Dry eye syndrome is a multifactorial condition associated with potential damage to the ocular surface.1 Dry eye syndrome has significant socioeconomic implications, including increased health care use and impact on daily social and physical functioning, productivity, and quality of life.1–4 The prevalence of dry eye is estimated to be as high as 11 to 22% of the general population, and further increased in Asian surveys (30%) compared with Caucasian studies (15%).1,5,6
Artificial tears and lubricants are still the popular treatment of choice.7,8 However, many dry eye patients are not adequately treated with artificial tears owing to the lack of efficacy or purely palliative nature of these products, suggesting the need for more effective treatment modalities.9
Certain products marketed recently directly address the tear film instability or mucus dysfunction in dry eye disease.10–13 One such product is the lubricant eye drop Systane Ultra (Alcon Laboratories, Fort Worth, TX), containing a novel gelling agent, hydroxypropyl-guar (HP-guar), which on contact with human tears can form a more viscous, longer-acting tear-protective layer, which may not be present in other lubricants.14,15 Systane Ultra and Systane are the only commercially available lubricants containing a gelling agent.
Systane has shown to be an effective mucomimetic in preclinical studies on rabbit dry eye models,16 and is able to reduce ocular surface evaporation up to 1 hour after instillation in dry eye patients.17 This formulation is well tolerated by patients, reducing dry eye symptoms, improving the patients’ quality of life,18 and is superior in protecting the ocular surface compared with eye drops without gelling agents such as Refresh Endura and Refresh Tears (Allergan, Irvine, CA).10 However, these studies had no control group,11,12,19 or used purified water as a control,13 or only reported tear lipid thickness,20 tear break-up time (TBUT), and ocular protective index up to an hour after instillation.10
None of the aforementioned studies have evaluated the effect of lubricant eye drops with gelling agents on Asians with dry eyes. We aimed to conduct a randomized, controlled, double-masked trial to compare the efficacy of a lubricant eye drop containing HP-guar gelling agent, Systane Ultra, with an eye drop with no gelling agent, Refresh Tears, for the treatment of dry eye in an adult Chinese patient population. Symptomatic change was the primary outcome, and conventional clinical evaluations of dry eye were secondary outcomes.
MATERIALS AND METHODS
This is a prospective, randomized, double-masked, double-arm, parallel, interventional single-site clinical study.
Thirty adult Chinese patients, aged between 40 and 65 years, diagnosed with dry eyes at the dry eye clinic of the Singapore National Eye Centre were enrolled in the study.
Informed written consent was obtained from all participating subjects, and the study was approved by the Singhealth centralized Institutional Review Board. This trial was carried out in accordance with the tenets of the Declaration of Helsinki.
Randomization and Sample Size Determination
All the subjects were randomly categorized into two groups, 15 patients each. A simple randomization process of picking the participants for each group from 30 blinded stubs was used.
The sample size to be recruited and the number of subjects in each arm were calculated using the published information.21 The online sample size calculator for the two-treatment parallel design study was used: http://hedwig.mgh.harvard.edu/sample_size/quan_measur/para_quant.html.
To detect a minimal clinically significant difference of 25%, with a standard deviation of 20%, based on a probability of 80% that the study will detect a treatment difference at a two-sided 5% significance level, the total sample size required is 24 patients (or 12 patients per group). (This expected the mean of one group to lie at about the 80th percentile of the other group.) We allowed for any potential loss to follow-up or withdrawal of three patients (20%) per arm by recruiting 15 patients per arm.
Subjects with corneal fluorescein staining present in at least one of the five sectors in at least one eye and having at least one of the six dry eye symptoms, namely, dryness, grittiness, redness, watering, crusting of lids, and sticking of lids together, which, based on the Salisbury Eye Evaluation study,5 must be present often or all the time to be included. The TBUT of ≤5 s or a Schirmer’s I result of <8 mm in at least one eye and Yamaguchi score of 2 in at least one sector of one of the four lids were required for inclusion. The Yamaguchi score is one of the screening tests that measure meibomian gland dysfunction, which is determined by the relative position of the Marx’s line to meibomian gland orifices, as published previously.22 In addition to the aforementioned criteria, participants should not have used non-lubricant ophthalmic drops within the past 30 days and should be able to abstain from non-trial topical ophthalmic drops for 6 weeks.
