CURRENT MEDICAL RESEARCH AND OPINION®

VOL. 21, NO. 2, 2005, 255–260

© 2005 LIBRAPHARM LIMITED

0300-7995

doi:10.1185/030079905X26252

All rights reserved: reproduction in whole or part not permitted

ORIGINAL ARTICLE

An open-label evaluation of HP-Guar gellable lubricant eye drops for the improvement of dry eye signs and symptoms in a moderate dry eye adult populationIlan Hartstein a, Steven Khwarg b and Johan Przydryga c

a La Palma Eye Care Center, La Palma, CA, USAb St Vincent Eye Surgery Institute, Los Angeles, CA, USAc Alcon Laboratories, Inc., Fort Worth, TX, USA

Address for correspondence: Dr Johan Przydryga, Alcon Laboratories, Inc., 6201 South Freeway, Fort Worth, Texas 76134, USA. Tel.: +1 817 551 4498; email: Johan.Przydryga@AlconLabs.com

Key words: Artificial tears – Dry eye syndrome – HP-Guar gellable lubricant eye drops – Polymer hydroxy propyl guar – Tear supplements

Objective: Evaluate the efficacy of a polymer hydroxy-propyl guar (HP-Guar) gellable lubricant eye drop (Systane* Lubricant Eye Drops) in reducing dry eye signs and symptoms among dry eye patients who exhibited at least moderate signs and symptoms.

Methods: 168 patients with moderate dry eye signs and symptoms were enrolled at 29 sites in this open label study. The mean age of patients was 62 years with a minimum age of 28 years and a maximum of 90 years. One hundred and forty-seven patients completed the study, 111 female and 35 male, excluding 1 subject (gender not captured). In order to be included in the study, subjects were required to have a total corneal staining score ≥ 4 (NEI grid) in at least one eye, with a grade ≥ 2 in at least one zone of the same eye. Patients also had to indicate that their eyes ‘felt dry enough to want to use eye drops’ at least ‘some of the time’ on a standardized frequency scale. Eligible patients were dispensed a run-in drop (Opti-Free Express Rewetting Drops*) to use QID for 7 days, and then examined. Patients continuing to meet the inclusion criteria were dispensed the test drops (HP-Guar gellable lubricant

eye drops) to use QID, and re-examined on Day 28. At each visit, corneal and conjunctival staining were measured, and six ocular discomfort symptoms were rated on a standardized 0–4 severity scale. At Days 0 and 28, patients subjectively rated product acceptability using a Likert scale.

Results: No significant changes in corneal or conjunctival staining were observed with the use of the run-in drop. After 28 days of test drop use, there was a statistically significant reduction in corneal staining ( p < 0.0001). Ninety-four percent of patients improved from baseline, with mean reduction in total corneal staining of 4.1 units (0–15 total scale) (62%). Conjunctival staining also improved significantly ( p < 0.0001) with a mean total reduction of 3.1 (59%). Patients experienced statistically significant symptomatic relief from day 0 to day 28 for all six ocular discomfort severity questions ( p < 0.0001).

Conclusion: Lubricating drops effectively relieved signs and symptoms associated with moderate dry eye, with measurable improvements evident in both objective staining and subjective questionnaire measures after 28 days in this study population.

A B S T R A C T

Paper 2828 255

* Systane Lubricant Eye Drops and Opti-Free Express Rewetting Drops are registered trade names of Alcon Laboratories, Inc., Fort Worth, TX

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256 HP-Guar gellable lubricant eye drops for dry eye © 2005 LIBRAPHARM LTD – Curr Med Res Opin 2005; 21(2)

Introduction

Dry eye syndrome is the term commonly used to describe the collection of signs and symptoms that can result from a number of conditions of the ocular surface1. All conditions causing dry eye can be characterized by tear film disorders, which result from a tear deficiency or excessive tear evaporation2. When the tear film is com promised, a healthy corneal and conjunctival epithelium cannot be maintained, and patients experience the symptoms of discomfort that are associated with dry eye3. Signs of dry eye commonly include corneal staining, conjunctival staining, rapid tear breakup time, and low Schirmer test scores4. Symptoms felt by patients may include dryness, burning, grittiness, and foreign body sensation. They tend to be most intense in the morning and the evening5,6.

