generally in severe cases of conjunctivitis. This is partly due to risks associated with steroid use. These risks include potential for prolonging adenoviral infections and potentiating/worsening herpes simplex virus infections, increased intraocular pressure, glaucoma, and cataracts. Most of these perceived risks are not, however, supported by high-quality clinical data. They are also associated with long-term steroid uses that are dissimilar to applications for infectious conjunctivitis. Clinical data show that ophthalmic formulations that combine corticosteroids with broad-spectrum anti-infectives could be effective and well tolerated when used for short-term treatment (≤2 weeks). CONCLUSIONS: Corticosteroids, in combination with anti-infectives, could be a promising treatment option for acute conjunctivitis subject to development of further evidence on their effectiveness and safety in conjunctivitis treatment.

Latanoprostene bunod ophthalmic solution 0.024%: a new treatment option for open-angle glaucoma and ocular hypertension.

Latanoprostene bunod (LBN) ophthalmic solution 0.024% is a novel, once-daily, nitric oxide-donating prostaglandin analogue for the lowering of intraocular pressure (IOP) in patients with open-angle glaucoma and ocular hypertension. The IOP-lowering actions of LBN are mediated by dual mechanisms of the molecule for increasing aqueous humour outflow. The prostaglandin analogue moiety (latanoprost acid) increases uveoscleral outflow, whereas nitric oxide, released by the nitric oxide-donating moiety (butanediol mononitrate), increases outflow through the trabecular meshwork and the Schlemm's canal. The clinical efficacy and safety of LBN 0.024% in patients with open-angle glaucoma or ocular hypertension were established in two similarly designed, double-masked, pivotal phase 3 studies, APOLLO and LUNAR, the pooled three-month efficacy phase of which demonstrated significantly greater IOP-lowering of once-daily LBN 0.024% over twice-daily timolol 0.5% at all time points. Additional support for the IOP-lowering effects of LBN 0.024% was provided by two phase 2 studies in patients with open-angle glaucoma or ocular hypertension (a dose ranging study versus latanoprost and a 24-hour IOP crossover study versus timolol) and a phase 1 study of healthy volunteers with IOP in the normal range. In addition, long-term efficacy and safety were demonstrated in the open-label safety-extension phases of the phase 3 pivotal studies and a phase 3 52-week open-label study of patients with open-angle glaucoma (including normal-tension glaucoma) or ocular hypertension. In conclusion, LBN 0.024% has demonstrated both short-term and long-term IOP-lowering efficacy in patients with open-angle glaucoma or ocular hypertension, including in healthy volunteers and patients with IOP in the normal range, without apparent clinically-limiting safety or tolerability concerns.

The development of a reference database with the Topcon 3D OCT-1 Maestro.

IMPORTANCE: The paper presents the range for measurements taken with a new spectral domain optical coherence tomography (OCT) device to establish a reference database for discrimination purposes. OBJECTIVE: To report the range of thickness values for the new Topcon Maestro 3D OCT device with 2 scan size settings: the 12×9 mm wide field and 6×6 mm scans. DESIGN: Prospective, multicenter cohort study conducted at 7 clinical sites across the USA. SETTING: Primary eyecare clinics within academic, hospital, and private practice locations. PARTICIPANTS: Healthy volunteers; all enrolled participants underwent a complete ophthalmological examination to confirm healthy ocular status prior to being enrolled in the study. MAIN OUTCOME MEASURE: Average and 1st, 5th, 95th, and 99th percentile ranges for OCT parameters Early Treatment Diabetic Retinopathy Study macula full retinal thickness, ganglion cell + inner plexiform layer thickness (GCL + IPL), ganglion cell complex (GCC) thickness, circumpapillary retinal nerve fiber layer (cpRNFL) thickness. RESULTS: Three hundred and ninety-nine eyes of 399 subjects were included in the analysis. Mean (SD) age was 46.3 (16.3) years (range 18-88 years). Forty-three percent of the subjects were male. Mean (SD) measurements (in µm) for the 12×9 mm wide scan were as follows: foveal thickness=237.079 (20.899), GCL + IPL=71.363 (5.924), GCC=105.949 (8.533), cpRNFL=104.720 (11.829); measurements for the 6×6 mm scans were as follows: foveal thickness=234.000 (20.657), GCL + IPL=71.726 (5.880), GCC=106.698 (9.094), cpRNFL=104.036 (11.341). CONCLUSION: The overall normal thickness values reported with Topcon 3D OCT-1 Maestro were like those studies with OCT from different manufactures. The reference limits at the 1st, 5th, 95th, and 99th percentile points establish the thresholds for the quantitative comparison of the cpRNFL and the macula in the human retina to a database of known healthy subjects.