Patients with a known history of systemic conditions such as thyroid disorders, Sjogren syndrome, and rheumatoid arthritis were excluded. Participants who had ocular surface diseases such as pterygium, obvious lid/orbital disease with lagophthalmos, previously been treated with punctal plugs or punctum cautery, been wearing contact lenses or felt the necessity to wear contact lens throughout the duration of the study, ocular surgery within the past 6 months and LASIK (laser-assisted in situ keratomileusis) within the past 1 year, intake of central nervous system or hormonal drugs within past 30 days or inability to withhold such drugs for at least 6 weeks were excluded from the study.
All the participants underwent a 7-day “washout” evaluating phase using only normal saline eye drops, at least four times a day, as treatment for dry eye. After completion of the “washout” phase, one group received treatment with the lubricant eye drop containing HP-guar gelling agent, Systane Ultra, whereas the other group received treatment with the lubricant eye drop with no gelling agent, Refresh Tears. The trial participants were instructed to use 1 drop of the study medication in each eye four times a day. Amount of study eye drops used were monitored throughout the period. A drug diary was kept to monitor the compliance.
Both study examiners and patients were masked to the type of treatment received by each patient. Masking was done by putting the bottles in a paper bag and removing the commercial labels.
The study consisted of a total of four visits. Patients underwent eligibility screening and ocular surface evaluation on baseline, Visit 1 (Day −7 ± 2). Posttreatment follow-up visits were on Visit 2 (week 1 ± 2), Visit 3 (week 3 ± 2), and Visit 4 (week 6 ± 2). Patients exited the study after the completion of Visit 4.
The primary outcome was the “Symptom Assessment in Dry Eye” (SANDE) Score21 quantifying the frequency and severity of dry eye symptoms, using a 100 mm visual analog scale ranging from rarely/very mild to all the time/very severe. This was recorded on all follow-up visits, and then global score was computed.
Secondary study outcomes included the corneal fluorescein staining score using Baylor grading score23 (which provides for a range of fluorescein staining from 0 to 4, with an additional 1 point for confluent staining in each of the five sectors individually and total), TBUT, and Schirmer’s I reading (wetting at 5 min) on all the visits. In addition to the aforementioned outcomes, we also recorded the visual acuity and intraocular pressure, slit lamp biomicroscopy findings, and adverse events. Study flow is shown in Fig. 1.
Significance level was set at α = 0.05. For parametric data, independent t tests were used to compare between the groups. Paired t tests were conducted for changes within a group over the time. Mann-Whitney U and Wilcoxon signed rank test were used for non-parametric data.
For data showing statistically significant changes within a group over the time, a general linear model repeated measures group comparison analysis was conducted. SPSS ver. 17 (IBM, Chicago, IL) was used for the analysis.
Patient Demographics and Participant Flow
A total of 30 Chinese patients were included, 15 patients (3 male, 12 female) in the Systane Ultra (HP-guar) group and 15 patients (1 male, 14 female) in the Refresh Tears (non–HP-guar) group. All patients completed the study visits. The mean age of the patients in each group, the global symptom score, TBUTs, and Schirmer’s I test results were not significantly different between the two groups (p > 0.05) (Table 1). In most of the zones of the cornea, there was no difference in the severity of fluorescein staining, with the exception of the left nasal and inferior zones, which showed more severe staining in the HP-guar group (Table 1).
The symptoms scores showed a significant improvement in both groups after 6 weeks of treatment (p < 0.001, Fig. 2); however, there was no significant difference in the SANDE scores between the two groups (p > 0.05, Table 2), with the non–HP-guar group improving by 37.5 (SD 29.4) and the HP-guar group by 33.2 (SD 26.6). One patient in HP-guar group had a SANDE score that worsened >2 standard deviations (SD of absolute change in the patients’ global symptom score between baseline and week 6 = 21.8) from the changes experienced by others, and this outlier would have skewed the data considerably if included in the line chart (Fig. 1). We checked that the inclusion or exclusion of this patient in the other analyses would not affect the conclusion of the analyses.
There was no significant difference in the TBUTs, Schirmer’s test results (Table 3), or corneal fluorescein staining at weeks 1, 3, or 6 (Table 4).
No adverse events were seen in any of the study groups after treatment.
In this study, we found that patients in both HP-guar and non–HP-guar groups symptomatically improved on follow-up, without any significant difference between the two ophthalmic drops. There were no significant differences in the improvement in corneal fluorescein staining, Schirmer’s test results, or TBUT between the two study groups (p > 0.05) posttreatment.