In the absence of any causal cure for dry eye, the predominant therapeutic choice has been, and continues to be, lubrication with tear supplements7. Tear supplements are generally hypotonic or isotonic buffered solutions containing surfactants, electrolytes and a viscosity agent, intended to increase the time the tear resides on the ocular surface7. The increased moistur-ization and lubrication provided by a tear supplement serve to minimize ocular surface desiccation and cell death while also improving comfort7. However, though comfort can increase substantially with artificial tear use8 , historically, tear supplements have only been able to provide short-term relief because of brief retention time on the ocular surface3. This protection may be enhanced with new technologies that provide longer retention time2.

A lubricant eye drop, containing polyethylene glycol 400 (0.4%) and polypropylene glycol (0.3%) demulcents with the polymer hydroxypropyl guar (HP-Guar) as a gelling agent has recently become available. When exposed to the pH of the ocular surface and tears, the HP-Guar in Systane* forms a gel with increased viscosity and bio-adhesive properties that are designed to promote the retention of the two demulcents, protecting the ocular surface environment9. This formulation is preserved with Polyquad* (0.001%) and contains the essential ions, potassium, calcium, magnesium, zinc, and sodium.

With many tear supplements available, it is increasingly important that their clinical efficacy be assessed under normal patient use conditions. Many patients presenting with dry eye are currently using or have used drops in the past without attaining relief10. A product that improves symptoms quickly and is long lasting would be expected to provide superior relief.

This study was designed to investigate the efficacy of the HP-Guar gellable lubricant eye drops in treating

patients with dry eye signs and symptoms. The drops were tested over a 1-month period in a specific patient population and in a clinical practice setting.

Patients and methods

The study employed an open-label, multi-center, prospective design of 5 weeks duration. One hundred and sixty-eight patients with a diagnosis of moderate dry eye were enrolled at 29 ophthalmology practices in environ mentally dry areas. Sites were chosen based on having a consistently dry environment so that results would be more consistent and better controlled.For inclusion at the screening visit (Day –7, which was the beginning of the run-in period), patients had to exhibit a total corneal staining score in one eye of four or above (NEI scale, using a five zone system with 0–3 grades in each zone) and with at least one zone having a grade two or higher in the same eye. Patients were asked the question, ‘How often have your eyes felt dry enough to want to use eye drops (artificial tears)’. An answer of ‘some’, ‘half ’, ‘most’ or ‘all of the time’ allowed for inclusion in the study, and an answer of ‘none of the time’ was exclusionary. These criteria were designed to exclude mild dry eye patients and include only those with at least moderate level of dry eye (herein labeled as ‘moderate’). Patients who did not meet these criteria, who had LASIK surgery in the previous 6 months, who required the use of topical ocular medications other than the study medication, or who were allergic to components of the test product were excluded from the study. Due to the short duration of the study, systemic medications were not part of the exclusion criteria.

At screening, each patient’s current use of medications and artificial tear products was noted. The severity of six ocular discomfort sensations was recorded on a standard-ized four-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). A slit lamp examination was conducted and conjunctival injection severity rated by investigators on a four-point (0–3) scale. Corneal staining in both eyes was visualized using sodium fluorescein and graded by investigators using the standardized NEI grid. In addition, a plastic-made corneal grid was designed to insure objective sign assessment. Lissamine green conjunctival staining was conducted on both eyes and results recorded for each of six zones on a five-point scale (0–4) (Figure 1). Patients were then dispensed Opti-Free Express Rewetting Drops (Alcon Laboratories, Fort Worth, TX), as a run-in drop (OFX). This served to normalize the incoming population to an identical regimen of tear use, and allowed for washout and minimization of any effect from previous tear substitutes. The rewetting drop preserved with

* Systane and Polyquad are registered trade names of Alcon Laboratories, Inc., Fort Worth, TX

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© 2005 LIBRAPHARM LTD – Curr Med Res Opin 2005; 21(2) HP-Guar gellable lubricant eye drops for dry eye Hartstein et al. 257

