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.

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.

Integrated phase III trials of bepotastine besilate ophthalmic solution 1.5% for ocular itching associated with allergic conjunctivitis.

Allergic conjunctivitis is a clinical reaction to environmental allergens and is manifested by ocular itching caused by IgE-induced mast cell degranulation. Bepotastine besilate is a selective H(1)-antagonist with mast cell stabilizing properties. This report examines the reduction of ocular itching integrated from two conjunctival allergen challenge (CAC) clinical trials comparing bepotastine besilate ophthalmic solution (BBOS) 1.5% to placebo in subjects with a history of allergic conjunctivitis. Two phase III, double-masked, placebo-controlled, parallel-group, CAC clinical trials evaluated BBOS 1.5% versus placebo to reduce ocular itching. Eligible subjects were randomly assigned 1:1 to either BBOS 1.5% (n = 78) or placebo (n = 79). Ocular itching was graded by subjects using a standardized scale (0­4 U). Adverse events and ophthalmic clinical findings were recorded for safety. BBOS 1.5% was superior to placebo for reducing CAC-induced ocular itching (p < 0.0001) as early as 3 minutes post-CAC and for at least 8 hours after dosing. Post hoc analyses examining several populations also showed a significant improvement (p < 0.0001) for subjects with more severe itching response at screening and for the proportion of subjects with complete or nearly complete resolution of CAC-induced itching, both outcomes supporting the clinical benefit of BBOS 1.5%. Adverse events were generally transient and mild. BBOS 1.5% is safe and effective in the treatment of ocular itching associated with allergic conjunctivitis within 3 minutes of a CAC and with a sustained duration of action of at least 8 hours. (ClinicalTrials.gov numbers: NCT00424398 and NCT00586664).

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.

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.

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.

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.

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.

Ocular comfort and drying effects of three topical antihistamine/mast cell stabilizers in adults with allergic conjunctivitis: a randomized, double-masked crossover study.

OBJECTIVE: The aim of this study was to compare short-term (5-minute) ocular comfort and drying effects of 3 topical antihistamine/mast cell stabilizers-epinastine, azelastine, and ketotifen-in patients with allergic conjunctivitis (AC). METHODS: Adults with a history of AC, as confirmed on skin testing conducted within the previous 2 years, were enrolled in this single-center, randomized, double-masked crossover study. At visit 1, patients were randomized to receive a single drop of epinastine in 1 eye and either azelastine or ketotifen in the other eye. Ocular comfort was assessed by patients on an 11-point scale (0 = very comfortable to 10 = very uncomfortable) immediately (0 minute) and at 0.5, 1, 2, and 5 minutes after instillation. Patients were also asked to describe how their eyes felt at 3 minutes using a standardized list of positive (soothing, smooth, refreshing, cool, and comfortable), neutral (thick, sticky, and filmy), and negative (stinging, irritating, and burning) descriptor words. At visits 2 to 4, patients were examined for ocular drying and tear-film stability using fluorescein staining and ocular protection index (OPI) evaluation, respectively. RESULTS: A total of 40 patients (27 women, 13 men; mean age, 40 years [range, 18-73 years]) were included in the study. The mean comfort score was significantly lower (indicating more comfort) with epinastine compared with azelastine at 0.5, 1, 2, and 5 minutes (between-treatment differences, 2.90, 1.85, 1.35, and 0.63, respectively; P < 0.001, P < 0.001, P = 0.001, and P = 0.019) and compared with ketotifen immediately after instillation (between-treatment difference, 1.2; P = 0.014). The mean ocular comfort score was significantly lower with ketotifen compared with azelastine at 0.5, 1, and 2 minutes (between-treatment differences, 2.35, 1.35, and 1.10, respectively; P = 0.001, P = 0.023, and P = 0.028). A majority (85%) of patients chose positive comfort descriptors to describe epinastine versus 34% with azelastine. No significant differences in fluorescein staining or OPI were observed. CONCLUSIONS: In this small study in patients with AC, following administration of a single drop, epinastine was rated as more comfortable than azelastine and ketotifen. None of the tested medications were associated with significant acute ocular drying effects.

Bioequivalence of two formulations of ketotifen fumarate ophthalmic solution: a single-center, randomized, double-masked conjunctival allergen challenge investigation in allergic conjunctivitis.

