Omidenepag Isopropyl Versus Timolol in Patients With Glaucoma or Ocular Hypertension: Two Randomized Phase 3 Trials (SPECTRUM 4 and 3).

PURPOSE: The SPECTRUM 4 and 3 studies assessed the intraocular pressure (IOP)-lowering efficacy and safety of omidenepag isopropyl (OMDI) 0.002% vs timolol 0.5% in patients with glaucoma or ocular hypertension (OHT). DESIGN: Phase 3, randomized, controlled, double-masked, noninferiority studies. METHODS: Multicenter studies in the US. Inclusion criteria for adults ≥ 18 years (SPECTRUM 4 [N = 409] and 3 [N = 413]) were open-angle glaucoma or OHT, and IOP ≥ 22 mm Hg and ≤ 34 mm Hg; and for pediatric patients < 18 years (N = 13, SPECTRUM 3) were pediatric glaucoma or OHT. The primary objective in both studies was OMDI noninferiority to timolol in reducing IOP (3 months). SPECTRUM 3 included an additional 9 months of OMDI treatment. Safety evaluations were of ocular/non-ocular adverse events (AEs). RESULTS: The IOP-lowering range of OMDI remained consistent in SPECTRUM 4 and 3 (-5.6 to -5.9 vs -5.3 to -5.7 mm Hg, respectively); however, timolol efficacy varied (-5.4 to -6.1 vs -6.4 to -7.0 mm Hg, respectively). OMDI noninferiority was achieved in SPECTRUM 4. Efficacy was maintained with 12-month treatment in SPECTRUM 3. Both studies reported more ocular AEs with OMDI, but lower rates of appearance-altering AEs vs timolol. No new safety concerns were identified. Rates of macular edema in pseudophakic patients increased with prolonged OMDI exposure. CONCLUSIONS: SPECTRUM 4 and 3 demonstrated consistent 3-month IOP-lowering efficacy and safety of OMDI vs timolol in patients with glaucoma or OHT. The 12-month data from SPECTRUM 3 suggest OMDI may have long-term benefits in patients with glaucoma or OHT.

Single Administration of Bimatoprost Implant: Effects on 24-Hour Intraocular Pressure and 1-Year Outcomes.

PURPOSE: To evaluate the effects of a single bimatoprost implant administration on 24-hour intraocular pressure (IOP) lowering at 8 weeks, and 1-year IOP-lowering efficacy and safety outcomes. DESIGN: Multicenter, open-label, 12-month, phase 3b study (NCT04285580). PARTICIPANTS: Adults with open-angle glaucoma or ocular hypertension. METHODS: Participants (n = 31) received 10-µg bimatoprost implant in the study eye on day 1; IOP (sitting and/or supine) was measured with pneumatonometry every 2 hours throughout a 24-hour period at baseline and week 8. IOP was measured by Goldmann applanation tonometry (GAT) at hour 0 (8 am ± 1 hour) at baseline, weeks 8 and 16, and months 6, 9, and 12. MAIN OUTCOME MEASURES: The primary endpoint was the week-8 hour-matched change from baseline in habitual position IOP over 24 hours assessed with pneumatonometry. Hour 0 IOP change from baseline measured with GAT in study eyes that received no additional (rescue) IOP-lowering treatment, treatment-emergent adverse events (TEAEs), and central corneal endothelial cell density (CECD) were evaluated through 12 months. RESULTS: The mean (standard deviation [SD]) baseline IOP at hour 0 was 24.2 (2.70) mmHg and 25.3 (7.15) mmHg by GAT and pneumatonometry, respectively. Pneumatonometer measurements of IOP taken over 24 hours at week 8 with the participant in habitual position (sitting from 8 am to 10 pm, supine from 12 am to 6 am) showed consistent IOP lowering through the day and night and reduced fluctuation in IOP. The range in IOP measurements over 24 hours was reduced from baseline by a mean (SD) of -1.6 (2.98) mmHg. All 31 bimatoprost implant-treated participants completed the 12-month study; 23 (74%) required no rescue IOP-lowering treatment. The mean (SD) IOP reduction from baseline at month 12 in nonrescued eyes was -4.3 (3.35) mmHg. The most common TEAE was conjunctival hyperemia (incidence 35.5%, 11/31). No implant-treated eye had a ≥ 15% loss in CECD from baseline. CONCLUSIONS: A single intracameral administration of the bimatoprost implant lowered IOP in the habitual position consistently throughout the day and night at week 8. The majority of participants continued to have reduced IOP for 1 year without additional therapy. The 1-year safety profile was favorable. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Two Randomized, Double-masked, Placebo-controlled Studies of the Local Anesthetic Effect of Articaine Ophthalmic Solution.

