Mike Christensen

Clinical evaluation of an HP-guar gellable lubricant eye drop for the relief of dryness of the eye

Purpose. To evaluate the efficacy of a new lubricant eye drop containing polyethylene glycol 400 and propylene glycol demulcents with hydroxypropyl-guar as a gelling agent (Test Product) to a system with carboxymethylcellulose (Control Product) for reducing dry eye signs and symptoms. Methods. Eighty-seven dry eye volunteers were enrolled at seven sites for this six-week, concurrently controlled, double-masked clinical study. Results. The Test Product significantly reduced conjunctival staining (p = 0.025) and temporal corneal staining (p = 0.024) compared to the Control. The Test Product also significantly reduced symptoms of dryness in the morning and evening, compared to the Control (p = 0.015 and p = 0.023, respectively). Subjects in the Test treatment group reported lower frequencies of foreign body sensation and felt their eyes were “refreshed longer” compared to those in the Control group (p = 0.033 and p = 0.037, respectively). Conclusions. The Test Product was more effective at reducing both the signs and symptoms of dry eye compared to the carboxymethylcellulose containing Control.

Precorneal residence time of artificial tears measured in dry eye subjects.

Purpose. The purpose of this investigation was to measure the precorneal residence time of saline and five marketed artificial tears in dry eye subjects using fluorometry. Methods. FITC-dextran, 70 kDa molecular weight, was admixed under sterile conditions (0.1% wt/vol) into buffered saline and the marketed artificial tear formulations of varying viscosity. Precorneal residence time (RT) was measured directly in 16 mild to moderate dry eye subjects, classified by sub-type, in a six-way cross-over, masked and randomized study. FITC-dextran tracer decay with a scanning fluorometer was used to estimate the gross RT (i.e., the time in minutes for the signal to return to baseline). Results. All subjects were classified as having non-inflammatory meibomian gland dysfunction except one, who had a mixture of aqueous deficiency and meibomian gland dysfunction. In two separate determinations, the saline RTs were 19.1 ± 7.4 and 17.6 ± 8.2 min. The RTs for the formulations varied to some degree by viscosity, with two higher viscosity formulations demonstrating the longest RTs of 36 to 41 min, approximately twice that of saline (p < 0.001 for both 0.4% polyethylene glycol/0.3% propylene glycol, and 1.0% carboxymethylcellulose). An oil emulsion, low viscosity carboxymethylcellulose and moderate viscosity hydroxypropylmethylcellulose-containing formulation were not statistically different from saline (RTs of 18, 22 and 24 min, p values = 0.983, 0.818 and 0.099, respectively). Conclusions. More than two-fold RT differences were found for the higher viscosity, more muco-adhesive formulations compared to saline. However, other formulations provided RTs close to saline, suggesting that RT is influenced by factors other than simple viscosity. Future studies should examine the interplay of spreading characteristics, pseudoplasticity and muco-adhesion relative to RT to determine the individual and cumulative effects on formulation retention.

The diagnosis and characteristics of moderate dry eye in non-contact lens wearers