BACKGROUND: Ketotifen fumarate ophthalmic solution 0.025% (reference formulation), a topical mast cell stabilizer/antihistamine combination, has been found to be effective and well tolerated in the prevention of ocular itching associated with allergic conjunctivitis (AC). A recently developed formulation of ketotifen fumarate ophthalmic solution 0.025% (test formulation) contains the same active ingredient in the same concentration as the reference formulation, is intended for twice-daily dosing, and may provide a treatment option in patients with AC. OBJECTIVE: The aim of this study was to determine the clinical bioequivalence of the test and reference formulations using a conjunctival allergen challenge (CAC) model. METHODS: This prospective, randomized, double-masked, active- and placebo-controlled CAC study was conducted in a clinical setting (ORA Clinical Research and Development, North Andover, Massachusetts). Patients aged <18 years who had AC, a successful allergen challenge during screening and allergen confirmation visits, a history of ocular allergies, and positive skin-test reactivity were enrolled. Patients' eyes were randomized to receive the test or reference formulation or inactive vehicle (1 drop of 1 study medication per eye per visit). The primary efficacy end point was ocular itching, and the secondary end points were ocular redness, chemosis, lid swelling, tearing, and mucous discharge. Efficacy was assessed following challenge at 8 hours and 15 minutes after instillation. The test and reference formulations were considered bioequivalent if the 95% CIs for the differences in mean ocular itching scores between the 2 groups were within the range of 0.40 to 0.40. RESULTS: There were 108 patients enrolled (61 men, 47 women; mean age, 42 years; 91.7% white). The test and reference formulations both yielded clinically significant results compared with placebo in the prevention of ocular itching at CACs performed 8 hours and 15 minutes after instillation. At the 8-hour posttreatment CAC, the mean ocular itching scores for test formulation-treated eyes were 1.158, 1.265, and 1.305 units lower, respectively, than for eyes at 3, 5, and 7 minutes that were administered placebo. At 15-minute posttreatment CAC, the mean ocular itching scores for reference formulation-treated eyes at 3, 5, and 7 minutes were 1.481, 1.622, and 1.565 units lower, respectively, than for eyes that were administered placebo. With regard to the primary and secondary efficacy variables, no statistically significant differences were observed between test and reference formulations at any post-CAC time point. CONCLUSIONS: In this population of patients with AC, the test formulation of ketotifen fumarate ophthalmic solution 0.025% met criteria for bioequivalence to the reference formulation, as established by the protocol. The test and reference formulations were well tolerated in the population studied.

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.

An open-label, investigator-masked, crossover study of the ocular drying effects of two antihistamines, topical epinastine and systemic loratadine, in adult volunteers with seasonal allergic conjunctivitis.

BACKGROUND: Systemic antihistamines such as loratadine are efficacious in the treatment of many allergic conditions. However, their use has been associated with drying effects, particularly of the ocular surface. OBJECTIVE: The purpose of this study was to compare the ocular drying effects of topical treatment with epinastine hydrochloride ophthalmic solution 0.05 % twice daily and systemic treatment with loratadine 10 mg once daily in patients with seasonal allergic conjunctivitis through the use of several standard clinical tests for dry eye. METHODS: This was a single-center, 4-visit, open-label, investigator-masked crossover study in healthy adult volunteers with a history of seasonal allergic conjunctivitis. Participants received 4 days of treatment with topical epinastine administered as 1 drop per eye twice daily and 4 days of treatment with systemic loratadine once daily, with a 10-day washout between treatments. Fluorophotometry was conducted at the baseline visit, at the crossover visit, and after 4 days of each treatment to assess tear volume, tear flow, and tear turnover rate. Decreases from baseline in tear volume, tear flow, or tear turnover rate were considered indicative of a drying effect. Keratitis, global (corneal and conjunctival) fluorescein staining (scale from 0-20 points), and tear film break-up time (TFBUT) were assessed after fluorophotometry at each visit. An increase in keratitis (as measured by global fluorescein staining) and conjunctival lissamine green staining, and a decrease in TFBUT were considered further evidence of a drying effect. RESULTS: Eighteen subjects were enrolled in and completed the study (78% female; 94% white; age range, 18-55 years). After 4 days of twice-daily use, topical epinastine was associated with no significant changes in tear volume, tear flow, or global fluorescein staining. After 4 days of once-daily use, systemic loratadine was associated with a 33.7% reduction in tear volume (mean reduction, 4.5 microL; range, -7.53 to 22.36 microL; P < 0.05), a 35.0% reduction in tear flow (mean reduction, 0.93 microL/min; range, -2.57 to 2.73 microL/min; P < 0.05), and a 21.7% increase in global fluorescein staining (mean increase, 0.74 point; range, -2.5 to 6.5 points; P < 0.05). No significant change in TFBUT was observed with either treatment. CONCLUSIONS: These healthy adult volunteers with a history of seasonal allergic conjunctivitis had no clinical signs of ocular drying after 4 days of twice-daily treatment with topical epinastine. After 4 days of once-daily dosing, systemic loratadine was associated with clinical signs of ocular dryness, including decreased tear volume and tear flow. Use of loratadine was also associated with an increase in global fluorescein staining, indicating an increase in ocular surface damage.

