Efficacy and Safety of the Melanocortin Pan-Agonist PL9643 in a Phase 2 Study of Patients with Dry Eye Disease.

Purpose: The melanocortin receptor pan-agonist PL9643, a potential therapy for ocular diseases, was investigated in a phase 2, 12-week study in patients with dry eye disease (DED). Methods: This was a placebo-controlled study evaluating efficacy and safety of thrice-daily PL9643. Placebo (vehicle) was similar to tears. Primary endpoints were intra-patient changes in inferior corneal fluorescein staining and ocular discomfort after 12 weeks. Secondary endpoints were changes in additional DED signs or symptoms. Multiple secondary endpoints were not adjusted for multiplicity. Patients with moderate or severe DED were analyzed in addition to the overall intent-to-treat (ITT) population. Results: In the ITT population (n = 160) the PL9643 group did not demonstrate significant treatment difference versus placebo at week 12/day 85 for the primary endpoints (P > 0.05). In patients with moderate or severe DED (n = 53), PL9643 treatment demonstrated either nominally significant (P < 0.05) or trending (P < 0.1) improvement over placebo in mean change from baseline at week 12/day 85 in several sign endpoints, including fluorescein staining in inferior, superior, corneal sum, and total sum regions; Lissamine Green staining in temporal, nasal, conjunctival sum, and total sum regions; and tear film breakup time. Conjunctival redness also showed (nonsignificant) improvement at week 12/day 85. There were no drug-related adverse events (AEs) and no drug-related discontinuations. Conclusions: PL9643 showed no significant efficacy for the ITT population; however, efficacy results across several signs and symptoms in the subpopulation of moderate to severe DED patients, the low number of ocular AEs, and no tolerability issues suggest that PL9643 shows promise as a therapeutic for DED. Clinical Trial Registration number: NCT04268069.

ONSET-1 Phase 2b Randomized Trial to Evaluate the Safety and Efficacy of OC-01 (Varenicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease.

PURPOSE: The purpose of this trial was to evaluate the safety and efficacy of OC-01 (varenicline solution), a nicotinic acetylcholine receptor agonist nasal spray, on signs and symptoms of dry eye disease. METHODS: A phase 2b, multicenter, randomized, double-masked, vehicle-controlled trial (ONSET-1; NCT03636061) was performed. Patients were aged 22 years or older with a physician's diagnosis of dry eye disease and previous use of artificial tears were randomized 1:1:1:1 to control (vehicle nasal spray twice daily [BID]), OC-01 0.006 mg BID, OC-01 0.03 mg BID, and OC-01 0.06 mg BID. The primary end point was the change in the anesthetized Schirmer test score from baseline to day 28 in the study eye. The secondary end points included the change in the eye dryness score from baseline to day 28. RESULTS: One hundred eighty-two patients were randomized. After 28 days, patients who received OC-01 0.03 or 0.06 mg showed a statistically significant improvement in tear film production relative to vehicle, with least squares mean differences from vehicle of 7.7 mm [95% confidence interval, 3.8-11.7; P < 0.001] with OC-01 0.03 mg and 7.5 mm (95% confidence interval, 3.4-11.6; P < 0.001) with OC-01 0.06 mg. Patients receiving OC-01 0.03 mg showed a significant reduction in the eye dryness score by day 28 versus vehicle (P = 0.021); those receiving the OC-01 0.06 mg dose showed a nonsignificant reduction versus vehicle. OC-01 administration was associated with sneezing (62%-84%) and cough (9%-25%); these were transient and predominantly mild in severity. CONCLUSIONS: OC-01 nasal spray administered BID at 0.03 and 0.06 mg resulted in significant improvements in signs and symptoms of dry eye disease, was well tolerated, and warrants further clinical investigation.

Efficacy and Safety of Single-dose OC-02 (Simpinicline Solution) Nasal Spray on Signs and Symptoms of Dry Eye Disease: The PEARL Phase II Randomized Trial.

