Effect of OTX-101 in Patients with Dry Eye Disease at Day 14 of Treatment: Ocular Surface Endpoint Results from the Phase 2b/3 Clinical Trial.

Dry eye disease (DED) is a multifactorial disorder characterized by loss of tear film homeostasis, which initiates a cycle of ocular surface inflammation and damage. As ocular discomfort symptoms associated with DED can decrease quality of life, affected patients prefer treatments that rapidly improve the underlying disease process. OTX-101 0.09% (CEQUA®) is indicated to increase tear production in patients with DED. The current analysis assessed early efficacy of OTX-101 0.09% in adult patients with bilateral DED by evaluating ocular surface endpoints after 14 days of treatment in the phase 2b/3 trial. In this randomized, double-masked, vehicle-controlled, dose-ranging study, patients received one drop of OTX-101 0.05%, OTX-101 0.09%, or vehicle per eye twice daily for 84 days. Corneal staining, conjunctival staining, tear breakup time (TBUT), and modified Symptom Assessment iN Dry Eye (SANDE) total global symptom score were assessed at baseline and Days 14, 28, 42, 56, and 84/early discontinuation. Overall, 455 patients were randomized (OTX-101 0.05%, n=151; OTX-101 0.09%, n=152; vehicle, n=152); only baseline and Day 14 results for the approved OTX-101 0.09% formulation and vehicle are presented. Least squares (LS) mean (standard error [SE]) change from baseline in conjunctival staining score was -1.3 (0.1) for OTX-101 and -1.0 (0.1) for vehicle. LS mean (SE) change from baseline in corneal staining score was -1.1 (0.17) for OTX-101 and -0.7 (0.17) for vehicle. LS mean (SE) change from baseline in TBUT was 0.52 (0.15) for OTX-101 and 0.36 (0.15) for vehicle. LS mean (SE) change from baseline in modified SANDE total global symptom score was -4.93 (1.54) for OTX-101 and -9.1 (1.54) for vehicle. OTX-101 0.09% demonstrated a numerically greater treatment effect compared with vehicle in conjunctival staining, corneal staining, and TBUT after 14 days.

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.

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.

Knowledge of patient emotional health status: impact on clinical care in glaucoma and retinal services.

OBJECTIVE: Knowledge of a patient's emotional health status and using patient-centred communication may be key to providing early intervention and referral to appropriate treatment/support services for ophthalmology patients. This study aims to determine if and how ophthalmologists use anxiety and depression scores to determine clinical care of patients with chronic eye disease. METHODS AND ANALYSIS: This cross-sectional study included 10 ophthalmologists and a convenience sample of 100 of their patients (>18 years). The Patient Health Questionnaire (PHQ-9) for depression and the Generalised Anxiety Disorder (GAD-7) tool were administered to patients. Scores from these instruments were provided to ophthalmologists just prior to the clinic visit. After the visit, ophthalmologists were given a questionnaire to assess self-reported change in clinical practice and whether knowledge of scores impacted their communication style, treatment plan and follow-up protocol. RESULTS: Of these patients (mean age=63), 27% reported mild-moderate anxiety or depression as their worst score, while 2% reported suicidal thoughts; 20% reported neither anxiety nor depression. Ophthalmologists' response to patients with mild or worse anxiety or depression was to change clinical approach (28%) and communication style (31%), both metrics increasing with severity of symptoms (Fisher's exact p<0.05). None reported changing their choice of treatment or modifying follow-up protocols; referral to social work/psychiatry services was 60%, 3.7% and 0% for patients with moderately severe or worse, mild-to-moderate, or minimal scores, respectively. CONCLUSION: Providing ophthalmologists with knowledge of the emotional health of their patients may change the clinical approach and referral pattern.

Phentolamine Mesylate Ophthalmic Solution Provides Lasting Pupil Modulation and Improves Near Visual Acuity in Presbyopic Glaucoma Patients in a Randomized Phase 2b Clinical Trial.

PURPOSE: Phentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population. PATIENTS AND METHODS: In this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change in diurnal IOP, and the key secondary outcome measures included changes in PD, distance-corrected near visual acuity (DCNVA), and conjunctival hyperemia. RESULTS: Use of 1% PMOS did not lead to a statistically significant decrease in diurnal IOP compared to placebo (P = 0.89) but trended toward a greater decrease in patients with lower IOP baselines. PMOS produced a statistically significant mean 20% PD reduction under both photopic and mesopic conditions that was sustained for 36 hours post-dosing. A statistically significant number of patients with PMOS compared to placebo demonstrated ≥1 line of improvement in photopic DCNVA at day 8 (P = 0.0018), day 15 (P = 0.0072), and day 16 (P = 0.0163), with a trend for 2- and 3-line improvements at all time points. There was no statistical difference in conjunctival hyperemia compared to placebo. CONCLUSION: Although mean IOP was not lowered significantly, daily evening dosing of 1% PMOS was found to be well tolerated with no daytime conjunctival redness and demonstrated improvement in DCNVA with sustained PD reduction in a glaucomatous and presbyopic population. Smaller pupil size can have beneficial effects in improving symptoms of presbyopia and DLD, which will be the focus of further studies.