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%.

A phase 2 randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye.

PURPOSE: To investigate the efficacy and safety of an investigational integrin antagonist (SAR 1118) ophthalmic solution compared to placebo (vehicle) in subjects with dry eye disease. DESIGN: Multicenter, prospective, double-masked, placebo-controlled trial. METHODS: A total of 230 dry eye subjects selected with use of a controlled adverse environment were randomized 1:1:1:1 to receive SAR 1118 (0.1%, 1.0%, 5.0%) or placebo eye drops twice daily for 84 days. Principal eligibility criteria included exacerbation in corneal staining and ocular symptoms with controlled adverse environment exposure, no active lid margin disease, and Schirmer test (mm/5 min) >1 and <10. Ocular signs and symptoms (Ocular Surface Disease Index, OSDI) were assessed at day 14, 42, and 84. No supplemental artificial tears were allowed. Primary outcome measure was inferior corneal staining score at day 84. RESULTS: A dose response for the corneal staining score (P = .0566) was observed for SAR 1118 at day 84 compared to placebo. Mean change from baseline to day 84 showed significant improvements (P < .05) in corneal staining score, total OSDI, and visual-related function OSDI scores for SAR 1118 compared to placebo; improvements in tear production and symptoms were observed as early as day 14 (P < .05). Adverse events were mild and transient in nature with no serious ocular adverse events. SAR 1118 5.0% showed increased instillation site adverse events relative to placebo but were limited to the initial dose. CONCLUSION: SAR 1118 demonstrated improvements in signs and symptoms of dry eye compared to placebo and appears safe when administered over 84 days.

Prolonged effectiveness of bepotastine besilate ophthalmic solution for the treatment of ocular symptoms of allergic conjunctivitis.

PURPOSE: This clinical trial evaluated the safety and effectiveness of bepotastine besilate ophthalmic solutions 1.0% and 1.5% compared with placebo for the treatment of ocular itching and conjunctival hyperemia (redness) using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis when dosed 16 h before a CAC test. METHODS: Subjects with a history of allergic conjunctivitis were assigned to receive placebo or bepotastine besilate ophthalmic solution 1.0% or 1.5% in a single-center, randomized, placebo-controlled clinical trial. Eligible subjects (n=107) aged 10 years and older with a history of allergic conjunctivitis who had a reproducible positive reaction to a CAC were enrolled and dosed with test agent. The primary trial objectives included assessment of ocular itching and conjunctival redness at 16 h after instillation of test agent. Reductions in several CAC-induced secondary symptoms and signs of allergic conjunctivitis were also evaluated for tearing, ciliary and episcleral redness, eyelid swelling, chemosis, and mucous discharge. RESULTS: Bepotastine besilate ophthalmic solution 1.5% demonstrated clinical effectiveness and statistical significance in comparison to placebo for the reduction in CAC-induced ocular itching 16 h after drug administration. Bepotastine besilate ophthalmic solution 1.0% also achieved statistical significance in comparison to placebo for reducing ocular itching at all time points 16 h after dosing. Statistically significant reduction (P≤0.05) was additionally seen in this CAC test for the secondary ocular efficacy variable of allergen-induced tearing for bepotastine besilate ophthalmic solution 1.5%. No clinical benefit was seen for reducing the coprimary efficacy variable of conjunctival redness with the CAC model of allergic conjunctivitis. CONCLUSIONS: Bepotastine besilate ophthalmic solution 1.5% produced predefined clinically meaningful reduction in CAC-induced ocular itching and tearing in a single-site trial and was more effective than bepotastine besilate ophthalmic solution 1.0% and placebo for reducing ocular itching in a CAC test 16 h after dosing.

Evaluation of clinical efficacy and safety of tobramycin/dexamethasone ophthalmic suspension 0.3%/0.05% compared to azithromycin ophthalmic solution 1% in the treatment of moderate to severe acute blepharitis/blepharoconjunctivitis.