PURPOSE: Dry eye disease is a multifactorial disorder that affects the ocular surface, with symptoms including ocular irritation, impaired vision, and pain. Nicotinic acetylcholine receptor (nAChR) agonists are novel treatments for dry eye disease; this study investigates the nAChR agonist OC-02 (simpinicline solution) as an aqueous nasal spray. METHODS: PEARL (Clinical Trial to Evaluate the Efficacy of OC-02 Nasal Spray on Signs and Symptoms of Dry Eye Disease) was a Phase II study that evaluated the efficacy and safety of OC-02 (simpinicline solution) nasal spray (OC-02 SNS) in adult patients with dry eye disease. Patients ≥22 years of age were eligible if they had an Ocular Surface Disease Index score ≥23, corneal fluorescein staining score ≥2 in >1 region or ≥4 for all regions, or Schirmer test score (STS) ≤10 mm; there were no restrictions on eye dryness score (EDS). Patients (N = 165) were randomly assigned 1:1:1:1 to vehicle (control; n = 42) or OC-02 SNS (0.11 mg, 0.55 mg, or 1.1 mg; n = 41 per group) and received a single dose of study drug (100 µL using a nasal spray atomizer) at visit 1 and visit 2 (15-19 days after visit 1). Primary efficacy outcomes were change in the STS from baseline to immediately after treatment administration (visit 1) and change in the EDS from before to 5 minutes after treatment during controlled adverse environment exposure (visit 2). FINDINGS: Baseline demographic and ocular clinical characteristics were similar across all groups. Single-dose OC-02 SNS improved the signs and symptoms of dry eye disease. For the STS, statistically significant and dose-dependent improvements were found from before to after treatment with OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, 3.0 mm; 0.11 mg OC-02 SNS, 9.0 mm; 0.55 mg, 17.5 mm; and 1.1 mg, 19.6 mm). For EDS, statistically significant and dose-dependent improvements were found from before to 5 minutes after treatment with higher doses of OC-02 SNS versus vehicle (least-squares mean change from baseline: vehicle, -6.5; 0.11 mg OC-02 SNS, -9.4; 0.55 mg, -17.4; and 1.1 mg, -20.7). OC-02 SNS was well tolerated: only 2 ocular adverse events were reported (eye pruritis and keratitis), and the most common nonocular events were cough and throat irritation. IMPLICATIONS: Single-dose OC-02 SNS over a range of doses immediately and significantly increased tear production and improved eye dryness. Together with previous studies of OC-01 (varenicline solution) nasal spray, our findings suggest that agonist stimulation of nAChRs in the nasal cavity is a valid and effective mechanism to elicit natural tear production in patients with dry eye disease. CLINICALTRIALS: gov identifier: NCT03452397.

Symptom improvement in dry eye subjects following intranasal tear neurostimulation: Results of two studies utilizing a controlled adverse environment.

PURPOSE: To evaluate the safety and effectiveness of the intranasal tear neurostimulator (ITN) in improving dry eye symptoms assessed in a controlled adverse environment (CAE®). METHODS: Study 1: Multicenter, subject-masked, randomized-sequence, crossover design. Single intranasal (active) and extranasal (control) ITN administration during CAE exposure. Study 2: Single-arm, open-label design. Intranasal ITN administration ≥2 times/day for 45 days, CAE assessment at days 0 and 45. In both studies, upon CAE entry, and every 5 min thereafter, subjects assessed eye dryness score (visual analog scale, 0-100 mm; EDS-VAS), and ocular discomfort score (ODS; Ora Calibra™, 0-4), for ≈2 h. Study 1: when ODS was ≥3 at 2 consecutive timepoints, subjects applied ITN intranasally or extranasally for ≈3 min, and again when achieving the same ODS criteria in randomized sequence. Study 2: days 0 and 45, ITN was applied for ≈3 min employing the same ODS criteria as Study 1. RESULTS: Study 1: Significantly greater pre- to post-application reductions in mean [SEM] EDS (-16.5 [1.7] vs -3.1 [1.7], P < 0.0001) and ODS (-0.93 [0.08] vs -0.34 [0.08], P < 0.0001; n = 143) with intranasal vs extranasal stimulation. Study 2: On day 0 (n = 52) and day 45 (n = 48), significant pre- to post-application reductions in mean [SEM] EDS (-15.9 [2.7] and -15.2 [2.4]; P < 0.0001), and ODS (-1.3 [0.2] and -1.3 [0.1]; P < 0.0001). Few device-related adverse events were reported, none serious. CONCLUSIONS: Acute symptom relief is significant with the ITN and remains undiminished after daily use.

A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease.

PURPOSE: To evaluate the safety and efficacy of topical TOP1630, a novel nonsystemic kinase inhibitor, in dry eye disease (DED). PATIENTS AND METHODS: A randomized, double-masked, parallel-group trial of 0.1% TOP1630 ophthalmic solution TID or placebo (vehicle without active drug) was conducted in DED subjects (n=61). Key eligibility criteria consistent with enrolling a moderate to severe DED population included >6 months DED history; OSDI© score ≥18; Schirmer's test score ≤10 and ≥1 mm/5 minutes; tear film break-up time >1 and <7 seconds; and dry eye exacerbation in corneal staining and ocular discomfort in a Controlled Adverse Environment (CAE®). After a 7-day run-in period with placebo TID, eligible subjects were randomized to TOP1630 or placebo for 28 days. No supplemental artificial tears or rescue medication were allowed. RESULTS: TOP1630 was safe, well-tolerated, and efficacious in treating DED symptoms and signs. No serious adverse events (AEs) or withdrawals due to treatment emergent AEs occurred. Drop comfort scores showed TOP1630 to be comfortable and comparable with placebo. Significant symptom improvements were seen for TOP1630 vs placebo for ocular discomfort (P=0.02 post-CAE), grittiness/foreign body sensation (on four independent assessment scales, each P<0.05), worst DED symptom (diary, P=0.06), and ocular pain (VAS, P=0.03). Sign improvements were seen for total ocular surface (all regions), corneal sum, and conjunctival sum staining with TOP1630 compared with placebo (each P<0.05). CONCLUSION: TOP1630 had placebo-like tolerability and produced improvements in multiple symptom and sign endpoints in both environmental and challenge settings. The emergent TOP1630 benefit-risk profile for DED treatment is highly favorable and supports further development.