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.

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Conjunctival Staining in Patients with Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and 3 Clinical Trials.

Purpose: Keratoconjunctivitis sicca (KCS), a multifactorial disease, is the most common ocular condition for patients seeking medical treatment and is characterized by ocular burning, stinging, and dryness. This pooled analysis examined the effect of OTX-101 0.09% versus vehicle on the total and individual conjunctival staining in patients with KCS from phase 2b/3 and phase 3 studies. Methods: In these randomized, multicenter, double-masked, and vehicle-controlled studies, patients received 1 drop of OTX-101 0.09% or vehicle in both eyes twice daily. The time points for the pooled analysis were baseline (day 0) and study days 28, 56, and 84/early discontinuation. Conjunctival staining was graded on a 0- to 3-point scale per zone and averaged over both eyes at each assessment. Pooled safety assessments included adverse event (AE) reporting. Results: The total mean (standard deviation) conjunctival staining scores at baseline were 5.4 (1.7) for OTX-101 (n = 523) and 5.5 (1.7) for vehicle (n = 525). OTX-101 versus vehicle significantly reduced the total conjunctival staining scores (P = 0.0316, <0.0001, and 0.0002) for days 28, 56, and 84, respectively. The most common treatment-related AE was instillation site pain (21.8% OTX-101 vs. 4.0% vehicle); most AEs were mild in nature. Conclusions: Treatment with OTX-101 versus vehicle significantly improved the conjunctival staining in KCS as early as 4 weeks, and the improvement was maintained through 12 weeks. OTX-101 was effective and well tolerated for use in KCS.

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies.

BACKGROUND: Keratoconjunctivitis sicca affects 5% to 33% of the population and is often accompanied by symptoms such as burning and dryness. This pooled analysis evaluated total and central corneal fluorescein staining (CFS) in patients receiving OTX-101 0.09% or vehicle in phase 2b/3 and 3 studies and whether improvements in corneal staining correlated with improved visual acuity. METHODS: In these randomized, vehicle-controlled studies, patients received 1 drop of OTX-101 or vehicle in both eyes twice daily. Corneal staining was performed at baseline and days 28, 56, and 84. CFS was evaluated in each zone (0-to-4 scale); total corneal staining (0-to-20 scale per eye) was averaged over both eyes. Pooled safety assessments included adverse event monitoring. RESULTS: Mean baseline CFS total scores (SD) were 4.2 (2.5) and 4.3 (2.6) for the OTX-101 (n = 523) and vehicle (n = 525) groups, respectively. For total corneal staining, least squares mean changes from baseline (standard error) were -0.9 (0.08) versus -0.5 (0.08) for OTX-101 and vehicle, respectively (P = 0.0008), on day 28 and -1.4 (0.09) versus -0.9 (0.09) on day 84 (P = 0.0002). There was a significantly high correlation (P = 0.0117) between reduced central corneal staining and improved visual acuity on day 84. Treatment-related adverse events were mostly mild, with instillation site pain reported by 21.8% and 4.0% of patients receiving OTX-101 and vehicle, respectively. CONCLUSIONS: Treatment with OTX-101 led to greater improvements versus vehicle in corneal surface staining as early as 4 weeks, and further improvements were seen up to 12 weeks. OTX-101 was well tolerated in patients with keratoconjunctivitis sicca.

The Effect of Fibular Reposition Taping on Postural Control in Individuals With Chronic Ankle Instability: A Critically Appraised Topic.

Clinical Scenario: History of acute ankle sprains can result in chronic ankle instability (CAI). Arthrokinematic changes resulting from CAI may restrict range of motion and contribute to postural control deficits. Mulligan or fibular reposition taping (FRT) has been suggested as a means to realign fibular positional faults and may be an effective way to improve postural control and balance in patients with CAI. Clinical Question: Is there evidence to suggest that FRT will improve postural control for patients with CAI in the affected limb compared with no taping? Summary of Key Findings: Three of the 4 included studies found no significant difference in postural control in patients receiving FRT compared with sham or no tape. Clinical Bottom Line: There is moderate evidence refuting the use of FRT to improve postural control in patients with CAI. Strength of Recommendation: There is grade B evidence to support that FRT does not improve postural control in people with CAI.

A Phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease.