Polyquad (0.001%) (Alcon Laboratories, Fort Worth, TX), does not incorporate an active lubricating agent and has no potentially toxic agents such as benzalkonium chloride (BAC). Patients were instructed to use the run-in drop QID in both eyes and to record usage in a provided diary to track compliance with this regimen. After 7 days, patients returned for an eligibility follow-up examination (Day 0) in which the above measurements and questions were repeated. Patients were allowed to proceed if they continued to meet the corneal staining eligibility criteria, and desired to use a drop at least some of the time. In addition, patients responded to six questions regarding the acceptability of the run-in drop on a 5 point Likert scale (0 = strongly disagree; 5 = strongly agree). The patients were dispensed the test drop (HP-Guar gellable lubricant eye drops; Systane Lubricant Eye Drops, Alcon Laboratories, Fort Worth, TX) and instructed to use it 1–2 drops in each eye QID upon awakening, noon, early evening and before bedtime and to record usage times in the diary. This second visit was deemed ‘day 0’to signify the beginning of the drug randomization period. On Day 28, patients returned for follow-up. This examination repeated the measurements from Day 0.

Statistical comparisons were made using GLM Repeated Measures ANOVA.

Results

Of the 168 subjects enrolled, 147 (87.5%) completed the study. Twenty-one patients exited the study. Of these, 15 were lost to follow-up, 2 discontinued for treatment failure, 3 discontinued for adverse events (1 allergy, 2 irritation), and 1 discontinued due to non-compliance. Patient ages ranged from 28 years to 90 years, with a mean age of 62 years. One hundred and eleven subjects were female and 35 male, excluding 1 undocumented subject. Eighty subjects had brown eyes, 28 blue, 16 hazel, 15 green, and 4 grey, with 4 undocumented subjects. Ninety-one patients were Caucasian, 26 Asian, 9 Hispanic, 2 Black, and 12 other, with 7 subjects not documented. Forty-eight patients were newly diagnosed with dry eye or not using any sort of dry eye therapy, and 120 were using a dry eye product prior to enrollment (Table 1). Of the patients using a product prior to this study, 40 different tear substitutes were reported, with Refresh (Allergan, Inc) being the most frequently reported brand (used by 10.71% of patient population). Analysis of the intent to treat data set is reported throughout.

Signs – corneal staining

At Day 28, a statistically significant reduction in mean corneal staining from Day 0 was seen with use of the

test drop for each of the five zones on the NEI grid and for the sum of all zones. The mean decrease from Day 0 (baseline) for the sum of the 5 zones (scale 0–15) was 4.1 ( p < 0.001), a reduction of 62% (Figure 2). Corneal staining was reduced for 94% (138) of the patients, 5% (7) were unchanged, and staining increased in 1% (2) of the patients. Staining was also reduced significantly for each of the five corneal zones ( p < 0.0001 for all) (Table 1).

Signs – conjunctival staining

A statistically significant decrease in total conjunctival staining from Day 0 (baseline) was seen at Day 28 with the test product ( p < 0.0001). Staining for the aggregate of the six areas decreased 3.1, a change of 59% (Figure 3). Compared to baseline, 78% (115) of the patients showed improvement, 14% (20) were unchanged and 8% (12) had worse aggregate conjunctival staining on Day 28. In each of the six conjunctival areas, average scores showed significant improvement ( p < 0.0001) (Table 2).

Figure 1. NEI grid scales for fluorescein and lissamine green staining by region

Area Delta* p value

Aggregate –4.1 < 0.0001 Central –0.8 < 0.0001 Superior –0.8 < 0.0001 Temporal –0.5 < 0.0001 Nasal –0.8 < 0.0001 Inferior –1.0 < 0.0001

*Change from baseline (days 7–35)

Table 1. Summary of change in corneal staining over treatment period; each zone was graded on a 4 point scale

(0–3) with aggregate score representing the sum of all zones (maximum of 15)

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258 HP-Guar gellable lubricant eye drops for dry eye © 2005 LIBRAPHARM LTD – Curr Med Res Opin 2005; 21(2)

Symptoms

At each visit, patients rated 6 ocular discomfort symp-toms on a 4-point scale. Symptoms measured were dryness, burning, scratching, foreign body sensation, grittiness and stinging. At Day 0, patients reported a significant decrease in dryness and grittiness ( p < 0.0001 dryness; p < 0.0214 grittiness) (Table 3). Changes in the other sensations were not significant. At Day 28 with the test drop, patients were significantly more comfortable for each of the six sensations compared to Day 0 ( p < 0.0001) (Figure 4, Table 3). The total severity rating decreased by 4.5 points from Day 0 to Day 28, and dryness, which was the highest scoring sensation at Day –7 (mean score 2.4), and at Day 0 (mean score 2.0) was rated a mean of 1.1 at Day 28.