Safety of cetirizine ophthalmic solution 0.24% for the treatment of allergic conjunctivitis in adult and pediatric subjects.

PURPOSE: The studies reported here aimed to assess the safety and tolerability of cetirizine ophthalmic solution 0.24%, a new topical ophthalmic medication approved by the US Food and Drug Administration for the treatment of ocular itching associated with allergic conjunctivitis. PATIENTS AND METHODS: Three clinical studies evaluated cetirizine ophthalmic solution 0.24% administration: a Phase I prospective, single-center, open-label, pharmacokinetic (PK) study (N=11) evaluating single-dose administration and twice-daily (BID) administration for 1 week in healthy adults, and two Phase III, multi-center, randomized, double-masked, vehicle-controlled, parallel-group studies evaluating the safety and tolerability in adult and pediatric populations (2-18 years of age) for up to 6 consecutive weeks. The first safety and tolerability study evaluated cetirizine BID (study 1, N=512), while the second study examined cetirizine three times daily (TID) (study 2, N=516). Each study assessed best corrected visual acuity, slit-lamp biomicroscopy, IOP, dilated ophthalmoscopy, treatment-emergent adverse events, vital signs, urine pregnancy test, and physical examination (general health, head, eyes, ears, nose, and throat). The PK study also measured hematology, blood chemistry, and urinalysis, while the two Phase III studies additionally assessed corneal endothelial cell counts (ECC) and ECC density in a subset of subjects (via specular microscopy), and drug administration tolerability. RESULTS: Bilateral administration of cetirizine ophthalmic solution 0.24% resulted in low systemic exposure in the PK study and was associated with a low incidence of mild adverse events. There were no drug-related severe or serious adverse events. The tolerability scores between the active and vehicle groups were comparable, demonstrating high comfort in the administration of cetirizine ophthalmic solution 0.24%. CONCLUSION: Cetirizine ophthalmic solution 0.24% dosed BID or TID demonstrated an acceptable safety profile and was well-tolerated when administered to subjects aged ≥2 years.

Management of Ocular Allergy Itch With an Antihistamine-Releasing Contact Lens.

PURPOSE: A contact lens (CL)-based drug delivery system for therapeutic delivery of the antihistamine ketotifen was tested in 2 parallel, conjunctival allergen challenge-based trials. METHODS: Both trials employed the same multicenter, randomized, placebo-controlled protocol. Test lenses were etafilcon A with 0.019 mg ketotifen; control lenses were etafilcon A with no added drug. Subjects were randomized into 3 treatment groups. Group 1 received test lens in one eye and control lens in the contralateral eye; the eye chosen to receive test lens was randomly selected in a 1:1 ratio. Group 2 received test lenses bilaterally, and group 3 received control lenses bilaterally. Allergen challenges were conducted on 2 separate visits: following lens insertion, the subjects were challenged at 15 minutes (to test onset) and 12 hours (to test duration). The primary endpoint was ocular itching measured using a 0 to 4 scale with half-unit steps. Secondary endpoints included ciliary, conjunctival, and episcleral hyperemia. RESULTS: The mean itching scores were lower for eyes wearing the test lens as compared to those that received control lenses, indicating that the test lens effectively reduced allergic responses. Mean differences in itching were statistically and clinically significant (mean score difference ≥ 1) at both onset and duration for both trials. CONCLUSIONS: This large-scale assessment (n = 244) is the first demonstration of efficacy for CL delivery of a therapeutic for ocular allergy. Results are comparable to direct topical drug delivery and suggest that the lens/ketotifen combination can provide a means of simultaneous vision correction and treatment for CL wearers with ocular allergies.

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.

Characterization of tear production in subjects with dry eye disease during intranasal tear neurostimulation: Results from two pivotal clinical trials.