Purpose. To identify and characterize moderate dry eye in non–contact lens wearers with a new scoring system-based dry eye questionnaire and to determine which objective tests better differentiate patients with moderate dry eye from healthy patients. Methods. Fifty-two healthy subjects (21 women and 31 men with a mean age of 27.8 ± 9.2 years) and 37 subjects with moderate dry eye (33 women and 4 men with a mean age of 36.4 ± 12.9 years) completed a 42-item dry eye questionnaire. Seventeen healthy subjects (11 women and 6 men with a mean age of 30.5 ± 9.7 years) and 28 subjects with moderate dry eye (24 women and 4 men with a mean age of 38.50 ± 3.8 years) underwent additional objective assessment of ocular surface health, tear osmolality, tear stability, and tear volume. Results. Subjects with moderate dry eye scored significantly higher (49.8 ± 20.3, P<0.0001) on the dry eye questionnaire than did normal subjects (11.7 ± 10.3). Ocular irritation symptoms worsened with progression of time of day in both groups of subjects. Internal reliability (0.95 Cronbach α) was excellent, and concurrent validity (Spearman ρ 0.507) was acceptable when compared to the McMonnies and Ho dry eye questionnaire. Significant differences in tear osmolality (P<0.00001), invasive tear breakup time (P<0.034), and corneal vital dye staining (P<0.0001) were detected between the two groups of subjects. A stepwise linear regression on objective clinical tests, however, did not account for 77% of the total variance in the questionnaire scores. Conclusions. A unique scoring system-based dry eye questionnaire was validated to separate non–contact lens wearers with moderate dry eye from healthy subjects. Objective tests of tear osmolality and stability and ocular surface integrity were better than other clinical measures at identifying differences between the two subject groups. The results strongly support the evidence that the diagnosis and treatment of moderate dry eye requires a detailed assessment of self-perceived symptoms and that objective clinical testing alone may be insufficient.

Corneal staining reductions observed after treatment with Systane® Lubricant Eye Drops

IntroductionBecause of the added emphasis on ocular surface damage included in the Dry Eye Workshop’s revised definition of dry eye, an evaluation of corneal staining reductions was conducted for propylene glycol/polyethylene glycol 400-based artificial tear drops (Systane® Lubricant Eye Drops; Alcon Laboratories, Fort Worth, TX, USA).MethodsAn analysis was conducted on the percent change from baseline in mean corneal staining scores as reported in two previously published, randomized, double-masked, 6-week clinical studies of Systane. A descriptive comparison was also made between the outcome of the composite analysis and data obtained for Optive™ Lubricant Eye Drops (Allergan, Inc., Irvine, CA, USA). Finally, results were reviewed for an open-label study that investigated corneal staining over a 5-week period after patients discontinued Systane therapy.ResultsThe composite analysis included 107 Systane-treated patients. The results showed that Systane consistently reduced corneal staining at each visit; the percent change from baseline to day 42 (exit) was 47.1% (P<0.0001). After discontinuing Systane, immediate and significant increases in corneal staining were reported by 20 patients, with an overall increase from baseline to day 35 (exit) of 195.0% (P<0.0001).ConclusionEvaluations of sum corneal ocular staining scores provide clinically meaningful evidence of dry eye severity, and are an important indicator of dry eye disease progression. The results of the composite analysis of two peer-reviewed studies indicate that Systane significantly reduced corneal staining (P<0.0001), indicating a reduction in the severity of dry eye. Finally, discontinuation of Systane results in a rapid increase in corneal staining that further confirms Systane’s ability to maintain ocular surface health.

Efficacy in Patients with Dry Eye After Treatment with a New Lubricant Eye Drop Formulation

PURPOSE The effective management of dry eye must include a clinically meaningful reduction in ocular staining. Evaluations of corneal and conjunctival staining and other ocular symptoms of dry eye were conducted for a new formulation of polyethylene glycol 400/propylene glycol-based lubricant eye drops containing hydroxypropyl guar as a gelling agent (Test Product) in comparison to Optive Lubricant Eye Drops (Control Product) in adult patients with dry eye. METHODS One hundred thirteen patients, 18 years of age and older, with dry eye were enrolled in a prospective, double-masked, multisite, parallel-group study. After a 2-week run-in period during which patients administered aqueous saline eye drops 4 times daily (QID) in each eye, patients were randomized (1:1) to receive either Test Product or Control Product to be administered QID for 6 weeks. Efficacy and safety were evaluated by corneal and conjunctival staining scores, tear film breakup time, assessments of ocular symptoms, ocular surface disease index (OSDI) scores, dry eye treatment satisfaction, visual function-14 questionnaires, and adverse events. RESULTS The intent-to-treat data set included 105 patients randomized to Test Product (n = 52) or Control Product (n = 53). Patients primarily were between the ages of 18-64 years (70.5%), female (73.3%), white (93.3%), and not Hispanic (81.9%). Patients in the Test Product group exhibited significantly lower mean corneal staining scores than the Control Product group at day 14 (P = 0.0009) and day 42 (P = 0.0106), and significantly lower mean conjunctival staining scores at day 28 (P = 0.0475) and day 42 (P = 0.0009). Patients in both treatment groups reported significant reductions in the mean scores for the ocular symptoms of dryness, gritty/sandy feeling, and burning (P <or= 0.0021 for all comparisons to baseline). Lastly, a significantly lower OSDI score than baseline was reported at day 42 by patients in both the Test Product (P = 0.0013) and Control Product (P < 0.0001) groups. CONCLUSIONS The results of this study indicate that the Test Product significantly reduced corneal and conjunctival staining, indicating a reduction in disease severity. Evaluations of ocular staining scores provide clinically meaningful evidence of dry eye severity and are an important indicator of dry eye disease progression.