Background: We wanted to develop a new topical ocular anesthetic with good bioavailability in anterior segment tissues. Given concerns about contamination and sterility in multi-dose products, we selected a unit-dose, nonpreserved presentation of AG-920 (articaine ophthalmic solution) in blow-fill-seal containers (similar to currently marketed pharmacological therapies for dry eye disease). Methods: Consistent with US Food and Drug Administration guidance, two pivotal, Phase 3, randomized, placebo-controlled, double-masked, parallel design studies conducted at two US private practices in 240 healthy subjects. A single dose of AG-920 or identical looking placebo into one (study) eye (2 drops 30 s apart). Subjects underwent a conjunctival pinch procedure and assessment of the pain associated with the pinch. The main outcome measure was the proportion of subjects with rating of "No pain at 5 minutes". Results: AG-920 provided a rapid onset of local anesthesia (less than one minute) with clinically and statistically significantly greater effect in AG-920 (68% and 83%) than placebo (3% and 18% for Study 1 and Study 2, respectively, P<0.0001). The most frequent adverse event was instillation site pain (27% vs 3%) followed by conjunctival hyperemia (probably related to the pinch, 9% vs 10%) in the AG-920 and placebo groups, respectively. Conclusion: AG-920 was found to be have a rapid onset and useful duration of local anesthesia with no major safety issues, and may be useful for the eye-care professional. Registered with clinicaltrials.gov as NCT04513652 and NCT04829344.

Efficacy and Safety of a Water-Free Topical Cyclosporine, 0.1%, Solution for the Treatment of Moderate to Severe Dry Eye Disease: The ESSENCE-2 Randomized Clinical Trial.

Importance: Dry eye disease (DED) is a common public health problem with significant impact on vision-related quality of life and well-being of patients. Medications with rapid onset of action and a good tolerability profile remain an unmet need. Objective: To assess efficacy, safety, and tolerability of a water-free cyclosporine ophthalmic solution, 0.1% (CyclASol [Novaliq GmbH]), applied twice daily in DED compared with vehicle. Design, Setting, and Participants: CyclASol for the Treatment of Signs and Symptoms of Dry Eye Disease (ESSENCE-2) was a phase 3, multicenter, randomized, double-masked, vehicle-controlled clinical study conducted from December 5, 2020, to October 8, 2021. Following a 14-day run-in period with an artificial tear administered 2 times per day, eligible participants were randomly assigned 1:1 to the treatment groups. Patients with moderate to severe DED were included in the study. Interventions: Cyclosporine solution vs vehicle administered 2 times per day for 29 days. Main Outcomes and Measures: The primary end points were changes from baseline in total corneal fluorescein staining (tCFS; 0-15 National Eye Institute scale) and in dryness score (0-100 visual analog scale) at day 29. Conjunctival staining, central corneal fluorescein staining, and tCFS responders were also assessed. Results: A total of 834 study participants were randomly assigned to cyclosporine (423 [50.7%]) or vehicle (411 [49.3%]) groups at 27 sites. Participants had a mean (SD) age of 57.1 (15.8) years, and 609 (73.0%) were female individuals. The majority of participants self-identified in the following race categories: 79 Asian (9.5 %), 108 Black (12.9%), and 635 White (76.1%). Participants treated with cyclosporine solution had greater improvement in tCFS (-4.0 grades) than the vehicle group (-3.6 grades) at day 29 (change [∆] = -0.4; 95% CI, -0.8 to 0; P = .03). The dryness score showed treatment benefits from baseline in both groups: -12.2 points for cyclosporine and -13.6 points for vehicle (∆ = 1.4; 95% CI, -1.8 to 4.6; P = .38). In the cyclosporine group, 293 participants (71.6%) achieved clinically meaningful reductions of 3 grades or higher in tCFS vs 236 (59.7%) in the vehicle group (∆ = 12.6%; 95% CI, 6.0%-19.3%; P < .001). These responders showed greater improvement in symptoms at day 29 including dryness (∆ = -4.6; 95% CI, -8.0 to -1.2; P = .007) and blurred vision (Δ = -3.5; 95% CI, -6.6 to -4.0; P = .03) compared with nonresponders. Conclusions and Relevance: The ESSENCE-2 trial confirmed that treatment with a water-free cyclosporine solution, 0.1%, results in early therapeutic effects on the ocular surface compared with vehicle. The responder analyses suggest that the effect is clinically meaningful in 71.6% of participants in the cyclosporine group. Trial Registration: ClinicalTrials.gov Identifier: NCT04523129.

