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Evaluation Of The Effect On Tear Film Break-up Time Extension
By Artificial Tears In Dry Eye Patients
MT Christensen, JM Stein, RP Stone, DL Meadows
Alcon Research, Ltd. Fort Worth, Texas
Abstract
Materials and Methods
Purpose
This was a single-center, randomized, double-masked, three-way crossover trial with visits on Days 0, 7 and 14.
Enrollment criteria included logMAR 0.6 or better, have a reported history of mild to moderate dry eye syndrome in both
eyes, TFBUT of < 5 seconds in one eye, report use and/or desire to use an artificial tear substitute and exhibit a deficient
OPI (TFBUT < IBI) at visits 1, 2 and 3. 88 patients were screened and fifty (50) dry eye subjects who met enrollment
criteria and signed informed consents were enrolled in this clinical study.
To evaluate the effect of three marketed lubricating eye drops on tear film break-up time (TFBUT) extension
in dry eye patients.
Methods
This was a single-center, randomized, double-masked, three-way crossover trial with visits on Days 0, 7 and 14.
The three artificial tears used in this study included: a novel lubricant eye drop containing HP-Guar as a gelling
agent and Polyethylene Glycol 400 and Propylene Glycol as demulcents (Systane™); Refresh Tears® containing
carboxymethylcellulose; and Refresh Endura™ containing glycerin and polysorbate 80. At each visit, a micropipette was
used to instill a controlled amount (40µl) of the assigned lubricant eye drop. Prior to each TFBUT evaluation, 1µl of 2%
preservative-free sodium fluorescein was instilled using a DET strip (Akorn, Inc.). TFBUT time was recorded with a
digital imaging device at baseline and 5, 10, 15, 20, 30, 45 and 60 minutes post instillation of the test drops.
Results
Fifty dry eye patients completed the study. The lubricating eye drop containing HP-Guar extended mean TFBUT up to 30
minutes post instillation (an increase from baseline of 4.26 seconds at 5 minutes; and 1.81 seconds at 30 minutes). This
difference in TFBUT extension was significantly more than the carboxymethylcellulose-based drop up to 20 minutes
post instillation (P<0.001); and significantly more than the glycerin/polysorbate 80-based drop up to 30 minutes post
instillation (P=0.033).
Conclusion
The new lubricating eye drop containing a novel gelling ingredient, HP-Guar, exhibited a lasting effect on TFBUT
extension up to 30 minutes post instillation. Moreover, it was statistically superior to the carboxymethylcellulose and
glycerin/polysorbate 80-based lubricant eye drops in TFBUT extension. This suggests the ability of Systane to stabilize
TFBUT, providing long-lasting relief. This study was sponsored by Alcon Research, Ltd., Fort Worth, Texas and was
conducted at Ophthalmic Research Associates (ORA) in North Andover, MA.
Introduction
The accuracy and reproducibility of tear film break-up time (TFBUT) has improved over the past few years. Researchers
have shown that TFBUT measurements are more precise when using well controlled, micro-quantities of sodium
fluorescein (5µl or less)1. When evaluating an agent’s affect on TFBUT, it is important to establish a definition for
significant improvements in tear film stability. This has been difficult due to a lack of consensus on interpreting the
clinical relevance associated with extensions in TFBUT and the inherent variability of TFBUT between patients.
It may be suggested that the interaction between TFBUT and the Inter-blink Interval (IBI = time between complete
blinks) is involved with the regulation of the integrity of the ocular surface. A protected surface exists when the TFBUT
is longer than the IBI and an unprotected surface exists when the TFBUT is shorter than the IBI. It is believed that the
existence of an unprotected ocular surface can result in the development of signs and symptoms associated with Dry Eye.
Studies have shown that within one second of TFBUT, patients report ocular discomfort and shortly thereafter develop
superficial punctate keratitis2.
23 Biennial Cornea
Research Conference
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At each visit (Day 0, 7 and 14), there were baseline measurements for blink rate and sodium fluorescein (NaFl) tear film
break-up time (TFBUT), followed bilaterally by a one time dosing with 40 μl of the assigned artificial tear. NaFl TFBUT
was measured post-dosing at 5, 10, 15, 20, 30, 45 and 60 minutes post-instillation of the artificial tear. Within 5 minutes
of the final TFBUT assessment, post-dose blink rate was assessed.
Measures
• Inter-Blink Interval
1. Patients instructed to perform a visual task for three minutes;
2. Number of blinks recorded with a digital imaging system (Blink Rate);
3. The amount of time (3 minutes) divided by the number of blinks = IBI.
• Tear Film Break-Up Time (TFBUT)
1. Measured 2 times per eye after using 1 μl non-preserved 2% NaFl (DET strip applied to the superior conjunctiva)
by a digital imaging system.