Efficacy of a Cyclosporine-Based Dry Eye Therapy with Two Marketed Artificial Tears as Supportive Therapy

Purpose. To evaluate the effectiveness of marketed artificial tears in relieving dry eye signs/symptoms when used as supportive therapy to a cyclosporine based ophthalmic emulsion. Methods. 61 patients were enrolled in this randomized, investigator masked, parallel study of 6-months duration. Enrollment criteria included corneal staining of ≥ 3 (NEI grid), Schirmer w/o anesthesia of ≤ 7mm and subjects had to answer that they needed artificial tears at least “some of the time”. Subjects were randomized to one of 3 treatment groups. Treatment (Tx)1: Restasis® (0.05% cyclosporine) BID w/Systane® (PEG 400/propylene glycol w/HP-Guar) used a minimum of 1/day as supportive therapy. Tx2: Restasis® BID w/Refresh Tears® (carboxymethylcellulose) used a minimum of 1/day as supportive therapy. Tx3: Systane alone QID. Signs and symptoms were measured at Days -7, 0, 7, 14, 28, 42, 120 and 180. Results. A statistical difference was seen in favor of Tx1 (Restasis+Systane) vs Tx2 (Restasis+Refresh Tears) for corneal staining (p=0.0048) and a trend (p=0.0725) for increased TFBUT at 6 months. Schirmer showed a non-significant increase from baseline Tx1=1.41, Tx2=2.15, Tx3=1.42 mm. Significant differences were seen in favor Tx1 vs Tx2 for less Ocular Burning (p=0.0210), Stinging (p=0.0314), Grittiness (p=0.0128) and Dryness (p=0.0132). Tx3 was better than Tx2 for less Burning (p=0.0288), Dryness (p=0.0480) and Scratchiness (p=0.0294). Both supportive therapies were compatible with Restasis. Conclusion. The choice of artificial tears used as supportive therapy with Restasis is important. There were significant clinical advantages with Restasis+Systane vs Restasis+Refresh Tears. While there were no clinical differences noted for Restasis+Systane vs Systane, Systane should be studied with more patients as a first line therapy. This study was sponsored and conducted by Alcon Research Ltd, Fort Worth, TX USA. INTRODUCTION In the prescription drug category, Restasis® Ophthalmic Emulsion (Allergan Inc. Irvine, CA) is specifically indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca (KCS). In clinical trials, Restasis demonstrated statistically significant increases in Schirmer wetting of 10 mm versus vehicle at six months in these patients. This effect was seen in approximately 15% of Restasis treated patients versus approximately 5% of vehicle. Restasis is non-preserved and is packaged in unit dose vials. The active ingredient is cyclosporine (0.05%) with glycerin, castor oil, polysorbate 80, carbomer 1342 and purified water as inactives. The package insert indicates that Restasis can be used concomitantly with artificial tears allowing a 15 minute interval between products. Systane® (Alcon) and Refresh Tears® (Allergan) Lubricant Eye Drops are both marketed under the FDA drug monograph as over-the-counter Lubricant Eye Drops. Systane contains polyethylene glycol and propylene glycol as actives and HP-guar as a gelling agent. Refresh Tears contains carboxymethylcellulose sodium 0.5% as the active demulcent. Clinical studies have shown statistically significant reductions in both signs and symptoms in mild to moderate dry eye patients in favor of Systane1 versus Refresh Tears and significant increases in tear film break-up time (TFBUT) vs Refresh Tears through 20 minutes and through 30 minutes when compared to Refresh Endura.2 The purpose of this study was to evaluate the safety, efficacy and compatibility of these two marketed artificial tears (Systane and Refresh Tears) when used as concomitant therapy with Restasis