NOV03 for Dry Eye Disease Associated with Meibomian Gland Dysfunction: Results of the Randomized Phase 3 GOBI Study.

PURPOSE: To evaluate the efficacy and safety of NOV03 (perfluorohexyloctane) ophthalmic drop in patients with dry eye disease (DED) associated with meibomian gland dysfunction (MGD). DESIGN: Eight-week, phase 3, multicenter, randomized, double-masked, saline-controlled study. PARTICIPANTS: Adults ≥ 18 years with a history of DED for ≥ 6 months, tear film breakup time of ≤ 5 seconds, Schirmer I test (without anesthesia) score ≥ 5 mm, MGD score ≥ 3 (0-15 scale), and total corneal fluorescein staining (tCFS) score ≥ 4 and ≤ 11 (0-15 National Eye Institute [NEI] scale). METHODS: Patients were randomized 1:1 to NOV03 or hypotonic (0.6%) saline 4 times daily. MAIN OUTCOME MEASURES: The primary sign and symptom end points were change from baseline in tCFS and eye dryness score (0-100 visual analog scale [VAS]) at week 8. Key secondary end points were change from baseline in eye dryness score at week 2, tCFS at week 2, eye burning or stinging score (0-100 VAS) at week 8, and central corneal fluorescein staining (cCFS; 0-3 NEI scale) at week 8. RESULTS: Of the 599 patients randomized, 597 were treated (NOV03, n = 303; saline, n = 294). At week 8, improvement from baseline was significantly greater (P < 0.001) with NOV03 versus saline for tCFS (least square [LS] mean treatment difference, -0.97; 95% confidence interval [CI]: -1.40, -0.55) and VAS dryness score (-7.6; 95% CI: -11.8, -3.4). Improvement from baseline also significantly (P < 0.01) favored NOV03 on all key secondary end points: LS mean treatment difference (95% CI) was -4.7 (-8.2, -1.2) for VAS dryness score at week 2, -0.6 (-0.9, -0.2) for tCFS at week 2, -5.5 (-9.5, -1.6) for VAS burning or stinging score at week 8, and -0.2 (-0.4, -0.1) for cCFS at week 8. Most ocular adverse events (AEs) were mild in severity; no serious ocular AEs occurred. One patient discontinued NOV03 because of an AE (eye irritation). CONCLUSIONS: In patients with DED associated with MGD, NOV03 demonstrated statistically significant and clinically meaningful improvements versus hypotonic saline in signs and symptoms of DED and was well tolerated. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Lotilaner Ophthalmic Solution, 0.25%, for the Treatment of Demodex Blepharitis: Results of a Prospective, Randomized, Vehicle-Controlled, Double-Masked, Pivotal Trial (Saturn-1).

PURPOSE: The purpose of this study was to evaluate the safety and efficacy of lotilaner ophthalmic solution, 0.25%, compared with vehicle for the treatment of Demodex blepharitis. METHODS: In this prospective, randomized, controlled, double-masked, phase 2b/3 clinical trial, 421 patients with Demodex blepharitis were randomly assigned in a 1:1 ratio to receive either lotilaner ophthalmic solution, 0.25% (study group), or vehicle without lotilaner (control group) bilaterally, twice daily for 43 days. Patients were evaluated at days 8, 15, 22, and 43. Outcome measures were complete collarette cure (collarette grade 0), clinically meaningful collarette cure (grade 0 or 1), mite eradication (0 mites/lash), erythema cure (grade 0), composite cure (grade 0 for collarettes/erythema), and drop comfort. Adverse events were also evaluated. RESULTS: At day 43, the study group achieved a statistically significantly higher proportion of patients with clinically meaningful collarette cure (81.3% vs. 23.0%; P < 0.0001), complete collarette cure (44.0% vs. 7.4%; P < 0.0001), mite eradication (67.9% vs. 17.6%; P < 0.0001), erythema cure (19.1% vs. 6.9%; P = 0.0001), and composite cure (13.9% vs. 1.0%; P < 0.0001) than the control group. Nearly 92.0% of patients rated the study drop as neutral to very comfortable. All ocular adverse events in the study group were mild, with the most common being instillation site pain. CONCLUSIONS: Twice-daily treatment with a novel lotilaner ophthalmic solution, 0.25% for 43 days, is safe and effective for the treatment of Demodex blepharitis compared with the vehicle control.

