Management of post-LASIK dry eye: a multicenter randomized comparison of a new multi-ingredient artificial tear to carboxymethylcellulose

Figures & data

Table 1 Key inclusion and exclusion criteria assessed at baseline (day 1)

Inclusion criteria

• Male or female ≥18 and ≤60 years of age and in good general health

• LASIK flap creation with femtosecond laser

• Pre-LASIK best-corrected visual acuity of 20/32 or better in each eye

• Normal pre-LASIK topography by Corneal Irregularity Measurement (Humphrey Atlas) or Index of Surface Variance (Pentacam^®) or Corneal Irregularity Index (Orbscan™), and normal Wavefront aberrometry

• Successful completion of the surgical procedure in both eyes with no flap complications, no central epithelial defects on flap, and no requirement for bandage contact lens

Exclusion criteria

• Signs or symptoms of dry eye greater than mild severity (OSDI score >22 and/or corneal staining score of >grade 2 [modified NEI grid] in a single zone or a cumulative score of >4 in all 5 zones)

• Preoperative antimetropia (ie, 1 eye myopic, 1 eye hyperopic)

• Soft contact lens wear within 7 days or rigid contact lens wear within

30 days before LASIK or during the study period

• Scheduled or planned ocular surgery (other than current LASIK surgery), systemic surgery, or other procedure during the study that may impact study participation

• Starting systemic medication (OTC, prescription, herbal, or nutritional supplement), which may affect dry eye or vision <3 months before screening or anticipated dose adjustment during the study

• Current use of topical ophthalmic medication other than prescribed for use in pre- or postoperative care; use of Restasis^® or other topical ophthalmic cyclosporine ≤6 months before screening; use of topical glaucoma medication or suspicion of glaucoma

• Active ocular infection, ocular inflammation, ocular allergy, or history of herpes keratitis

• Corneal disorder or abnormality affecting corneal sensitivity or normal spreading of the tear film and/or severe blepharitis or inflammation of the lid margin that may interfere with results

• Insertion of punctal plugs within 6 months before screening

• History of prior intraocular or anterior segment surgery (eg, radial keratotomy, cataract surgery, vitrectomy), and/or history of intraocular or anterior segment trauma

Abbreviations: LASIK, laser-assisted in situ keratomileusis; OSDI, Ocular Surface Disease Index^©; NEI, National Eye Institute; OTC, over-the-counter.

Table 2 Study artificial tear formulations*

Brand name	CMC-HA	CMC
	Refresh Optive Fusion^® Sensitive‡	Refresh Plus^®
Composition	CMC 0.5%, HA 0.1%, glycerin, sodium lactate, l-carnitine, erythritol, potassium chloride, calcium chloride, magnesium chloride, purified water, and sodium hydroxide to adjust pH to 6.8	CMC 0.5%, sodium lactate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, purified water, and sodium hydroxide to adjust pH to 6.5

Notes:

* Sterile and isotonic formulations packaged in unit dose vials; manufactured by Allergan plc, Dublin, Ireland.

‡ Trade name in Canada, not commercially available in all countries.

Abbreviations: CMC, carboxymethylcellulose 0.5%; CMC-HA, carboxymethylcellulose 0.5%, hyaluronic acid 0.1%.

Figure 1 Mean overall Ocular Surface Disease Index^© (OSDI) scores at study visits.

Note: Error bars indicate standard error of the mean (per-protocol population).
Abbreviations: CMC, carboxymethylcellulose 0.5%; CMC-HA, carboxymethylcellulose 0.5%, hyaluronic acid 0.1%.

Table 3 OSDI scores at baseline (screening visit) and follow-up visits based on preoperative refractive error stratification (ITT population)

Treatment/study visit	OSDI by refractive strata, mean (SD)			Difference between strata (95% CI)
	Standard myope	Moderate myope	Hyperope	Standard myope vs hyperope	Moderate myope vs hyperope	Standard myope vs moderate myope
CMC-HA	n=60	n=12	n=3
Baseline	3.7 (4.7)	5.7 (5.3)	5.6 (5.2)	−1.9 (−5.8, 1.9)	0.1 (−4.1, 4.3)	−2.0 (−4.6, 0.6)
Day 10	12.6 (14.3)	8.2 (10.7)	12.2 (17.4)	0.4 (−10.4, 11.1)	−4.1 (−15.8, 7.7)	4.4 (−2.8, 11.7)
Day 30	6.4 (9.9)	5.6 (7.5)	6.2 (7.2)	0.2 (−7.0, 7.4)	−0.6 (−8.5, 7.2)	0.8 (−4.0, 5.7)
Day 60	4.2 (9.3)	3.6 (8.1)	2.8 (2.4)	1.4 (−5.4, 8.2)	0.8 (−6.7, 8.2)	0.6 (−4.0, 5.2)
Day 90	2.7 (9.1)	4.5 (9.5)	3.2 (3.2)	−0.5 (−7.5, 6.5)	1.3 (−6.3, 9.0)	−1.8 (−6.5, 2.9)
CMC	n=59	n=11	n=3
Baseline	3.9 (4.8)	4.1 (5.3)	5.6 (9.6)	−1.6 (−5.8, 2.6)	−1.5 (−6.1, 3.2)	−0.2 (−3.1, 2.8)
Day 10	12.0 (12.9)	17.9 (12.8)	18.3 (23.8)	−6.3 (−17.2, 4.6)	−0.4 (−12.5, 11.7)	−5.9 (−13.5, 1.7)
Day 30	6.9 (8.2)	7.1 (9.8)	14.6 (20.9)	−7.7 (−15.5, 0.2)	−7.4 (−16.1, 1.2)	−0.2 (−5.7, 5.2)
Day 60	3.5 (6.9)	5.6 (7.5)	14.6 (16.6)	−11.1 (−17.4, −4.8)*	−9.0 (−16.0, −2.0)*	−2.1 (−6.6, 2.3)
Day 90	3.1 (8.0)	2.6 (7.1)	11.1 (18.2)	−8.1 (−15.1, −1.1)*	−8.5 (−16.2, −0.8)*	0.5 (−4.4, 5.3)

Note:

* P<0.05 for the difference between strata by one-way ANOVA model with fixed effect of strata and using the weighted least square method.