2. TFBUT images viewed with a digital imaging system and on-screen timer by a masked observer
3. Wratten (yellow #12) filter used to enhance observation of TFBUT at 10X magnification.
Figure 2: Percentage of Eyes Achieving a Positive OPI Post Treatment.
• Ocular Protection Index (OPI): OPI= TFBUT/IBI
1. OPI ≥ 1.00 = Sufficient (protected ocular surface)
2. OPI < 1.00 = Deficient (unprotected ocular surface)
3. The TFBUT must be at least 1.00 second less than the IBI
Results
TFBUT Evaluation –
When evaluating this population of 50 patients and comparing Systane vs Refresh Tears, a significant difference in those
patients achieving a positive OPI (> 1) was obtained at 15 (p=0.02) and 30 (p=0.03) minutes with a trend at 5 (p=0.58)
and 20 (p=0.07) minutes. When comparing Systane to Refresh Endura a significant difference in the percent of eyes
obtaining a positive OPI was seen at 5 minutes (p=0.02) with trends at 10 (p=0.08), 15 (p=0.07), 20 (p=0.07) and 30
(p=0.09) minutes. There were no differences in the percent of eyes achieving a positive OPI between Refresh Tears and
Refresh Endura at any time point.
Discussion
A recent environmental study comparing Systane Lubricant Eye Drops to Refresh Tears Lubricant Eye Drops was
conducted on mild to moderate dry eye patients5. The Systane group demonstrated significant reductions in corneal
and conjunctival staining as well as significant improvement in various symptoms during a 6-week study with dosing
4 times per day with each artificial tear. It was surmised that the in situ gellation of HP-Guar in Systane provided a
matrix that reduced tear clearance and allowed the demulcents (PEG 400 and Propylene Glycol) to act on the
comprised ocular surface.
The relationship between TFBUT and blink rate (number of times per minute that the eye blinks) can be demonstrated
by the Ocular Protection Index (OPI). OPI = TFBUT divided by the time between blinks, or Inter-blink Interval (IBI).
If the OPI is <1, a patient is at greater risk of developing ocular signs and symptoms and if the OPI > 1, a patient is not.
This approach to measuring clinically relevant alterations in TFBUT, known as the Ocular Protection Index (OPI) has
proven useful in assessing factors that cause dry eye and evaluating its therapeutic agents3, 4. The objective of this study
was to evaluate the effect of Systane™ lubricant eye drops compared to Refresh Tears® and Refresh Endura™
on TFBUT and the OPI with mild to moderate dry eye patients.
The current study was an attempt to demonstrate a measurable effect caused by the ingredients of Systane to improve
TFBUT as a demonstration of improved retention and enhanced tear film stability. This independent study demonstrated
significant improvements in both TFBUT and the OPI values with Systane versus the competitor products and may be
the reason that the environmental study was so successful.
Conclusion
This study allowed us to conclude that:
1. Systane demonstrated longer TFBUT than Refresh Tears through 20 minutes post instillation.
2. Systane demonstrated longer TFBUT than Refresh Endura through 30 minutes post instillation.
3. Although the percent of patients reaching a positive OPI was numerically superior through all time points, only the
15 minute and 30 minute time points were statistically superior when compared to Refresh Tears and only the 5
minute time point was statistically superior when compared to Refresh Endura.
References
1. Foulks GN. Challenges and Pitfalls in Clinical Trials of Treatments for Dry Eye. The Ocular Surface. 2003;1(1):
20-30.
2. Nally LA, Ousler III GA, Abelson MB. Ocular Discomfort and Tear Film Break-up Time in Dry Eye Patients:
A Correlation. (Poster Presentation), The Association of Research in Vision and Ophthalmology, May 2000.
3. Ousler III GW, Abelson MB, Welch D. An Index for Measuring Clinically Relevant Alterations in Tear Film BreakUp Time. (Poster Presentation), Biennial Cornea Research Conference, September 2001.
Figure 1: Mean Extension in Tear Film Break-Up Time (TFBUT) (baseline corrected)
Baseline values of TFBUT were as follows: Systane = 2.89 sec, Refresh Tears 3.68 sec and Refresh Endura 3.25 sec.
Mean TFBUT was significantly increased for Systane vs Refresh Tears through 20 minutes with a trend p=0.06 at 30
minutes. Mean TFBUT was significantly increased for Systane vs Refresh Endura through 30 minutes. There were no
differences in TFBUT between Refresh Tears or Refresh Endura at any time points.
4. Ousler GW, Emory TB, Welch D, Abelson MB. Factors that Influence the Inter-Blink Interval (IBI) as Measured by
the Ocular Protection Index (OPI) (poster presentation) The Association of Research in Vision and Ophthalmology,
May 2002.
5. Christensen MT, et al, Clinical Evaluation of an HP-Guar Gellable Lubricant Eye Drop for the Relief of Dryness
of the Eye. Accepted for Publication, Current Eye Research 2003.