A randomized, vehicle-controlled, Phase 2b study of two concentrations of the TRPM8 receptor agonist AR-15512 in the treatment of dry eye disease (COMET-1).

PURPOSE: Dry eye disease (DED) symptoms can negatively impact quality of life (QoL). AR-15512, a transient receptor potential melastatin 8 (TRPM8) agonist, was evaluated as a potential therapy for DED. METHODS: In a Phase 2b study, patients with DED were randomized 1:1:1 to 0.0014% AR-15512, 0.003% AR-15512, or vehicle twice daily for 12 weeks. Eligibility criteria included DED signs and symptoms of prespecified severity levels. Outcomes assessed were DED signs (Schirmer score ± anesthetic, ocular surface staining, hyperemia), symptoms (Ocular Discomfort [ODS-VAS], Symptoms Assessment iN Dry Eye [SANDE], Eye Dryness-VAS, Ocular Pain-VAS), QoL-VAS, and adverse events. Co-primary endpoints were changes from baseline in ODS-VAS and anesthetized Schirmer score at Day 28. RESULTS: 0.003% AR-15512 (n = 122) was associated with early and sustained improvements in unanesthetized Schirmer score (Days 1 and 14, p < 0.0001), as well as improvements in ocular surface staining (Days 14 and 84, p ≤ 0.0365) and hyperemia (Day 84, p < 0.0215). Statistically significant improvements in symptoms were observed for the 0.003% concentration on SANDE (Days 14, 28, and 84, p ≤ 0.0254), ODS-VAS (Day 84, p = 0.0281), Eye Dryness-VAS (Day 84, p = 0.0302), and multiple QoL measures (Days 14, 28, and 84, p < 0.05). There were no significant differences between active and vehicle groups for the co-primary endpoints. The most common adverse events were burning and stinging upon instillation. CONCLUSIONS: Although predefined co-primary study endpoints were not met, AR-15512 demonstrated statistically significant improvements in DED signs, symptoms, and disease-related QoL.

Phase 2b, Randomized, 3-Month, Dose-Finding Study of Sepetaprost in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: The ANGEL Study.

Purpose: This phase 2b, randomized, observer-masked, placebo- and active-controlled, parallel-group, multinational (USA and Japan), multicenter study (NCT03216902) assessed the optimal dose of sepetaprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension. Methods: After washout, patients ≥18 years (USA) or ≥20 years of age (Japan) received once-daily sepetaprost for 3 months [0.0005% (n = 43); 0.001% (n = 43); 0.002% (n = 44); and 0.003% (n = 45)], latanoprost 0.005% (n = 44) or placebo until week 6, followed by sepetaprost 0.003% until month 3 (n = 22). Safety assessments included adverse event (AE) occurrence. Results: Baseline mean diurnal intraocular pressure (IOP) was 24.3 mmHg for latanoprost and ranged between 24.1 and 24.5 mmHg for the sepetaprost groups. Sepetaprost 0.002% had the lowest IOP at each month 3 time point (9:00 AM; 1:00 PM; 5:00 PM) of all sepetaprost concentrations (mean ± standard error: 17.6 ± 0.5; 17.4 ± 0.4; 16.7 ± 0.4 mmHg); similar values were observed with latanoprost (18.1 ± 0.6; 17.3 ± 0.5; 17.2 ± 0.5 mmHg). A positive dose-response relationship was observed with the 3 lower sepetaprost doses; sepetaprost 0.002% had numerically greater IOP-lowering effects than sepetaprost 0.003%. All sepetaprost doses had statistically significantly greater IOP reductions from baseline versus placebo at week 6 (P < 0.0001). This IOP-lowering effect was consistent between Japan- and USA-based patients. Most AEs were mild and occurred numerically less frequently with sepetaprost 0.002% (34.1%) versus latanoprost (50.0%). The most frequently reported AE was conjunctival hyperemia. Conclusion: In this study, sepetaprost 0.002% was the optimal concentration, showing comparable IOP-lowering efficacy and safety with latanoprost 0.005%. Most AEs were mild; occurrence was numerically lower with sepetaprost 0.002% than latanoprost 0.005%.

Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2).

OBJECTIVE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). RESULTS: Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2-7.4, 6.5-7.8, and 6.1-6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. CONCLUSIONS: The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma. CLINICALTRIALS. GOV IDENTIFIER: NCT02250651.

Safety of Once-Daily Oxymetazoline HCl Ophthalmic Solution, 0.1% in Patients with Acquired Blepharoptosis: Results from Four Randomized, Double-Masked Clinical Trials.

PURPOSE: An oxymetazoline 0.1% ophthalmic solution was recently approved for treatment of acquired blepharoptosis in adults. This study's objective was to evaluate the safety profile of oxymetazoline 0.1% when administered once daily for 14-84 days. PATIENTS AND METHODS: Pooled analysis examined safety outcomes from four randomized, double-masked, placebo-controlled clinical trials conducted at 6, 16, 27, and 35 sites, respectively, in the United States. In total, 568 participants with acquired blepharoptosis were evaluated. Median age was 66 years and 74.8% of participants were female. Overall, 375 participants self-administered oxymetazoline 0.1% to both eyes once/day and 193 self-administered placebo (vehicle) daily. Treatment-emergent adverse event (TEAE) rates, severity, and causality were evaluated in the overall population and within participant subgroups defined based on age, race, and ethnicity. Vital signs and ophthalmic findings were evaluated at predefined study visits. Patient-reported treatment tolerability was recorded at study end. RESULTS: TEAE incidence was similar among participants using oxymetazoline 0.1% (31.2%) or vehicle (30.6%). Nearly all TEAEs were mild-to-moderate, and most were not suspected of being treatment related. Serious TEAEs occurred in four participants receiving oxymetazoline 0.1% and one participant receiving vehicle. Nine and two participants in the oxymetazoline 0.1% and vehicle groups, respectively, discontinued due to a TEAE. Ocular TEAEs occurring in ≥2% of participants receiving oxymetazoline 0.1% were punctate keratitis, conjunctival hyperemia, dry eye, blurred vision, instillation site pain, and corneal vital dye staining, with none occurring in >3.5% of participants. TEAE rates were similar across subgroups based on age, race, and ethnicity. No clinically significant mean changes in vital signs or ophthalmologic findings occurred, and >98% of participants rated oxymetazoline 0.1% as causing no/mild discomfort. CONCLUSION: Once-daily oxymetazoline 0.1% was safe and well tolerated in participants with acquired blepharoptosis when used for 14-84 days. Safety did not appear to differ based on age, race, or ethnicity.

A Water-free 0.1% Cyclosporine A Solution for Treatment of Dry Eye Disease: Results of the Randomized Phase 2B/3 ESSENCE Study.

PURPOSE: To assess the efficacy, safety, and tolerability of a topical water-free cyclosporine A formulation (CyclASol 0.1% ophthalmic solution) in comparison with vehicle for the treatment of dry eye disease (DED). METHODS: Three hundred twenty-eight patients were enrolled in this prospective, 12-week, multicenter, randomized, double-masked, confirmatory, vehicle-controlled clinical study. After a 2-week run-in period, eligible DED patients were randomized 1:1 to either CyclASol 0.1% or vehicle twice daily. The primary efficacy endpoint was change from baseline in total corneal fluorescein staining (National Eye Institute scale), and the second hierarchical primary efficacy endpoint was change from baseline in the Ocular Surface Disease Index score, both at 4 weeks. Secondary efficacy and safety assessments included conjunctival lissamine green staining (Oxford scale), visual analog scales for dry eye symptoms, and adverse event. RESULTS: Treatment with CyclASol 0.1% was superior to vehicle in the primary endpoint: total corneal fluorescein staining at week 4 (Δ -0.8; 95% confidence interval, -1.3 to -0.4; P = 0.0002, analysis of covariance). This difference had already reached statistical significance after 2 weeks and was maintained throughout the study. The study did not statistically meet its second hierarchically tested primary endpoint: Ocular Surface Disease Index score (P = 0.2634). However, CyclASol 0.1% treatment showed statistically significant improvement compared with that of vehicle in the eye dryness score at week 4 (Δ -4.783; 95% confidence interval, -9.129 to -0.438; P = 0.0311). CONCLUSIONS: CyclASol 0.1% was effective in treating signs and symptoms of DED. It significantly reduced corneal and conjunctival staining and improved ocular dryness compared with vehicle. CyclASol 0.1% was safe and showed excellent tolerability.