Ophthalmic Emulsion in aqueous deficient patients with corneal staining. METHODS This was a six-month concurrently controlled, randomized, investigator masked, multi-site clinical study. The study was performed in compliance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice. An IRB approved this study and all patients provided written informed consent. Masking was maintained by relabeling all bottles and only the study coordinator interacted with study patients concerning product use and compliance. Sixty-one adult volunteers who signed informed consents and had a diagnosis of dry eye were enrolled at seven clinical sites, 60 were evaluable by intent-to-treat analysis. To be eligible for enrollment, patients had to express a desire to use eye drops and demonstrate sodium fluorescein corneal staining score ≥ 3 (NEI grid; 15 points possible) at the screening visit (Day -7) in one eye and again at the eligibility visits (Day 0) in the same eye. In addition patients must have demonstrated ≤ 7 mm Schirmer 1 without anesthesia at the screening visit (Day -7). All patients who qualified at the screening visit (Day -7) were dispensed relabeled Sensitive Eyes Rewetting Drops (Bausch and Lomb, Rochester, NY), an aqueous saline solution without polymers, for use in both eyes four times per day for one week. On Day 0 (baseline), if still eligible (sum corneal staining ≥ 3 in the same eye), patients were randomized (1:1:1) to one of three treatment regimens resulting in 20 patients per group. Regimen 1: Restasis+Systane: Restasis dosed two times per day (BID) per package instructions and Systane dosed a minimum of 1 time/day as concomitant therapy (minimum 15 minutes between drops). Regimen 2: Restasis+Refresh: Restasis dosed BID and Refresh Tears dosed a minimum of 1 time/day as concomitant therapy (minimum 15 minutes between drops). Regimen 3: Systane: Systane used alone dosed a minimum of four times a day. An Eppendorf Pipette was used to instill 5 mL of non-preserved 2% sodium fluorescein (NaFl) into each eye. TFBUT was immediately measured followed by an evaluation of corneal staining, using the NEI scale (Figure 1), within 4-5 minutes. The sum of the 5 areas is reported as a composite score. Conjunctival staining was assessed by applying a Lissamine Green Strip moistened with non-preserved saline to the bulbar conjunctiva of both eyes. The degree of conjunctival staining was determined 2-3 minutes later using the NEI grid for conjunctival staining (6 areas; 0-3 scale; 18 points possible) (Figure 1). The sum of the 6 areas is reported as a composite score. Conjunctival Injection was assessed at each visit prior to instillation of any vital dyes or ocular manipulation (i.e. Schirmer test). The Schirmer 1 test (without anesthesia) was taken at Day -7, Day 42 and at the 6-month visit. Figure 1: NEI corneal and conjunctival grids A 5 point Ocular Comfort Frequency scale (0-none to 4-continuously) was used to assess burning, stinging, dryness, grittiness, scratchiness and foreign body sensation as felt by the patient over the previous three days prior to each visit. Last observation carried forward was used to impute data for missed visits and discontinued patients in the intent-to-treat dataset. Baseline differences between treatment groups were evaluated with two-sided, two-sample t-tests or Chi-Square/Fisher tests as applicable. Efficacy variables were evaluated with a repeated measures analysis of variance. Least squares means comparisons were used to investigate treatment differences at each day. The type 1 error rate was set to 0.05, and 0.05<p-value<0.10 indicated a trend toward statistical significance.