PURPOSE: The intranasal tear neurostimulator (ITN) activates the nasolacrimal pathway, which is involved with basal and bolus tear secretion. These studies characterized the acute and long-term effectiveness of the ITN in stimulating tear production in subjects with dry eye disease (DED). METHODS: Study 1: Randomized, double-masked, dual-controlled, 1-day crossover. Study 2: Single-arm, open-label, 180-day prospective cohort. Eligible subjects had basal unstimulated Schirmer test (with anesthesia) ≤10 mm and intranasal cotton swab-stimulated Schirmer test at least 7 mm greater in the same eye, and Ocular Surface Disease Index® ≥13 and ≥ 23, in Studies 1 and 2, respectively. Study 1: Subjects (n = 48) received three randomized test applications: active intranasal, extranasal (active control), and sham intranasal (inactive control) stimulation, 3 min/application with 1-hour minimum between applications. Primary outcome measure was the difference in Schirmer test scores during active intranasal and control applications. Study 2: Subjects (n = 97) performed intranasal neurostimulation for ≤3 min/application, 2-10 times/day. Primary outcome measure was the difference in Schirmer scores (stimulated minus unstimulated) at day 180. Both studies recorded device-related adverse events (AEs). RESULTS: Study 1: Schirmer scores (mean ±â€¯SEM) were significantly greater (p < 0.0001) with active intranasal (25.3 ±â€¯1.5 mm) vs extranasal (9.5 ±â€¯1.2 mm) and sham (9.2 ±â€¯1.1 mm) applications. Study 2: Schirmer scores were significantly greater (p < 0.0001) with ITN stimulation vs unstimulated at day 180 (17.3 ±â€¯1.3 mm vs 7.9 ±â€¯0.7 mm). No serious device-related AEs were reported in either study. CONCLUSION: The ITN was well-tolerated and effective in stimulating tear production with acute and long-term use in DED. CLINICALTRIALS. GOV IDENTIFIER: NCT02680158 and NCT02526290.

Low-dose brimonidine for relief of ocular redness: integrated analysis of four clinical trials.

BACKGROUND: The aim of this study was to provide an integrated analysis of safety and efficacy data for brimonidine tartrate ophthalmic solution 0.025 per cent (low-dose; Bausch & Lomb Incorporated), a topical vasoconstrictor for relief of ocular redness. METHODS: Integrated efficacy data from two randomised, double-masked, vehicle-controlled studies in subjects with ocular redness as well as safety data from the two efficacy studies, a vehicle-controlled safety study, and a pharmacokinetic study were analysed. Efficacy outcomes analysed included investigator-assessed ocular redness (scale, 0-4) before treatment instillation and at five to 240 minutes post-instillation on Day 1, at five minutes post-instillation on Days 15 and 29, and one week after treatment discontinuation (Day 36), and redness self-assessed by subjects recorded daily in diaries. Safety assessments included adverse events, ophthalmic examinations, and rebound redness upon treatment discontinuation. Drop comfort (scale, 0-10) was a tolerability measure. RESULTS: The efficacy population included 117 subjects (brimonidine, n = 78; vehicle, n = 39). The safety population included 635 subjects (brimonidine, n = 426; vehicle, n = 209). Investigator-assessed ocular redness was significantly lower with brimonidine versus vehicle at all post-instillation time points on Day 1 (mean change from pre-instillation of -1.4 units for brimonidine and -0.2 units for vehicle; p < 0.0001). Subject-assessed ocular redness was also significantly lower with brimonidine versus vehicle (mean treatment difference in average daily ratings of -0.9; p < 0.0001). There was no evidence of tachyphylaxis through Day 29 and rebound redness was rare. Incidence of ocular adverse events was low, the most common being reduced visual acuity (brimonidine, 4.0 per cent; vehicle, 4.3 per cent) and conjunctival hyperaemia (2.6 and 2.9 per cent, respectively). Both brimonidine and vehicle were rated as very comfortable (mean post-instillation scores, 0.4-0.5). CONCLUSION: In this integrated analysis, low-dose brimonidine significantly reduced ocular redness with no tachyphylaxis, and minimal rebound redness, and was generally safe and well tolerated.

Phase III trials examining the efficacy of cetirizine ophthalmic solution 0.24% compared to vehicle for the treatment of allergic conjunctivitis in the conjunctival allergen challenge model.