Rapid and Sustained Eyelid Elevation in Acquired Blepharoptosis with Oxymetazoline 0.1%: Randomized Phase 3 Trial Results.

PURPOSE: Oxymetazoline 0.1% is a novel ophthalmic agent for the treatment of acquired blepharoptosis in adults that has been shown to improve upper eyelid elevation and superior visual field deficits. This analysis characterized the rapid onset of upper eyelid elevation with once-daily oxymetazoline 0.1% and durability of this effect over 42 days. MATERIALS AND METHODS: Pooling data from two prospective, randomized, placebo-controlled, phase 3 studies, change in marginal reflex distance 1 (MRD-1) was evaluated at a range of post-instillation time points on treatment days 1, 14, and 42. Onset of effect was assessed beginning at 5 minutes post-administration (one study) and through 6 hours at the first two visits (both studies). Overall, 203 subjects received oxymetazoline 0.1% and 101 received vehicle. RESULTS: Oxymetazoline 0.1% demonstrated a rapid onset of action on all days evaluated. Mean changes from baseline 5 and 15 minutes post-oxymetazoline 0.1% instillation on day 1 were 0.59 ± 0.72 mm and 0.93 ± 0.81 mm, respectively (vs 0.20 ± 0.57 mm and 0.32 ± 0.64 mm with vehicle; both p<0.001). On day 14, mean changes from baseline 5 and 15 minutes post-oxymetazoline 0.1% instillation were 0.77 ± 0.85 mm and 1.11 ± 0.92 mm, respectively (vs 0.42 ± 0.78 mm and 0.41 ± 0.83 mm with vehicle; both p<0.05). This effect was also observed immediately post-instillation on day 42, where mean increases 5 and 15 minutes post-oxymetazoline 0.1% instillation were 0.86 ± 0.85 mm and 1.04 ± 0.91 mm, respectively (vs 0.42 ± 0.80 mm and 0.47 ± 0.93 mm with vehicle; both p<0.005). Significant improvements vs vehicle (p<0.001) were also observed at 2-6 hours on days 1 and 14. At all time points, the proportion of subjects showing a positive response to treatment (>0% MRD-1 increase) was >15% greater in the oxymetazoline 0.1% group (range 16.6-36.1% more responders vs vehicle), with the largest differences observed 2 and 6 hours post-instillation. CONCLUSION: Oxymetazoline 0.1% provided rapid and sustained upper eyelid elevation. Together with data demonstrating superior visual field improvement and a favorable safety profile, this analysis supports oxymetazoline 0.1% as an effective non-surgical treatment for acquired ptosis.

Mydriasis with micro-array print touch-free tropicamide-phenylephrine fixed combination MIST: pooled randomized Phase III trials.

Design: Prospective, double-masked, controlled, cross-over superiority studies. Materials & methods: Eligible volunteers in two pooled Phase III trials received microdosed mydriatics. MIST-1 study subjects received fixed-combination TR-PH, phenylephrine 2.5% (PH) or tropicamide 1% (TR). MIST-2 study subjects received TR-PH or placebo. Mean change from baseline in pupil diameter was measured by digital pupillometry at 35 min postadministration. Results: Pooled efficacy analysis included 131 subjects. Compared with TR-PH, treatment group difference in 35-min change in mean pupil dilation from baseline was 0.58 mm (p < 0.0001) with TR, 3.87 mm (p < 0.0001) with PH and 4.65 mm (p < 0.0001) with placebo. Adverse events reported were infrequent, transient and mostly mild. Conclusion: TR-PH demonstrated superior pupil dilation compared with each component and placebo. TR-PH was safe & well-tolerated.

Combinations of Pilocarpine and Oxymetazoline for the Pharmacological Treatment of Presbyopia: Two Randomized Phase 2 Studies.

