A multicenter evaluation of the efficacy and duration of action of alcaftadine 0.25% and olopatadine 0.2% in the conjunctival allergen challenge model

Background: The purpose of this study was to evaluate the efficacy and duration of action of once-daily dosing with alcaftadine 0.25% ophthalmic solution and olopatadine 0.2% ophthalmic solution as compared with placebo in the prevention of ocular itching, and to directly compare the efficacy of alcaftadine 0.25% with olopatadine 0.2% in the prevention of ocular itching associated with allergic conjunctivitis using the conjunctival allergen challenge model. Methods: Subjects with allergic conjunctivitis (n = 127) were enrolled in a multicenter, double-masked, randomized, active-controlled and placebo-controlled clinical trial. Using the conjunctival allergen challenge model, this study was conducted over the course of approximately 5 weeks. Subjects were randomized into one of three treatment arms: alcaftadine 0.25% ophthalmic solution, olopatadine 0.2% ophthalmic solution, or placebo. Study medications were administered twice over the course of the trial. The primary efficacy measure for the study was ocular itching evaluated by the subject at 3, 5, and 7 minutes post challenge. Secondary endpoints, measured at 7, 15, and 20 minutes post challenge, included conjunctival, ciliary, and episcleral redness, lid swelling, chemosis, and tearing. Duration of action was measured at 16 and 24 hours post-instillation of the study medication at visits 3 and 4, respectively. Results: For the primary measure of ocular itching, both actives, alcaftadine 0.25% and olopatadine 0.2%, were statistically superior to placebo at all three measured time points for both the 16-hour and 24-hour measures (P < 0.0001). Eyes treated with alcaftadine 0.25% had numerically lower mean ocular itching scores than eyes treated with olopatadine 0.2% at every time point, and this difference was statistically significant at the 3-minute time point 16 hours post instillation (P = 0.026). Eyes treated with alcaftadine 0.25% and with olopatadine 0.2% displayed significantly less lid swelling relative to placebo at every time point for the 16-hour and 24-hour post-instillation visits (P < 0.005). Alcaftadine 0.25% was the only active treatment that provided statistically significant relief of chemosis at every time point of the 24-hour post-instillation visit. Conclusion: Both the alcaftadine 0.25% and olopatadine 0.2% ophthalmic solutions provided highly effective relief of ocular itching at both 16 and 24 hours post-instillation. Treatment differences between the actives were most pronounced at the earliest time point (3 minutes post-challenge) following conjunctival allergen challenge (16 hours), when alcaftadine 0.25% ophthalmic solution was statistically superior to olopatadine 0.2% ophthalmic solution. Alcaftadine 0.25% was the only treatment to provide significant relief from chemosis at both 16 and 24 hours post-instillation. Both active treatments and placebo were generally safe and well tolerated

Reliable intraocular pressure measurement using automated radio-wave telemetry

Purpose To present an autonomous intraocular pressure (IOP) measurement technique using a wireless implantable transducer (WIT) and a motion sensor. Methods: The WIT optical aid was implanted within the ciliary sulcus of a normotensive rabbit eye after extracapsular clear lens extraction. An autonomous wireless data system (AWDS) comprising of a WIT and an external antenna aided by a motion sensor provided continuous IOP readings. The sensitivity of the technique was determined by the ability to detect IOP changes resulting from the administration of latanoprost 0.005% or dorzolamide 2%, while the reliability was determined by the agreement between baseline and vehicle (saline) IOP. Results: On average, 12 diurnal and 205 nocturnal IOP measurements were performed with latanoprost, and 26 diurnal and 205 nocturnal measurements with dorzolamide. No difference was found between mean baseline IOP (13.08±2.2 mmHg) and mean vehicle IOP (13.27±2.1 mmHg) (P=0.45), suggesting good measurement reliability. Both antiglaucoma medications caused significant IOP reduction compared to baseline; latanoprost reduced mean IOP by 10% (1.3±3.54 mmHg; P<0.001), and dorzolamide by 5% (0.62±2.22 mmHg; P<0.001). Use of latanoprost resulted in an overall twofold higher IOP reduction compared to dorzolamide (P<0.001). Repeatability was ±1.8 mmHg, assessed by the variability of consecutive IOP measurements performed in a short period of time (≤1 minute), during which the IOP is not expected to change. Conclusion: IOP measurements in conscious rabbits obtained without the need for human interactions using the AWDS are feasible and provide reproducible results