PURPOSE: The purpose of these Phase III studies was to evaluate the efficacy and safety of cetirizine ophthalmic solution 0.24% compared with vehicle in the treatment of allergen-induced conjunctivitis using the Ora conjunctival allergen challenge (CAC)® model. METHODS: The single-center (Study 1) and multi-center (Study 2), double-masked, randomized, vehicle-controlled, parallel group, CAC studies were conducted over ~5 weeks and four study visits. The study design only differed in entry criteria: Study 2 required more severe allergic conjunctivitis symptoms. Subjects were screened for an allergen response at Visits 1 and 2 and then randomized at Visit 3. Approximately 100 subjects were randomized in each study. The primary efficacy endpoints were ocular itching and conjunctival redness 15 minutes and 8 hours post-treatment, post-CAC. RESULTS: Cetirizine treatment administered 15 minutes or 8 hours prior to CAC resulted in significantly lower ocular itching at all time points post-CAC (P<0.0001) compared to vehicle in both studies. Conjunctival redness measured by the investigator was significantly lower after cetirizine treatment compared to vehicle at 7 minutes post-CAC at both 15 minutes and 8 hours post-treatment in both studies (P<0.05). All secondary endpoints were in favor and confirmatory of cetirizine efficacy with significant improvement in chemosis, eyelid swelling, tearing, ciliary redness, and episcleral redness, as well as nasal symptoms (rhinorrhea, nasal pruritus, ear or palatal pruritus, and nasal congestion) post-CAC. The most robust treatment differences were observed in Study 2 where more severe symptoms were required for study entry (P<0.05). No safety concerns for cetirizine ophthalmic solution 0.24% were identified. CONCLUSION: Cetirizine ophthalmic solution 0.24% was shown to be efficacious in the treatment of ocular and nasal signs and symptoms associated with allergic conjunctivitis and demonstrated a favorable safety profile. Clinical efficacy was demonstrated with a 15-minute onset of action and añ8-hour duration of action.

Evaluation of Efficacy and Safety of Brimonidine Tartrate Ophthalmic Solution, 0.025% for Treatment of Ocular Redness.

Purpose/Aims: This study assessed the efficacy and safety of brimonidine tartrate ophthalmic solution, 0.025% for treating ocular redness in adult subjects. MATERIALS AND METHODS: This was a single-center, double-masked, randomized, vehicle-controlled, parallel-group study in subjects ≥40 years, with ocular redness. Subjects were randomized 2:1 to brimonidine or vehicle, instilled QID for four weeks. Subjects completed four visits, the last occurring one week after treatment discontinuation. The investigator assessed ocular redness on a scale of 0-4 pre-instillation and 5-240 minutes post-instillation on Day 0, pre-instillation and 5 minutes post-instillation on Days 14 and 28, and on Day35; subjects assessed redness in diaries throughout the 28-day treatment period and following treatment discontinuation. Safety assessments included adverse events (AEs), rebound redness on treatment discontinuation, comprehensive ophthalmic exams, and vital signs. Drop comfort was assessed upon instillation, and 30 seconds and 1 minute post-instillation at Day 0. RESULTS: Fifty-seven subjects (brimonidine, n = 38; vehicle, n = 19) were randomized. Investigator-assessed ocular redness was significantly reduced with brimonidine across the entire post-instillation time period (overall treatment difference: -1.37; P < 0.0001) and at all individual time points (P < 0.0001). Subject-assessed ocular redness was also significantly lower with brimonidine (P ≤ 0.0005). No tachyphylaxis was evident. There were few ocular AEs, all mild to moderate in severity, and no redness rebound was observed upon brimonidine discontinuation. There were no effects on any safety measures, and both brimonidine and its vehicle were reported to be very comfortable. CONCLUSIONS: Brimonidine 0.025% appeared safe, well tolerated, and reduced ocular redness for at least 4 hours. No tachyphylaxis or rebound redness upon treatment discontinuation was observed.

Evaluation of a new artificial tear formulation for the management of tear film stability and visual function in patients with dry eye.

PURPOSE: Artificial tears are the first line of therapy for dry eye disease (DED) and are also the most frequently used treatment approach for this common condition. Despite this, there are few published studies that directly compare the effectiveness of different drop preparations, especially those formulated specifically for dry eye. In this study, we tested a new artificial tear product, Rohto® Dry-Aid™, for its ability to relieve the signs and symptoms of DED. The study used a second drop, Systane® Ultra, as a positive comparator. MATERIALS AND METHODS: This was a prospective, single-center, open-label, parallel-group study comparing the effects of the two products when used continuously over ~30 days (Clinical Trials registration number NCT03183089). Subjects were randomly assigned to one of the two test groups and were monitored 2 and 4 weeks after enrollment. Efficacy endpoints included ocular staining, visual function, and ocular discomfort. RESULTS: Treatment groups had similar ocular staining and ocular comfort scores, and both showed statistically significant ocular discomfort score improvement. Subjects in the Rohto group reported significant improvements in visual tasking activities such as watching television and driving at night. There was also a tendency for diary symptom scores to worsen from morning to evening in the Systane group, but not in the Rohto group; this trend was not significant, but warrants further study. CONCLUSION: The two products, Rohto Dry-Aid and Systane Ultra, elicited comparable effects on the signs and symptoms of DED. While both products are designed to provide long-lasting relief, subjects in the Rohto group experienced a superior relief from discomfort associated with visual tasking activities and daily diaries, indicating that the Rohto drops may provide a longer duration of symptomatic relief over the course of the day.