Purpose: To determine the safety, efficacy, and tolerability of combinations of pilocarpine (Pilo) and oxymetazoline (Oxy) ocular drops dosed once daily and identify the optimal concentration of each for the pharmacologic treatment of presbyopia. Design: Two concurrent Phase 2, multicenter, double-masked, randomized, vehicle-controlled studies, 1 short-term and 1 extended study. Participants: Emmetropic individuals affected by presbyopia and in good general health. Methods: Uncorrected near visual acuity (UNVA) was measured throughout both studies with various concentrations and combinations of Pilo (0%, 0.5% 1.0%, and 1.5%) and Oxy (0%, 0.0125%, 0.05%, and 0.125%). For safety, uncorrected distance visual acuity (UDVA) was measured, treatment-emergent adverse events (TEAEs) were recorded, and a temporal/supraorbital headache assessment was completed. Main Outcome Measures: The primary efficacy end point was mean change from baseline in UNVA. Results: In the short-term study, Pilo was shown to produce a significant dose response in the average increase of letters (P < 0.001), whereas Oxy did not have a significant impact (P = 0.4797). The addition or increase in concentration of Oxy did not reduce incidence or severity of headaches when compared with Pilo alone. Efficacy results from the extended study supported the results from the short-term study. As early as 15 minutes postadministration, a dose response could be seen, with peak effect at 1 hour. Peak improvement increased from day 1 to day 14 and was maintained up to day 28. The most common TEAE was headache. There was no clinically significant reduction in UDVA. A polynomial regression model was developed and determined that the optimal concentration range of Pilo is between 1.16% and 1.32%. Conclusions: On the basis of the results of the 2 Phase 2 studies, AGN-190584, a reading drop containing an optimized concentration of pilocarpine HCl (1.25%) delivered using a proprietary formulation, was developed and is currently under investigation in Phase 3 studies.

A Randomized Clinical Study (SEECASE) to Assess Efficacy, Safety, and Tolerability of NOV03 for Treatment of Dry Eye Disease.

PURPOSE: NOV03 has a unique dual mode of action to address dry eye disease (DED) associated with meibomian gland dysfunction. SEECASE evaluated the efficacy, safety, and tolerability of NOV03 at 2 dosing regimens compared with a saline comparator in patients with DED. METHODS: SEECASE was a prospective, multicenter, randomized, double-masked, saline-controlled clinical study. A total of 336 DED patients [tear film breakup time ≤5 seconds, abnormal meibum secretion, total corneal fluorescein staining (tCFS) score of 4 ≤ X ≤ 11 (National Eye Institute scale), Schirmer of ≥5 mm] were randomized in a 2:2:1:1 manner to NOV03 4 times daily (QID), NOV03 twice daily (BID), saline BID, and saline QID, respectively. The primary efficacy endpoint was tCFS staining at 8 weeks for both regimens. Secondary endpoints included visual analog scales and the Ocular Surface Disease Index questionnaire for symptom assessment. RESULTS: The study met its primary endpoint, change from baseline of tCFS over control, for both dosing regimens QID and BID (P < 0.001 and P = 0.009, respectively). NOV03 also showed pronounced improvement in various symptoms. For the Eye Dryness Score, changes from baseline were statistically significant compared with those of the control at week 8 [P < 0.001 (QID) and P = 0.002 (BID)]. Benefits on tCFS and symptoms started at 2 weeks after start of treatment and were maintained over the study duration. The effects were dosing schedule dependent. NOV03 was well tolerated with instillation site reactions below 3% in both treatment regimes. CONCLUSIONS: The SEECASE study demonstrated that NOV03 improves signs and symptoms in patients with highly symptomatic evaporative dry eye disease.

Association of Oxymetazoline Hydrochloride, 0.1%, Solution Administration With Visual Field in Acquired Ptosis: A Pooled Analysis of 2 Randomized Clinical Trials.