Abbreviations: CMC, carboxymethylcellulose 0.5%; CMC-HA, carboxymethylcellulose 0.5%, hyaluronic acid 0.1%; ITT, intent-to-treat; OSDI, Ocular Surface Disease Index^©.

Figure 2 Change in mean uncorrected visual acuity in the worse eye post-LASIK surgery.

Notes: Error bars indicate standard error of the mean (per-protocol population). *P=0.013 for between group difference in the change from day 2 in total number of letters read correctly (ANOVA model with fixed effects of treatment and the stratification factor using the type III sum of squares).
Abbreviations: CMC, carboxymethylcellulose 0.5%; CMC-HA, carboxymethylcellulose 0.5%, hyaluronic acid 0.1%; LASIK, laser-assisted in situ keratomileusis.

Figure 3 Mean (A) corneal staining, (B) Schirmer’s test score, and (C) tear break-up time at study visits.

Notes: Error bars indicate standard error of the mean (A), per-protocol population; (B and C), intent-to-treat population. *P<0.01; **P<0.05 for within-group comparison with baseline (paired t-test).
Abbreviations: CMC, carboxymethylcellulose 0.5%; CMC-HA, carboxymethylcellulose 0.5%, hyaluronic acid 0.1%.

Table 4 Severity of ocular symptoms at baseline (screening visit) and follow-up study visits after LASIK (ITT population)

Ocular symptom	CMC-HA (n=75) Mean (SD) score P-value*			CMC (n=73) Mean (SD) score P-value*
	Baseline	Day 2	Day 90	Baseline	Day 2	Day 90
Burning/stinging	2.4 (3.8)	29.6 (28.6)	2.7 (6.5)	3.1 (10.9)	31.5 (29.2)	2.3 (10.1)
	–	<0.001	0.692	–	<0.001	0.647
Grittiness/foreign body sensation	2.7 (5.2)	30.3 (28.0)	4.5 (8.1)	2.2 (10.3)	29.6 (26.7)	2.5 (4.9)
	–	<0.001	0.110	–	<0.001	0.811
Dryness	4.9 (7.4)	19.7 (22.1)	8.4 (11.9)	7.1 (14.0)	22.3 (24.4)	11.3 (15.3)
	–	<0.001	0.023	–	<0.001	0.047
Difficult/uncomfortable vision	2.3 (8.8)	24.8 (23.3)	5.2 (13.2)	3.3 (10.9)	33.2 (27.2)	2.2 (5.0)
	–	<0.001	0.124	–	<0.001	0.384
Overall ocular pain/discomfort	2.1 (6.1)	26.3 (25.8)	1.9 (4.3)	2.3 (11.4)	27.4 (27.3)	1.9 (5.6)
	–	<0.001	0.816	–	<0.001	0.791

Note:

* P-value for within-group comparison to baseline (paired t-test).

Abbreviations: LASIK, laser-assisted in situ keratomileusis; CMC, carboxymethylcellulose 0.5%; CMC-HA, carboxymethylcellulose 0.5%, hyaluronic acid 0.1%; ITT, intent-to-treat.

Table S1 Ethics committees providing study protocol approval

Australian study site	Investigator/site
Bellberry Human Research Ethics Committee	Patrick Versace, Bondi Junction, NSW
229 Greenhill Road
Dulwich SA 5065, Australia
Canadian study sites	Investigator/site
Clinical Research Ethics Committee	Hugh Jellie, Waterloo, ON
University of Waterloo
200 University Avenue West
Waterloo, ON N2L 3G1, Canada
Health Research Ethics Authority	Michael Bense, St John’s, NL
95 Bonaventure Avenue, Suite 200, 2nd Floor	Chris Jackman, St John’s, NL
St John’s, Newfoundland and Labrador A1B 2X5, Canada
Health Research Ethics Board of Alberta – Clinical Trials and Research Ethics Review Committees	Joseph King, Edmonton, AB
1500, 10104 – 103 Avenue NW
Edmonton, AB T5J 4A7, Canada
Ottawa Health Science Network-Research Ethics Board	W Bruce Jackson, Ottawa, ON
725 Parkdale Avenue, Suite 411
Ottawa, ON K1Y 4E9, Canada
Schulman Associates Institutional Review Board, Inc	Jeffrey Chambers, Kelowna, BC
4445 Lake Forest Drive, Suite 300	Clara Chan, Toronto, ON
Cincinnati, OH 45242, USA	Sameh Fanous, Saint-Laurent, QC
	Sheldon Herzig, Toronto, ON
	Christoph Kranemann, Toronto, ON
	Andrew Taylor, Niagara Falls, ON
	Avi Wallerstein, Montreal, QC
	James Wiens, Winnipeg, MB