Pooled analysis of two studies evaluating efficacy and safety of olopatadine hydrochloride 0.77% in patients with allergic conjunctivitis.

PURPOSE: Two individual phase 3 conjunctival allergen challenge (CAC) studies of similar design have assessed the efficacy and safety of olopatadine hydrochloride (HCl) 0.77% for the treatment of allergic conjunctivitis. The purpose of this study is to evaluate the integrated efficacy and safety of olopatadine HCl 0.77% from a larger dataset by pooling data from the two individual CAC studies. METHODS: Data were pooled from two phase 3, randomized, multicenter, double-masked, active- and vehicle-controlled CAC studies. The primary comparison was on ocular itching scores between olopatadine HCl 0.77% versus vehicle (at onset and 24 hours) and olopatadine HCl 0.77% versus olopatadine 0.2% (at 24 hours). Additional end points included conjunctival redness, total redness, and proportion of itching responders at onset and 24-hour duration of CAC. For both primary and secondary analysis, mixed model repeated measures analysis was used, except for proportion of ocular itching responders. Sensitivity analyses were carried out using a two-sample t-test. RESULTS: This analysis included 448 patients. Olopatadine HCl 0.77% was superior to vehicle (P<0.0001) at onset and 24-hour duration of action (difference in means: -1.14 to -1.52) and to olopatadine 0.2% (P=0.0009) at 24-hour duration of action in relieving ocular itch. Additionally, olopatadine HCl 0.77% substantially reduced conjunctival redness and total redness over vehicle and olopatadine 0.2% at onset and 24-hour duration of action. At 24 hours CAC, there were a higher proportion of itching responders with olopatadine HCl 0.77% compared to vehicle or olopatadine 0.2% (difference in proportion of responders: 43.17%, P<0.0001, and 17.25%, P=0.0012, respectively). No safety concerns were identified. CONCLUSION: This analysis confirms the findings from the individual studies. The rapid onset and prolonged duration of action (for 24 hours) of olopatadine HCl 0.77% supports once-daily dosing in the treatment of allergic conjunctivitis.

Vehicle-Controlled, Phase 2 Clinical Trial of a Sustained-Release Dexamethasone Intracanalicular Insert in a Chronic Allergen Challenge Model.

PURPOSE: To evaluate the efficacy and safety of a sustained-release dexamethasone intracanalicular insert (Dextenza™) in a model of allergic conjunctivitis. METHODS: This was a randomized, double-masked, vehicle-controlled, Phase 2 study. Subjects had to have a positive conjunctival allergen challenge (CAC) reaction to allergen (bilateral +2 itching and redness on 5-point, 0-4 scales) at Visit 1, and for 2 of 3 time points on subsequent visits. Subjects who met entry criteria were randomized to receive Dextenza or PV (vehicle insert). Challenges occurred over 42 days, with efficacy assessed at 14 (primary endpoint visit), 28, and 40 days postinsertion. Outcome measures included the evaluation of ocular itching, redness, tearing, chemosis, eyelid swelling, rhinorrhea, and congestion. RESULTS: Twenty-eight subjects completed the study in the Dextenza group and 31 in the vehicle group. At 14 days postinsertion, Dextenza was statistically superior to PV, with least square mean differences for ocular itching of -0.76, -0.97, and -0.87 at 3, 5, and 7 min post-CAC, and for conjunctival redness of -0.46, -0.66, and -0.68 at 7, 15, and 20 min post-CAC. Clinical significance, defined as a 1-U decrease from PV, was not met for primary efficacy. Secondary endpoints, including number of subjects reporting itching and conjunctival redness, indicated superior performance of Dextenza compared with vehicle. Eleven Dextenza-treated (35.5%) and 10 vehicle-treated (30.3%) subjects each experienced a single adverse event. CONCLUSION: This Phase 2 study demonstrated preliminary efficacy and safety data of Dextenza for treatment of allergic conjunctivitis.

The IMPACT study: a prospective evaluation of the effects of cyclosporine ophthalmic emulsion 0.05% on ocular surface staining and visual performance in patients with dry eye.