The Role of Minimally Invasive Glaucoma Surgery Devices in the Management of Glaucoma.

SIGNIFICANCE: Noncompliance is a problem affecting glaucoma patients. Approaches to improve adherence include the use of drug-delivery systems and safer forms of surgery. Minimally invasive glaucoma surgery (MIGS) has reduced complications, particularly in combination with cataract surgery, and with its good intraocular pressure (IOP) reduction may reduce or eliminate glaucoma medications.Glaucoma is a progressive disease and a leading cause of irreversible blindness. Elevated IOP is the most important risk factor, but effective medical management is dependent on patient adherence. This review summarizes the adherence problem in glaucoma and the efforts, including MIGS, to provide effective IOP control that is not dependent on patient compliance.The current understanding of patient adherence to pharmacological treatment of glaucoma is discussed including the challenges facing glaucoma patients. Historical approaches to providing IOP control in a sustained and reliable way are presented culminating in a review of the burgeoning use of MIGS devices.It is estimated that, in the United States, 27% of prescriptions written, across all medications, are not filled or are filled but not taken. For ocular hypotensive medications, even when filled, a large percentage (which varies widely by study) are not instilled as prescribed. To address this problem, methods for sustained drug delivery have been and continue to be developed, as well as surgical and laser approaches. Most recently, MIGS devices have gained popularity because of the ease of implantation during cataract surgery, favorable safety profile, and the possibility for effective and long-lasting IOP lowering, as well as the reduction or elimination of need for IOP-lowering medication.Poor adherence to treatment is relatively common among glaucoma patients and is associated with progression of disease. Recommending MIGS implantation during cataract surgery may offer optometrists a valuable treatment option in managing glaucoma patients, particularly where good adherence is in doubt.

Normative Databases for Imaging Instrumentation.

PURPOSE: To describe the process by which imaging devices undergo reference database development and regulatory clearance. The limitations and potential improvements of reference (normative) data sets for ophthalmic imaging devices will be discussed. METHOD: A symposium was held in July 2013 in which a series of speakers discussed issues related to the development of reference databases for imaging devices. RESULTS: Automated imaging has become widely accepted and used in glaucoma management. The ability of such instruments to discriminate healthy from glaucomatous optic nerves, and to detect glaucomatous progression over time is limited by the quality of reference databases associated with the available commercial devices. In the absence of standardized rules governing the development of reference databases, each manufacturer's database differs in size, eligibility criteria, and ethnic make-up, among other key features. CONCLUSIONS: The process for development of imaging reference databases may be improved by standardizing eligibility requirements and data collection protocols. Such standardization may also improve the degree to which results may be compared between commercial instruments.

The effects of race, optic disc area, age, and disease severity on the diagnostic performance of spectral-domain optical coherence tomography.

PURPOSE: To evaluate the effect of race (African or European descent), age, disc area, and severity of disease on the diagnostic ability of spectral-domain optical coherence tomography (SDOCT) imaging of the optic nerve, macula, and retinal nerve fiber layer (RNFL) in the detection of glaucomatous injury. METHODS: In this cross-sectional observational study, data from SDOCT images of 312 eyes of 167 subjects without ocular disease and 233 eyes of 163 patients with open-angle glaucoma. A receiver operating characteristic (ROC) regression modeling technique was used to evaluate the influence of race on the diagnostic accuracy of the ONH, RNFL, and macular parameters in SDOCT in glaucoma, while adjusting and evaluating the possible confounding effects of age, disease severity, and size of the optic disc. RESULTS: The optimal performing measurements of the RNFL and macula were more effective than optic nerve (aROC(RNFL) = 0.87, aROC(inner macula) = 0.88, and aROC(rim area) = 0.81) for the overall group. No variation was noted in the diagnostic performance of SDOCT between racial groups nor was there any association of race with differences in disc area for structural parameters of the optic nerve, RNFL, and macula. Advanced disease severity was associated with increased diagnostic accuracy, with improved performance in eyes with more severe visual field loss. CONCLUSIONS: The diagnostic ability of ONH, RNFL, and macular measurements in the detection of glaucoma was similar across racial groups, and disc area had a minimal effect on the overall diagnostic efficacy of SDOCT. No significant differences were seen in the diagnostic performance of the SDOCT between these groups when generalized or race-specific normative data were used.

Evaluation of decision rules for frequency-doubling technology screening tests.