PURPOSE: The aim of this study was to evaluate the safety and efficacy of OTX-101, a clear nanomicellar aqueous solution of cyclosporine, in the treatment of dry eye disease (DED). PATIENTS AND METHODS: This was a 12-week multicenter, randomized, prospective, double-masked, vehicle-controlled, dose-ranging clinical trial. Subjects were adults aged ≥18 years, with a total conjunctival staining score of ≥3 and ≤9, and global DED symptom score ≥40 (0-100 visual analogue scale). Following a 14-day vehicle run-in, subjects were randomized in a 1:1:1 ratio to twice daily treatment with OTX-101 0.09%, OTX-101 0.05%, or vehicle for 84 days. Co-primary efficacy end points were changes, from baseline to Day 84, in the total lissamine green conjunctival staining score in the designated study eye and in the global symptom score (both eyes). Secondary end points included total corneal fluorescein staining score, tear breakup time, and Schirmer's test score. RESULTS: In total, 455 subjects were randomized. Subjects treated with active drug experienced greater improvement in conjunctival staining than vehicle-treated patients (P<0.01 for both concentrations). All groups demonstrated improvements in global symptom score, but there were no differences among groups. Nominally significant differences were found between the active drug arms and vehicle for corneal staining scores and Schirmer's test scores. Most treatment-emergent adverse events were mild in severity; no serious ocular adverse events were reported. CONCLUSIONS: Both concentrations of OTX-101 met the co-primary sign end point (conjunctival staining) but not the co-primary symptom end point. OTX-101 0.09% demonstrated a notable impact on multiple signs of DED relative to vehicle and was well-tolerated.

An ex vivo human aqueous humor-concentration comparison of two commercial bromfenac formulations.

PURPOSE: The purpose of this study was to quantify the concentration of bromfenac in the aqueous humor utilizing high-performance liquid chromatography mass spectrometry between two commercial nonsteroidal anti-inflammatory drugs, using aqueous humor concentrations to characterize pharmacokinetic proportional differences between 0.075% bromfenac ophthalmic solution in DuraSite (BromSite®) and 0.09% bromfenac ophthalmic solution (Bromday®). METHODS: In this multicenter, randomized, double-masked, two-arm, parallel-group, comparative, Phase II clinical trial, subjects were assigned to receive bromfenac in DuraSite or bromfenac ophthalmic solution in a 1:1 ratio. One drop of the masked test article was instilled into the study eye once a day for 2 days prior to and 3 hours prior (last instillation) to the subject's cataract surgery. Aqueous humor samples were collected upon initial cataract incision for analysis of bromfenac levels. The primary end point was aqueous humor concentration of bromfenac at Day 3, at the initiation of cataract surgery. Aqueous humor samples were collected and analyzed for bromfenac levels. RESULTS: A total of 60 subjects completed the study, 30 in each group. The mean bromfenac aqueous humor concentration in subjects who received bromfenac in DuraSite was more than twice (49.33±41.87 ng/mL, P=0.004) that of subjects who received bromfenac ophthalmic solution (23.65±16.31 ng/mL) after three doses. CONCLUSION: Mean bromfenac aqueous humor concentration in subjects receiving the DuraSite-containing bromfenac in DuraSite (0.075%) was significantly higher compared to subjects receiving bromfenac ophthalmic solution (0.09%) after 3 days of dosing.

Advocacy evaluation: challenges and emerging trends.

Devising, promoting, and implementing changes in policies and regulations are important components of population-level health promotion. Whether advocating for changes in school meal nutrition standards or restrictions on secondhand smoke, policy change can create environments conducive to healthier choices. Such policy changes often result from complex advocacy efforts that do not lend themselves to traditional evaluation approaches. In a challenging fiscal environment, allocating scarce resources to policy advocacy may be particularly difficult. A well-designed evaluation that moves beyond inventorying advocacy activities can help make the case for funding advocacy and policy change efforts. Although it is one thing to catalog meetings held, position papers drafted, and pamphlets distributed, it is quite another to demonstrate that these outputs resulted in useful policy change outcomes. This is where the emerging field of advocacy evaluation fits in by assessing (among other things) strategic learning, capacity building, and community organizing. Based on recent developments, this article highlights several challenges advocacy evaluators are currently facing and provides new resources for addressing them.

Extended daily access to cocaine results in distinct alterations in Homer 1b/c and NMDA receptor subunit expression within the medial prefrontal cortex.

Human cocaine addicts show altered function within the basal ganglia and the medial prefrontal cortex (mPFC) and altered glutamate function within these areas is postulated to be critical for cocaine addiction. The present project utilized a highly valid animal model of cocaine addiction, to test whether excessive use of cocaine alters glutamate function within these brain areas. Rats were trained to lever-press for i.v. saline vehicle or cocaine (0.25 mg/infusion) over seven 1-h daily sessions, after which, saline controls and half of cocaine self-administering animals (brief access condition) received 10 more 1-h daily sessions, whereas the remaining cocaine animals received 10 additional 6-h daily sessions (extended access condition). One, 14, or 60 days after the last self-administration session, animals were sacrificed. Tissue samples from the ventral tegmental area (VTA), nucleus accumbens (N.Acc) core and shell, and mPFC were analyzed by immunoblotting for expression of Homer1b/c, Homer2a/b, mGluR1, mGluR5, NR2a, and NR2b subunits of the NMDA receptor. Brief and extended access to cocaine failed to alter protein levels within the VTA, and produced transient and similar changes in N.Acc protein expression, which were more pronounced in the core subregion. In contrast, extended access to cocaine resulted in distinct and long lasting alterations of protein expression within the mPFC that included: increased levels of Homer1b/c at 1 day, NR2b at 14 days, and NR2a at 60 days, of withdrawal. These data support the notion that altered NMDA function within the mPFC may contribute, in part, to the transition to excessive uncontrolled consumption of cocaine.