OBJECTIVE: The aim of this study was to evaluate the effects of cyclosporine ophthalmic emulsion 0.05% on ocular surface staining and visual performance in patients with dry eye. METHODS: This was a single-center, 6-month, open-label, Phase IV study. Patients with bilateral dry eye disease and a symptom score of ≥2 on the Ocular Discomfort and 4-Symptom Questionnaire, an Ocular Surface Disease Index score of >12, at least one eye with Schirmer's score <10 mm/5 minutes, and central corneal staining graded as ≥2 on the Ora Calibra™ Corneal and Conjunctival Staining Scale were enrolled. Cyclosporine ophthalmic emulsion 0.05% (Restasis(®)) was instilled twice daily in each eye. The primary efficacy endpoints were ocular surface staining and visual function at 6 months. Secondary outcome measures included Schirmer's test, tear film breakup time, symptoms, and adverse events. RESULTS: A total of 40 patients with the mean age of 59.4 years (range, 40-78 years) were enrolled; 35 (87.5%) were female and 37 (92.5%) completed the study. At 6 months, inferior corneal, central corneal, total corneal, and total ocular surface fluorescein staining were significantly improved from baseline in both eyes (P<0.001). Patient responses on the Ocular Surface Disease Index showed significant improvement in blurred vision and visual function related to reading, driving at night, working with a computer or bank machine, and watching television (P≤0.041). At 6 months, 35.1% of patients achieved ≥5 mm improvement and 18.9% achieved ≥10 mm improvement in the average eye Schirmer score. Mean tear film breakup time improved by >50% in both eyes (P>0.001). Patients reported significant improvement in ocular discomfort and dry eye symptoms (P<0.001). No patients discontinued treatment because of stinging or any other ocular adverse event. CONCLUSION: Dry eye patients with difficulties with day-to-day visual function demonstrated improvement in both signs and symptoms of dry eye and reported improved visual function after 6 months of treatment with cyclosporine ophthalmic emulsion 0.05%.

Safety and comfort evaluation of a new formulation of Visine(®) lubricant eye drops containing HydroBlend™ and GentlePur™.

PURPOSE: To evaluate the clinical safety and comfort of a new benzalkonium chloride-free Visine(®) lubricant eye drop formulation (Hydroblend™ and GentlePur™) in healthy and dry eye subjects. METHODS: This was a single-site, open-label clinical study comprised of 22 healthy and 22 dry eye subjects. Subjects were instructed to instill 1-2 drops of the test product four times a day for 2 weeks and were examined at visit 1 (day 0), visit 2 (day 7), and visit 3 (day 14). Assessments at each visit included postdosing product usage comfort scores, predosing fluorescein corneal staining score, predosing visual acuity, and pre- and postdosing ocular structure change using slit-lamp biomicroscopy. Adverse events were monitored throughout the course of the study. RESULTS: Throughout the 14 days of the trial period, subjects from both healthy and dry eye groups rated the eye drops as "very comfortable". For dry eye group, the mean product usage comfort scores for the first 3 minutes postdosing ranged from 8.5 to 8.8 at visit 1 and 9.2 to 9.6 at visit 3 on a 0-10 point scale, with 0 being very uncomfortable and 10 being very comfortable. The mean corneal staining scores over five corneal regions changed from 0.65 at visit 1 to 0.39 at visit 3 for dry eye group. The individual region corneal staining scores were also decreased from visits 1 to 3 for dry eye group. All subjects maintained pretreatment means visual acuity at visits 2 and 3. Biomicroscopic examination indicated no structural changes at all visits. There were no significant adverse events reported during the course of the study. CONCLUSION: The study confirms that GentlePur™ is an appropriate choice as a preservative for ocular application. The new formulation was safe and comfortable when used four times a day in healthy and dry eye subjects.

Efficacy and safety of olopatadine hydrochloride 0.77% in patients with allergic conjunctivitis using a conjunctival allergen-challenge model.

BACKGROUND: Symptom relief for the duration of 24 hours after treatment would benefit patients with allergic conjunctivitis. OBJECTIVE: To compare the safety and efficacy of olopatadine 0.77% with vehicle or olopatadine 0.2% in patients with allergic conjunctivitis in a conjunctival allergen-challenge clinical study. PATIENTS AND METHODS: In this Phase III, multicenter, double-masked, parallel-group, randomized trial, patients with allergic conjunctivitis received olopatadine 0.77%, its vehicle, or olopatadine 0.2%, administered once at visits 3A (day 0), 4A (day 14 ±2), and 5 (day 21 +3). Allergic conjunctivitis-associated sign and symptom assessments included ocular itching, conjunctival redness, total redness, chemosis, and tearing scores. Adverse events and ocular safety parameters were also assessed. RESULTS: A total of 202 qualifying patients were randomized. Olopatadine 0.77% was superior (P<0.001) to vehicle for treatment of ocular itching at 3, 5, and 7 minutes postchallenge at onset of action and 16- and 24-hour duration of action. Conjunctival redness mean scores were significantly lower for olopatadine 0.77% versus vehicle at all three post-conjunctival allergen-challenge time points: onset (-1.52 to -1.48; P<0.001), 16 hours (-1.50 to -1.38; P<0.01), and 24 hours (-1.58 to -1.38; P<0.05). At 24 hours, olopatadine 0.77% was superior to olopatadine 0.2% at all three postchallenge time points for ocular itching (P<0.05), conjunctival redness (P<0.05), and total redness (P<0.05). No clinically relevant differences in safety parameters or adverse events were observed between the treatment groups. CONCLUSION: Olopatadine 0.77% is superior to both its vehicle and olopatadine 0.2% for the treatment of allergen-mediated ocular itching and conjunctival redness. Ocular itching symptom relief is maintained over 24 hours, supporting once-daily dosing and demonstrating a comparable safety profile to olopatadine 0.2%.