OBJECTIVE: To evaluate the clinical efficacy and safety of tobramycin/dexamethasone (TobraDex ST ; 'ST') ophthalmic suspension 0.3%/0.05% compared to azithromycin (Azasite) ophthalmic solution (1%) in the treatment of moderate to severe blepharitis/blepharoconjunctivitis. RESEARCH DESIGN AND METHODS: The study was a multicenter, randomized, investigator-masked, and active-controlled, 15-day study. Enrolled in the study were 122 adult subjects (at least 18 years of age) diagnosed with moderate to severe blepharitis/blepharoconjunctivitis, defined by a minimum score of at least '1' for one of the lid signs, one of the conjunctival signs, and one of the symptoms in at least one eye and a minimum global score (total signs and symptoms score) of '5' in the same eye. One group of 61 subjects received ST with instructions to dose 1 drop four times daily (QID) for 14 days. The other group of 61 subjects received azithromycin and dosed with 1 drop twice daily (BID) for 2 days followed by once daily (QD) dosing for 12 days. Visits were conducted at Day 1 (baseline), Day 8 and Day 15. The a priori primary outcome parameter of the study was the seven-item global score defined as the total score of lid margin redness, bulbar conjunctival redness, palpebral conjunctival redness, ocular discharge (0-3 scale), and lid swelling, itchy eyelids, and gritty eyes (0-4 scale). The study utilized standardized, validated photograph control scales developed by Ora, Inc. (Andover, MA). CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov under the registry number NCT01102244. RESULTS: A statistically significant lower mean global score (p = 0.0002) was observed in subjects treated with ST compared to subjects treated with azithromycin at Day 8. No serious adverse events were reported during the course of the study in either group. CONCLUSION: ST provides a fast and effective treatment of acute blepharitis compared to azithromycin. Initial therapy with the combination of tobramycin/dexamethasone provides faster inflammation relief than azithromycin for moderate to severe blepharitis/blepharoconjunctivitis.

Bepotastine besilate ophthalmic solution for the relief of nonocular symptoms provoked by conjunctival allergen challenge.

BACKGROUND: Bepotastine besilate is a selective histamine1-receptor antagonist and mast cell stabilizer with inhibitory effects on eosinophilic activity. OBJECTIVE: To evaluate the safety and efficacy of 1.5% bepotastine besilate ophthalmic solution in alleviating nonocular symptoms induced by a conjunctival allergen challenge (CAC), a clinical model of allergic conjunctivitis. METHODS: This was a single-center, double-masked, randomized, placebo-controlled clinical trial performed from March 1 to April 4, 2007. Patients 10 years or older with a history of allergic conjunctivitis and a reproducible, positive, clinical response to a CAC were eligible. Patients received either placebo or 1.5% bepotastine besilate, 1 drop in each eye. After 15 minutes, 8 hours, or 16 hours after dosing, a CAC was performed and patients evaluated nonocular symptoms using standardized grading scales. RESULTS: Seventy-one patients were enrolled in the study, and 66 comprised the per protocol population. A clinically meaningful reduction (> or = 1.0 unit) compared to placebo was achieved for rhinorrhea and nasal congestion at most time points after 1.5% bepotastine besilate instillation at 8 hours before a CAC test. Significant reductions (P < or = .05) in mean values were seen with 1.5% bepotastine besilate at 15 minutes and 8 hours after dosing for CAC-induced nasal congestion, rhinorrhea, ear or palate pruritus, nasal pruritus, and summed nonocular composite symptom (NOCS) scores and also at 16 hours after dosing for nasal congestion and rhinorrhea. CONCLUSIONS: The 1.5% bepotastine besilate formulation produced statistically significant reductions after a CAC in individual nonocular symptoms and NOCS scores at onset of allergic response and for at least 8 hours after instillation, with the greatest reduction seen for nasal congestion and rhinorrhea.

Multicenter open-label study evaluating the efficacy of azithromycin ophthalmic solution 1% on the signs and symptoms of subjects with blepharitis.