A statistically significant difference was observed with the acceptability Likert questions at Day 28 ( p < 0.0001). Compared to Day 0, patients using the test drop were more likely to agree with the self-developed statements ‘My eyes feel refreshed longer than expected when I use the drops’, ‘I frequently forgot my symptoms during use of the drops’, ‘My eyes feel refreshed when I use the drops’, and ‘My eyes feel comfortable on the instillation of the drops’ and to disagree with the statements ‘My eyes feel dry in the morning’ and ‘My eyes feel dry at the end of the day’.

Figure 2. Fluorescein corneal staining: sum of 5 zones. No significant changes were evident in corneal staining from day –7 (screening) to day 0, following a week of washout from prior artificial tear use. Significant decrease in sum

scores of corneal staining was present after use of HP-Guar gellable lubricant eye drops for 28 days ( p < 0.0001)

Figure 3. Conjunctival staining: sum of 6 zones. No significant changes observed before and after washout

period. Significant decrease in staining from baseline was evident after 4 weeks use of HP-Guar gellable lubricant eye

drops ( p < 0.0001)

Area Delta* p value

Aggregate –3.1 < 0.0001 Superior nasal –0.5 < 0.0001 Nasal –0.6 < 0.0001 Inferior nasal –0.6 < 0.0001 Superior temporal –0.4 < 0.0001 Temporal –0.5 < 0.0001 Inferior temporal –0.6 < 0.0001

*Change from baseline (days 7–35)

Table 2. Summary of change in conjunctival staining over treatment period; each zone was graded on a 4 point scale

(0–3) with aggregate score representing the sum of all zones (maximum of 18)

Table 3. Summary of discomfort symptoms over treatment period (see Figure 4); each symptom was rated on a 4-

point scale on day 0 and day 28

Symptom p value delta day –7 to day 0

p value delta day 0–day 28

Dryness < 0.0001 < 0.0001 Burning < 0.0214 < 0.0001 Scratching Not significant < 0.0001 Foreign body

sensation Not significant < 0.0001 Grittiness Not significant < 0.0001 Stinging Not significant < 0.0001

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© 2005 LIBRAPHARM LTD – Curr Med Res Opin 2005; 21(2) HP-Guar gellable lubricant eye drops for dry eye Hartstein et al. 259

Discussion

Some variability exists in the prevalence of dry eye observed through various epidemiological studies, but the currently available body of work suggests that the prevalence of dry eye is between 5% and 28% of the population11,12. These data can vary from study to study in a predictable manner based on the restrictive nature of the diagnosis criteria used13. In 2003, an epidemiological study of the prevalence of dry eye syndrome (DES), as defined by clinical signs or the symptoms of frequent to constant dryness or irritation, found that DES affects more than 5.2 million US women age 50 years or older14.

In addition, it has been noted that one in four patients who visit ophthalmic clinics report symptoms of dry eye, making it one of the most common conditions seen by ophthalmologists today15. Among many risk factors involved, being female in gender and over the age of 50 years have been found to be relatively common characteristics in those suffering from dry eye16,17.

This study was performed using an open label study design and measured the efficacy of a lubricant eye drop in a clinical practice setting with normal patient use conditions. These conditions attempt to mimic those experienced by a typical dry eye patient during a doctor’s visit in which they receive dry eye therapy. The observ-ations made have value with regard to our understanding of the efficacy of this test eye drop in relieving signs and symptoms of dry eye following a 4-week treatment period. These results provide insight into the benefits of this drop use through the measurement of both objective and subjective parameters. However, it is recognized that the data presented in this study have limited applicability considering the real world study design, which did not incorporate a masked placebo arm or a direct comparison of the test drop to patients’ previous regimen. Further research comparing the test drop to other tear supplements and/or placebo is warranted to gain a more complete picture of the efficacy of this drop relative to other currently available therapies.