Phase 3 Randomized Double-Masked Study of Efficacy and Safety of Once-Daily 0.77% Olopatadine Hydrochloride Ophthalmic Solution in Subjects With Allergic Conjunctivitis Using the Conjunctival Allergen Challenge Model.

PURPOSE: To assess the efficacy and safety of a novel once-daily 0.77% olopatadine hydrochloride ophthalmic solution in subjects with allergic conjunctivitis (AC) using the conjunctival allergen challenge (CAC) model. METHODS: In this 5-week, multicenter, double-masked, phase 3, randomized trial, subjects aged ≥18 years with a history of AC and a confirmed positive bilateral CAC response were randomized 2:2:2:1 to receive olopatadine 0.77%, olopatadine 0.2%, olopatadine 0.1%, or vehicle, respectively, following a single topical dose in each eye. The primary objective was superiority of olopatadine 0.77% over all comparators on ocular itching according to a 0 to 4 scale (0 = none and 4 = incapacitating itch) at 24-hour duration of action and over vehicle only at the onset of action (3, 5, and 7 minutes after CAC for both). RESULTS: In total, 345 subjects were randomized. Olopatadine 0.77% was superior to the vehicle at alleviating ocular itching at all post-CAC time points at the onset of action and at 24 hours (difference in means: -0.9 to -1.5; P < 0.0001). Superiority in relieving ocular itching was also demonstrated for olopatadine 0.77% versus olopatadine 0.2% and 0.1% at 24 hours (difference in means: -0.3 to -0.5; P < 0.05). Additionally, olopatadine 0.77% significantly improved conjunctival redness and total redness compared with all comparators at the onset of action (differences in means: -0.3 to -0.6 and -0.8 to -2.0, respectively; both P < 0.05). No safety concerns for olopatadine 0.77% were identified. CONCLUSIONS: Olopatadine 0.77% demonstrated a rapid onset and prolonged duration of action. It was superior to all comparators in alleviating AC-associated ocular itching with a favorable safety profile.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01743027.

Lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study.

PURPOSE: To assess the efficacy and safety of lifitegrast ophthalmic solution 5.0% compared with placebo in subjects with dry eye disease. DESIGN: Prospective, randomized, double-masked, placebo-controlled, parallel arm, multicenter clinical trial. PARTICIPANTS: A total of 588 adult subjects with dry eye disease. METHODS: Eligible subjects were randomized 1:1 to receive topically administered lifitegrast (5.0%) or placebo (vehicle) twice daily for 84 days after a 14-day open-label placebo run-in period. After enrollment (day 0), subjects were evaluated at days 14, 42, and 84. Key objective (fluorescein and lissamine staining scores [Ora scales]) and subjective (Ocular Surface Disease Index [OSDI], 7-item visual analog scale, and ocular discomfort score [Ora scale]) measures were assessed at all visits. MAIN OUTCOME MEASURES: The primary objective efficacy measure (sign) was mean change from baseline inferior corneal staining score (ICSS) at day 84. The co-primary subjective efficacy measure (symptom) was the mean change from baseline in the visual-related function subscale score of the Ocular Surface Disease Index (VR-OSDI). Supportive measures included corneal fluorescein scores (superior, central, total region) and conjunctival lissamine scores (nasal, temporal, total region) and symptom scores at day 84. RESULTS: The study met the primary objective efficacy ICSS end point in demonstrating superiority of lifitegrast compared with placebo (P = 0.0007). Lifitegrast significantly reduced corneal fluorescein staining (superior, P = 0.0392; total cornea, P = 0.0148) and conjunctival lissamine staining (nasal, P = 0.0039; total conjunctiva, P = 0.0086) at day 84 versus placebo. Significant (P < 0.05) improvements in nasal and total lissamine scores were observed at day 14 and maintained through day 84. The study did not meet the co-primary subjective VR-OSDI measure (P = 0.7894). However, significant improvements were observed at day 84 in ocular discomfort (P = 0.0273) and eye dryness (P = 0.0291), the most common and severe symptoms reported at baseline in both groups. There were no unanticipated or serious ocular adverse events (AEs). The most frequent reported ocular AEs were transient intermittent instillation site symptoms (irritation, discomfort) primarily on the initial lifitegrast dose at day 0. CONCLUSIONS: Lifitegrast ophthalmic solution 5.0% significantly reduced corneal fluorescein and conjunctival lissamine staining and improved symptoms of ocular discomfort and eye dryness compared with placebo when administered twice daily over 84 days.