Reliable intraocular pressure measurement using automated radio-wave telemetry

Purpose To present an autonomous intraocular pressure (IOP) measurement technique using a wireless implantable transducer (WIT) and a motion sensor. Methods: The WIT optical aid was implanted within the ciliary sulcus of a normotensive rabbit eye after extracapsular clear lens extraction. An autonomous wireless data system (AWDS) comprising of a WIT and an external antenna aided by a motion sensor provided continuous IOP readings. The sensitivity of the technique was determined by the ability to detect IOP changes resulting from the administration of latanoprost 0.005% or dorzolamide 2%, while the reliability was determined by the agreement between baseline and vehicle (saline) IOP. Results: On average, 12 diurnal and 205 nocturnal IOP measurements were performed with latanoprost, and 26 diurnal and 205 nocturnal measurements with dorzolamide. No difference was found between mean baseline IOP (13.08±2.2 mmHg) and mean vehicle IOP (13.27±2.1 mmHg) (P=0.45), suggesting good measurement reliability. Both antiglaucoma medications caused significant IOP reduction compared to baseline; latanoprost reduced mean IOP by 10% (1.3±3.54 mmHg; P<0.001), and dorzolamide by 5% (0.62±2.22 mmHg; P<0.001). Use of latanoprost resulted in an overall twofold higher IOP reduction compared to dorzolamide (P<0.001). Repeatability was ±1.8 mmHg, assessed by the variability of consecutive IOP measurements performed in a short period of time (≤1 minute), during which the IOP is not expected to change. Conclusion: IOP measurements in conscious rabbits obtained without the need for human interactions using the AWDS are feasible and provide reproducible results

Ocular Itch Relief with Alcaftadine 0.25% Versus Olopatadine 0.2% in Allergic Conjunctivitis: Pooled Analysis of Two Multicenter Randomized Clinical Trials

Introduction: The efficacy and safety of the once-daily topical ophthalmic solutions, alcaftadine 0.25% and olopatadine 0.2%, in preventing ocular itching associated with allergic conjunctivitis were evaluated. Methods: Pooled analysis was conducted of two double-masked, multicenter, active- and placebo-controlled studies using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis. Subjects were randomized 1:1:1 to receive alcaftadine 0.25%, olopatadine 0.2%, or placebo. The primary efficacy measure was subject-evaluated mean ocular itching at 3 min post-CAC and 16 h after treatment instillation. Secondary measures included ocular itching at 5 and 7 min post-CAC. Ocular itch was determined over all time points measured (3, 5, and 7 min) post-CAC and the proportion of subjects with minimal itch (itch score <1) and zero itch (itch score = 0) was also assessed. Results: A total of 284 subjects were enrolled in the two studies. At 3 min post-CAC and 16 h after treatment instillation, alcaftadine 0.25% achieved a significantly lower mean itch score compared with olopatadine 0.2% (0.50 vs. 0.87, respectively; P = 0.0006). Alcaftadine demonstrated a significantly lower mean itch score over all time points compared with olopatadine (0.68 vs. 0.92, respectively; P = 0.0390); both alcaftadine- and olopatadine-treated subjects achieved significantly lower overall mean ocular itching scores compared with placebo (2.10; P < 0.0001 for both actives). Minimal itch over all time points was reported by 76.1% of alcaftadine-treated subjects compared with 58.1% of olopatadine-treated subjects (P = 0.0121). Treatment with alcaftadine 0.25% and olopatadine 0.2% was safe and well tolerated; no serious adverse events were reported. Conclusion: Once-daily alcaftadine 0.25% ophthalmic solution demonstrated greater efficacy in prevention of ocular itching compared with olopatadine 0.2% at 3 min post-CAC (primary endpoint), and over all time points, 16 h post-treatment instillation. Alcaftadine and olopatadine both provided effective relief compared with placebo and were generally well tolerated. Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0155-3) contains supplementary material, which is available to authorized users