This study showed statistically significant improve-ments in signs and symptoms after 28 days of QID use of the test drops by patients with moderate dry eye seen in typical practice environments. With the use of the rewetting drops, no significant changes were observed in conjunctival or corneal staining between Days –7 and 0. This was expected due to the inactive nature of the solution, and its use was intended as a washout to eliminate any possible effects of previous drop use by patients entering the study in order to gain a consistent baseline evaluation for all at Day 0.

Following the 28-day test period, patients demon-strated statistically significant reductions in corneal and conjunctival staining as well as significant relief of symptoms with the test drops ( p < 0.0001 for all). Corneal staining was reduced for 94% of patients and each zone had an average decrease of at least 0.5. Conjunctival staining was reduced for 78% of the patients, with an average decrease of at least 0.4 for each zone.

This reduction in corneal signs may be a result of the test drop formulation, with the actions of polyethylene glycol 400 (PEG 400) and polypropylene glycol enhanced by HP-Guar, creating an ocular shield, allowing for epithelial repair. When the test drops, at pH 7.0 in the bottle, combine with the natural tears, pH 7.3–pH 7.7, the pH change facilitates the formation of reversible cross-links of the borate ions with HP-Guar

Figure 4. Symptom ratings, in 6 symptom parameters (each rated on 0–3 standardized scales). Each symptom

showed a significant decrease in the patient-rated severity from day 0 to day 28 ( p < 0.0001 for all). No significant

differences were evident from screening to Day 0 for 4 of the 6 symptoms evaluated; grittiness and dryness did

exhibit significant decreases from screening to day 0 ( p < 0.0001 dryness; p < 0.0214)

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260 HP-Guar gellable lubricant eye drops for dry eye © 2005 LIBRAPHARM LTD – Curr Med Res Opin 2005; 21(2)

creating a matrix that reduces tear clearance and allows the demulcents (PEG 400 and propylene glycol) to adhere to the ocular surface. This matrix prolongs protection by enhancing the integrity of the tear film, providing a protective environment, which allows the natural healing process of the ocular surface underneath, to occur18.

After 7 days with the run-in drops, dryness and grittiness both showed significant improvement from Day –7 ( p < 0.0001 dryness; p < 0.0214 grittiness), indicating that drop use on a regular basis can provide some symptomatic relief. The severity of all six measured symptoms of dry eye among study patients was significantly reduced from baseline after 28 days of QID test drop use ( p < 0.0001). Dryness ratings were also reduced from ‘moderate’ (2.1) to ‘mild’ (1.1) over this period of time. Patients were aware of the relief that the test drops provided, agreeing more strongly that ‘my eyes feel refreshed when I use the drops’ and less strongly that ‘my eyes feel dry in the morning’ or ‘at the end of the day’. Frequency of symptoms was also reduced with patients agreeing more strongly that ‘my eyes feel refreshed longer than I expected’. Changes from baseline, ranging from 0.5 to 0.9 on a 5 point Likert scale were significant ( p < 0.0001).

Conclusions

Within the patient population studied, the test drops (HP-Guar gellable lubricant eye drops) reduced both objective signs and subjective symptoms of dry eye. Significant reductions were evident in both corneal and conjunctival staining from day 0 to day 28, while subjective measures of symptoms also showed significant improvement. Future research should compare the test drops to existing tear supplements, and utilize a control group to further strengthen results. It would also be of interest to evaluate dry eye signs and symptoms more frequently to assess onset of relief more accurately. This study is valuable in understanding the efficacy with which HP-Guar gellable lubricant eye drops relieve dry eye signs and symptoms, specifically indicating that both objective and subjective parameters improved significantly after 28 days of drop use in the test population.

Acknowledgments

This study was supported by an unrestricted grant from Alcon Laboratories, Inc, Fort Worth, TX.

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CrossRef links are available in the online published version of this paper:http://www.cmrojournal.com

Paper CMRO-2828_3, Accepted for publication: 05 January 2005Published Online: 26 January 2005doi:10.1185/030079905X26252

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