PURPOSE: Frequency-doubling technology (FDT) perimetry has shown promise as a screening test for glaucoma. This study investigates different possible decision rules for FDT screening by applying them to groups of normal and glaucoma subjects. METHODS: Within three centers, 218 subjects (aged 15-88 years; 78 with glaucoma, 140 without ocular disease) were each tested twice with the screening program of the FDT perimeter. The subjects consisted of 140 normal subjects with no evidence of glaucoma or other ocular disease likely to affect the visual field and 78 subjects with a diagnosis of glaucoma and no other ocular disease. Fifteen decision rules were applied to the data to compare their sensitivity and specificity. RESULTS: Estimated specificities of the different decision rules ranged from 78% to 99%, although with this sample size, the confidence intervals for these estimates are quite large. Estimated sensitivities ranged from 40% to 72%. Suggested criteria for distinguishing normal subjects from those with glaucoma seem to be either a cluster of two or more adjacent locations abnormal at the p < 2% level with at least one location confirmed or a single location very abnormal (p < 1%) and confirmed. CONCLUSIONS: Specificity was clearly improved by confirming an apparently abnormal test result by repeating the screening test outweighing the resultant small loss in sensitivity. These findings provide useful information for making an informed choice of decision rules for FDT screening results.

Evaluation of screening versus regular polarimetry.

PURPOSE: The purpose of this study is to evaluate a new screening program for the GDx VCC (variable corneal compensation) retinal nerve fiber layer analyzer. This new method uses a fast screening approach to detect retinal nerve fiber layer loss associated with glaucoma. The study evaluates the sensitivity and specificity of the screening program and compares the results with those from the GDx VCC full examination. METHODS: One hundred seventeen eyes from 60 subjects with a mean age of 60.65 years (range, 41-79 years old) were analyzed. Subjects were divided into a normal or glaucoma group based on an ophthalmic examination. Each individual underwent a GDx VCC screening examination, GDx full examination, Humphrey HFA II 24-2 SITA Standard visual field, intraocular pressure assessment, and dilated optic nerve examination. The outcome for the GDx screening examination was within normal limits, borderline, or outside normal limits and compared with the GDx full examination results. RESULTS: The sensitivity and specificity for the GDx full examination were 73% and 79%, respectively. The sensitivity and specificity for the screening method were 67% and 91%, respectively. The full examination was more sensitive; however, the screening examination was more specific. CONCLUSION: The screening examination is more conservative than the full examination algorithm and may miss some individuals with glaucomatous damage that the full examination may identify. However, the number of false-positives for the screening examination is less than the full examination method.

Five rules to evaluate the optic disc and retinal nerve fiber layer for glaucoma.

A systematic approach for the examination of the optic disc and retinal nerve fiber layer is described that will aid in the detection of glaucoma. This approach encompasses 5 rules: evaluation of optic disc size, neuroretinal rim size and shape, retinal nerve fiber layer, presence of parapapillary atrophy, and presence of retinal or optic disc hemorrhages. A systematic process enhances the ability to detect glaucomatous damage as well as the detection of progression, and facilitates appropriate management.

Characteristics of the normative database for the Humphrey matrix perimeter.

PURPOSE: The Humphrey Matrix (Carl Zeiss Meditec, Dublin CA; Welch-Allyn, Skaneateles, NY) is a high-spatial-resolution perimeter that uses frequency-doubling stimuli. It incorporates an efficient test strategy that assumes that age, eccentricity, and test procedure type have only small effects on sensitivity. The results used to create the normative database for the perimeter were examined, to see whether these assumptions were met and to examine the form of the normative data. METHOD: Visual fields were measured (Matrix 30-2, 24-2, 10-2 and Macula patterns) in >275 subjects judged to be normal by a battery of clinical procedures. The right eye was always tested first. RESULTS: Sensitivity decreased by approximately 0.7 dB per age decade across all eccentricities; sensitivity decreased with eccentricity, typically by <5 dB at the most peripheral points tested. Although there was no systematic difference in sensitivity between the 30-2 and 24-2 tests, the Macula test sensitivities were typically 1 dB higher than for the 10-2 test. Sensitivity in the left eye was slightly lower than in the right, with the difference being significantly greater in the temporal visual field. In most test locations, the 95% confidence interval of normal sensitivity was approximately 6 dB below the median sensitivity. CONCLUSIONS: The performance of the test strategy in the Matrix perimeter is appropriately matched to the response characteristics of the normal population. The finding of a spatially nonuniform difference in sensitivity between left and right eyes is attributable to light-adaptation differences between the eyes. This effect is accounted for in the perimeter's normative database.