Inflammation and the Nervous System: The Connection in the Cornea in Patients with Infectious Keratitis

Purpose. To study the density and morphologic characteristics of epithelial dendritic cells, as correlated to subbasal corneal nerve alterations in acute infectious keratitis (IK) by in vivo confocal microscopy (IVCM). Methods. IVCM of the central cornea was performed prospectively in 53 eyes with acute bacterial (n = 23), fungal (n = 13), and Acanthamoeba (n = 17) keratitis, and in 20 normal eyes, by using laser in vivo confocal microscopy. Density and morphology of dendritic-shaped cells (DCs) of the central cornea, corneal nerve density, nerve numbers, branching, and tortuosity were assessed and correlated. It should be noted that due to the “in vivo” nature of the study, the exact identity of these DCs cannot be specified, as they could be monocytes or tissue macrophages, but most likely dendritic cells. Results. IVCM revealed the presence of central corneal DCs in all patients and controls. The mean DC density was significantly higher in patients with bacterial (441.1 ± 320.5 cells/mm2; P < 0.0001), fungal (608.9 ± 812.5 cells/mm2; P < 0.0001), and Acanthamoeba keratitis (1000.2 ± 1090.3 cells/mm2; P < 0.0001) compared with controls (49.3 ± 39.6 cells/mm2). DCs had an increased size and dendrites in patients with IK. Corneal nerves were significantly reduced in eyes with IK compared with controls across all subgroups, including nerve density (674.2 ± 976.1 vs. 3913.9 ± 507.4 μm/frame), total nerve numbers (2.7 ± 3.9 vs. 20.2 ± 3.3), main trunks (1.5 ± 2.2 vs. 6.9 ± 1.1), and branching (1.2 ± 2.0 vs. 13.5 ± 3.1; P < 0.0001). A strong association between the diminishment of corneal nerves and the increase of DC density was observed (r = −0.44; P < 0.0005). Conclusions. IVCM reveals an increased density and morphologic changes of central epithelial DCs in infectious keratitis. There is a strong and significant correlation between the increase in DC numbers and the decreased subbasal corneal nerves, suggesting a potential interaction between the immune and nervous system in the cornea

Safety and Efficacy of the Multitargeted Receptor Kinase Inhibitor Pazopanib in the Treatment of Corneal Neovascularization

Purpose. To evaluate the safety and efficacy of topical pazopanib in the treatment of corneal neovascularization (CNV). Methods. Twenty eyes of 20 patients with stable CNV were enrolled in a prospective, open label, noncomparative study and treated with topical pazopanib 0.5% for 3 weeks, and followed for 12 weeks. The primary endpoint was to determine the tolerability and safety of topical pazopanib in the treatment of CNV defined by the occurrence of ocular and systemic adverse events during the study. The secondary endpoint was to evaluate the effect of topical pazopanib on the reduction of (1) neovascular area (NA), defined as the area of the corneal vessels themselves, (2) invasion area (IA), defined as the fraction of the total cornea into which the vessels extend, (3) vessel length (VL), defined as the mean measurement of the extent of vessels from end to end, and (4) vessel caliber (VC), defined as the mean diameter of the corneal vessels. Results. There were no severe adverse events following the use of topical pazopanib. Compared with the baseline visit, NA and VL showed a statistically significant decrease at week 3 (P = 0.02 and 0.01, respectively); and NA, IA, and VL statistically significantly decreased at week 12 (P = 0.03, 0.04, and <0.01, respectively). Visual acuity maintained without changes after the 12 week follow-up. Conclusions. This preliminary study suggests that topical treatment with pazopanib 0.5% is safe, well tolerated, and may have a role as an alternative for the treatment of CNV (ClinicalTrials.gov number, NCT01257750)

Toxic Keratoconjunctivitis from Coral Reef

The final, published version of this article is available at https://doi.org/10.1159/000517350A 25-year-old woman presented with right eye pain, lid edema, conjunctival injection and chemosis, and mild corneal epitheliopathy after exposure to fluid content from an aquarium coral reef. Topical moxifloxacin and prednisolone were started 4 times daily, with full clinical resolution after 2 weeks. Toxin-mediated keratoconjunctivitis may occur after exposure to zoanthid coral reef, particularly in aquarium enthusiasts. Topical corticosteroids in tandem with topical antibiotics appear to be effective in mild disease. However, in severe cases that exhibit corneal infiltrates and stromal thinning, close observation is warranted in case of possible keratolysis