PURPOSE: To evaluate the effect of 4 weeks of treatment with azithromycin ophthalmic solution 1% on eyelid bacterial load, tear cytokines, and signs and symptoms of blepharitis. METHODS: Twenty-six subjects (mean age 64.2 years; 65% female; 100% white) with moderate to severe blepharitis received azithromycin ophthalmic solution 1% in the absence of warm compresses or eyelid scrubs for 28 days (twice a day on days 1 and 2 and once a day on days 3-28). Blepharitis signs and symptoms were evaluated at baseline (day 1) and compared with end of treatment (day 29) and 2 follow-up visits (2 and 4 weeks posttreatment). Tear collection and eyelid margin bacterial cultures were performed at baseline and end of treatment. Tear cytokines were measured by a multiplex immunobead assay. RESULTS: Four-week azithromycin treatment demonstrated significant decreases from baseline in investigator-rated signs of meibomian gland plugging, eyelid margin redness, palpebral conjunctival redness, and ocular discharge (P < or = 0.002) at day 29, which persisted 4 weeks posttreatment (P < or = 0.006). Subject-reported symptoms of eyelid itching, foreign body sensation/sandiness/grittiness, ocular dryness, ocular burning/pain, and swollen/heavy eyelids also demonstrated significant improvement from baseline (P < 0.001 for all symptoms and time points, except P = 0.037 for ocular dryness at visit 4). Eyelid margin culture exhibited significant decreases in coagulase-negative staphylococci and Corynebacterium xerosis bacteria. Changes in tear cytokine concentrations were not observed. Twelve subjects experienced 19 adverse events, 15 of which were ocular and none of which were serious. CONCLUSIONS: Azithromycin provided significant improvement in signs and symptoms of blepharitis after 4 weeks of treatment compared with baseline and persisted in the 4-week follow-up period.

Time to onset and duration of action of the antihistamine bepotastine besilate ophthalmic solutions 1.0% and 1.5% in allergic conjunctivitis: a phase III, single-center, prospective, randomized, double-masked, placebo-controlled, conjunctival allergen challenge assessment in adults and children.

BACKGROUND: Bepotastine besilate is a highly selective histamine H(1)-receptor antagonist with antihistaminic, mast cell stabilizing, and anti-inflammatory activity. Based on a history of clinical effectiveness and tolerability of oral bepotastine besilate in the treatment of allergic symptoms, bepotastine besilate is being tested as a potential ophthalmic medication for allergic conjunctivitis. OBJECTIVE: The aim of this study was to assess the effects of bepotastine besilate ophthalmic solution 1.0% and 1.5% for the treatment of ocular itching and conjunctival hyperemia in a conjunctival allergen challenge (CAC) model in adults and children. METHODS: This Phase III, single-center, prospective, randomized, double-masked, placebo-controlled, CAC clinical trial enrolled patients >or=10 years of age with a history of allergic conjunctivitis, skin-test reaction, and CAC response. Patients received bepotastine besilate ophthalmic solution 1.0%, bepotastine besilate ophthalmic solution 1.5%, or placebo, 1 drop on each eye on days 14 +/- 3 and 28 +/- 3. The primary efficacy end points, patient-assessed ocular itching (at 3, 5, and 7 minutes) and investigator-assessed conjunctival hyperemia (at 7, 15, and 20 minutes), were determined after CAC according to standardized 5-point scales (0 = none to 4 = severe). Clinical significance was defined in the protocol as >or=1.0-U between-group difference in mean ocular itching scores at the majority of time points at a study visit and also a >or=0.5-U difference at all time points. Tolerability of the test agent was assessed by visual acuity, slit-lamp biomicroscopy, intraocular pressure, dilated funduscopy, and adverse events. RESULTS: A total of 107 patients (male, 54%; age range, 11-73 years; white race/ethnicity, 93%) received investigational product and comprised the intent-to-treat (ITT) population (bepotastine besilate ophthalmic solution 1.0%, 36 patients; bepotastine besilate ophthalmic solution 1.5%, 35; and placebo, 36). All 107 patients received investigational product at visit 3A (day 0) and were included in the ITT population. Of the 107 patients who were enrolled, 103 completed the study without a protocol deviation or violation. The 1.0% and 1.5% solutions were associated with clinically and statistically significant reductions in mean ocular itching scores compared with placebo on the 15-minute onset-of-action and 8-hour duration-of-action CAC tests (reductions, 1.3-1.5 U and 1.0-1.7 U respectively; all, P < 0.001). Statistically significant reductions in conjunctival hyperemia were achieved with both bepotastine besilate concentrations. Overall, 13 patients experienced a treatment-emergent adverse event considered related to the study drug (bepotastine besilate ophthalmic solution 1.0%, 6 patients; bepotastine besilate ophthalmic solution 1.5%, 4; and placebo, 3). CONCLUSIONS: In this CAC model of allergic conjunctivitis in adults and children, bepotastine besilate ophthalmic solutions 1.0% and 1.5% were associated with clinically and statistically significant reductions in ocular itching, but not conjunctival hyperemia, within 15 minutes that were maintained for at least 8 hours after administration. Both solutions were well tolerated. ClinicalTrials.gov identifier: NCT00424398.