Comparison with Previous Studies
No consistent conclusion can be drawn from previously published clinical studies that compared lubricants with and without gelling agents, as different studies have shown different results.
A recent study concluded that both lubricant eye drops, with and without HP-guar gelling agent, were found to be cost-effective.24
In a randomized controlled multisite study, patients treated with a lubricant containing HP-guar reported reduced frequencies of foreign body sensation and dryness after 6 weeks of treatment in an acceptability questionnaire compared with those treated with a lubricant without gelling agent.25 There were no significant changes in corneal staining between the two products.
In contrast, another study comparing lubricant eye drops containing gelling agent with a lubricant with no gelling agent showed no difference in improvement in symptoms of dry eye between the two products.26 In this study, dry eye symptoms were evaluated using a Treatment Satisfaction Questionnaire and Visual Function Index-14 Questionnaire. There was also no significant difference in TBUT between the two arms. However, in this study, there was a significant reduction in both corneal and conjunctival staining after 6 weeks of treatment, favoring lubricant eye drop containing gelling agent to the lubricants with no gelling agent.
A recent study on contact lens wearers showed no significant improvement in corneal fluorescein staining after instilling HP-guar lubricant eye drops for 2 weeks,14 whereas another showed reduced corneal fluorescein staining after 6 weeks of instillation and increased staining after cessation of treatment.27
One of the clinical trials that evaluated the efficacy of combination therapy of lubricant eye drops with and without HP-guar gelling agent, with topical cyclosporine eye drops, found the former combination to be superior in terms of changing corneal fluorescein staining from baseline, and was associated with less dryness, stinging, grittiness, and burning symptoms at 6 months.28
However, in the aforementioned studies, evaluations were made only at the follow-up time point after treatment instead of changes from baseline, and did not consider the severity, but just frequency, of symptoms.28
Previous studies have also shown that lubricants with gelling agents can significantly prolong TBUT.11,12,13 Lubricant with HP-guar was able to produce a longer TBUT, up to 20 to 30 min after instillation, and was more effective compared with lubricants that do not contain gelling agents.10 The methodologies of these studies were very different from the present study.
HP-guar is a pH-dependent gelling agent, which when exposed to the higher pH (pH 7.5) of the ocular surface and tears, forms cross-links with borate, forming a gel matrix that has viscoelastic and bio-adhesive properties that protect the ocular surface.8,25 The gel matrix on administration of Systane has the disadvantage of considerable blurring, which led to the development of Systane Ultra, which forms a more loosely cross-linked meshwork than Systane, and hence less visual blurring.
CLINICAL SIGNIFICANCE AND CONCLUSIONS
This study suggests that either formulations, with or without HP-guar gelling agent, is effective in relieving dry eye symptoms. There was no significant difference in the efficacy of these drugs in terms of improving symptoms and altering objective signs of dry eye such as corneal fluorescein staining, TBUT, and Schirmer’s test results. Both products were not associated with any adverse events. Although further studies may be needed to substantiate the compatibility of these products in Asian patients, this clinical study provides evidence of safety and efficacy in treating symptomatic dry eye with this novel lubricant eye drop containing HP-guar gelling agent.
Singapore National Eye Centre
11 Third Hospital Avenue
This work was supported by grants NMRC/1206/2009, NMRC/0808/2003, NMRC/CPG/002/2003, NMRC/0982/2005, and NMRC/1206/2009 from National Medical Research Council (NMRC), Singapore, and Alcon Inc. (Alcon Inc. Funder) provided funding for consumables and study medication. Systane Ultra—the eye drop with gelling agent—is a marketed product for Alcon. This does not alter our adherence to all the journal policies on sharing data and materials. The sponsors or funding organizations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There are no patents or other products in development to declare.
Results have been partially presented as a poster at ASIA—ARVO (Association for Research in Vision and Ophthalmology), Singapore, January 2011, and an oral presentation at SGH 19th Annual Scientific Meeting, Singapore, April 2011, and 27th Malaysia Singapore Joint Ophthalmic Congress, Malaysia, June 2011.
Trial Registration: ClinicalTrials.gov; NCT00796926; http://clinicaltrials.gov/ct2/show/NCT00796926.
Received February 6, 2012; accepted July 13, 2012
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