Pivotal clinical trials of novel ophthalmic drugs and medical devices: retrospective observational study, 2002–2012

Objectives: Novel therapeutics are an important part of ophthalmologists’ armamentarium, and the risks and benefits of these therapies must be carefully evaluated. We sought to quantify the characteristics of the pivotal clinical trials supporting the regulatory approval of new ophthalmic drugs and medical devices. Design: Retrospective observational study. Setting and data source Medical review dossiers for new ophthalmic drug and high-risk device approvals released publicly by the US Food and Drug Administration (FDA). Main outcome measures Proportion of pivotal trials with randomisation, masking, active or placebo controls and subgroup analyses; total and median number of trial enrollees; and the number of drugs and devices approved with required postapproval studies. Results: From 2002 to 2012, the FDA approved 11 ophthalmic drugs and 25 devices. The pivotal trials underlying the approvals of ophthalmic drugs in our study cohort enrolled a median of 809 patients. Virtually all drug trials were randomised and masked (91%), of which 7 (70%) used a placebo control. Pivotal trials for ophthalmic devices enrolled 324 patients on average, and significantly fewer trials for ophthalmic devices versus drugs were randomised (16% vs 91%; p<0.001) or masked (12% vs 91%; p<0.001). 8 (32%) ophthalmic devices and 6 (55%) ophthalmic drugs were approved with required postapproval studies. Conclusions: Ophthalmic therapeutics were approved based on varying levels of evidence. Postapproval studies could be used to confirm or refute early indications of safety and effectiveness of these therapeutics, with the study results accessible to patients and clinicians who need to make informed treatment decisions

Brimonidine Ophthalmic Solution 0.025% for Reduction of Ocular Redness: A Randomized Clinical Trial

SIGNIFICANCE The α2-adrenergic receptor agonist brimonidine has been reported to induce conjunctival blanching in cataract, strabismus, laser refractive, and filtration procedures. Clinicians are often faced with red eyes with no apparent underlying pathology. Low-dose brimonidine reduced ocular redness in such subjects with efficacy maintained over 1 month and negligible rebound redness. PURPOSE The aim of this study was to evaluate the safety and efficacy of brimonidine tartrate ophthalmic solution 0.025% for the treatment of ocular redness. METHODS In this single-center, double-masked, phase 3 clinical trial, adult subjects with baseline redness of more than 1 unit in both eyes (0- to 4-unit scale) were randomized 2:1 to brimonidine 0.025% or vehicle. A single dose was administered in-office (day 1); thereafter subjects instilled treatment four times a day for 4 weeks, with clinic visits on days 15, 29, and 36 (7 days post-treatment). Efficacy end points included investigator-evaluated redness 5 to 240 minutes post-instillation on day 1 (primary); investigator-evaluated change from baseline 1, 360, and 480 minutes post-instillation on day 1, and 1 and 5 minutes post-instillation on days 15 and 29; total clearance of redness, and subject-assessed redness. Safety/tolerability measures included adverse events, rebound redness, and drop comfort. RESULTS Sixty subjects were randomized (n = 40 brimonidine, n = 20 vehicle). Investigator-assessed redness was lower with brimonidine versus vehicle over the 5- to 240-minute post-instillation period (mean [SE], 0.62 [0.076] vs. 1.49 [0.108]; P < .0001) and at each time point within that period (P < .0001). At 1, 360, and 480 minutes post-instillation, respectively, the mean differences (95% confidence interval) between treatments were −0.73 (−1.05 to −0.41), −0.57 (−0.84 to −0.29), and −0.39 (−0.67 to −0.10), respectively. No tachyphylaxis was evident with brimonidine on days 15 and 29, and minimal rebound redness was observed following discontinuation. Adverse events were infrequent, and brimonidine was rated as very comfortable. CONCLUSIONS Brimonidine 0.025% appeared safe and effective for reduction of ocular redness, with an 8-hour duration of action, no evidence of tachyphylaxis, and negligible rebound redness