Importance: Treatment of acquired blepharoptosis (ptosis) is currently limited to surgical intervention. Objective: To examine the efficacy and safety of oxymetazoline hydrochloride, 0.1%, ophthalmic solution (oxymetazoline, 0.1%) in participants with acquired ptosis. Design, Setting, and Participants: This pooled analysis of 2 randomized, double-masked, placebo-controlled, multicenter phase 3 clinical trials included participants 9 years and older with acquired ptosis and superior visual field deficit. The 2 studies were conducted across 16 and 27 sites in the United States. Patients were enrolled from May 2015 to April 2019. Analyses for the individual trials were initiated after database lock and completed on September 6, 2017, and May 16, 2019. Pooled analysis was completed on August 25, 2019. Interventions: Participants (randomized 2:1) received oxymetazoline, 0.1%, or vehicle, self-administered as a single drop per eye, once daily, for 42 days. Main Outcomes and Measures: The primary efficacy end point was change from baseline in the number of points seen on the Leicester Peripheral Field Test, a test to detect superior visual field deficits due to ptosis, on days 1 (6 hours after instillation) and 14 (2 hours after instillation). The secondary end point, change from baseline in marginal reflex distance 1, was assessed at the same time points. Results: In total, 304 participants were enrolled (mean [SD] age, 63.8 [13.8] years; 222 women [73%]). Overall, 97.5% (198 of 203) of participants receiving oxymetazoline, 0.1%, and 97.0% (98 of 101) of participants receiving vehicle completed the studies. Oxymetazoline, 0.1%, was associated with a significant increase in the mean (SD) number of points seen on the Leicester Peripheral Field Test vs vehicle (day 1: 5.9 [6.4] vs 1.8 [4.1]; mean difference, 4.07 [95% CI, 2.74-5.39]; P < .001; day 14: 7.1 [5.9] vs 2.4 [5.5]; mean difference, 4.74 [95% CI, 3.43-6.04]; P < .001). Oxymetazoline, 0.1%, also was associated with a significant increase in marginal reflex distance 1 from baseline (mean [SD]: day 1: 0.96 [0.89] mm vs 0.50 [0.81] mm; mean difference, 0.47 mm [95% CI, 0.27-0.67]; P < .001; day 14: 1.16 [0.87] mm vs 0.50 [0.80] mm; mean difference, 0.67 mm [95% CI, 0.46-0.88]; P < .001). Treatment-emergent adverse events (TEAEs) occurred in 31.0% (63 of 203) of participants receiving oxymetazoline, 0.1%, and 35.6% (36 of 101) of participants receiving vehicle. Among participants receiving oxymetazoline, 0.1%, with a TEAE, 81% (51 of 63) had a maximum TEAE intensity of mild, and 62% (39 of 63) had no TEAE suspected of being treatment related. Conclusions and Relevance: Oxymetazoline, 0.1%, was associated with positive outcomes and was well tolerated in phase 3 trials after instillation at days 1 and 14, demonstrating its potential promise for the treatment of acquired ptosis, although further study is needed to elucidate the clinical relevance of these findings beyond 6 weeks.

A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease.

PURPOSE: To compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1% and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED). An open-label Restasis (Allergan, Irvine, CA) arm was included to allow a direct comparison with an approved therapy. DESIGN: An exploratory phase II, multicenter, randomized, vehicle-controlled clinical trial, double-masked between CyclASol and vehicle with an open-label comparator. PARTICIPANTS: Two hundred and seven eligible patients with a history of dry eye disease were randomized 1:1:1:1 to 1 of 4 treatment arms (CyclASol 0.05%, n = 51; CyclASol 0.1%, n = 51; vehicle, n = 52, and Restasis, n = 53). METHODS: After a 2-week run-in period with twice-daily dosing of Systane Balance (Alcon, Fort Worth, TX), patients were randomized to the respective treatment arm and dosed twice daily for 16 weeks. MAIN OUTCOME MEASURES: The study was set up to explore efficacy on a number of sign and symptom end points including total and subregion corneal fluorescein staining, conjunctival staining, visual analog scale (VAS) for dry eye symptoms VAS severity, and Ocular Surface Disease Index (OSDI) questionnaire. RESULTS: CyclASol showed a consistent reduction in corneal and conjunctival staining compared with both vehicle and Restasis over the 16-week treatment period, with an early onset of effect (at day 14). A mixed-effects model-based approach demonstrated that the CyclASol drug effect was statistically significant over vehicle (total corneal staining P < 0.1, central corneal staining P < 0.001, conjunctival staining P < 0.01). This model-based analysis suggests a significant CyclASol effect for OSDI as symptom parameter (P < 0.01). The numbers of ocular adverse events were low in all treatment groups. CONCLUSIONS: CyclASol showed efficacy, safety, and tolerability at 2 concentrations in moderate-to-severe DED. In a direct head-to-head against open-label Restasis, CyclASol was found to have an earlier onset of action, as early as after 2 weeks of treatment, in relieving the signs of DED, as measured by corneal and conjunctival staining. The central region of the cornea, an important area for visual function in dry eye sufferers, was shown to have the most benefit from treatment. Excellent safety, tolerability, and comfort profile supports this new CsA formulation as having a positive benefit-to-risk ratio.