Efficacy of Topical Azithromycin & Cyclosporine A(CsA) vs CsA Alone in the Treatment of Dry Eyes Associated with Blepharitis Kenneth A. Beckman, M.D., F.A.C.S. Disclosure: Author is a consultant for Inspire Pharmaceuticals, Inc. & Allergan Pharmaceuticals, Inc.

Study Details Pilot study, open-label Single center Study population: 23 patients with dry eyes and blepharitis (19 patients completed the study) Treatment: All patients applied CsA ophthalmic solution twice a day for three months. The Azithromycin group also applied Azithromycin ophthalmic solution twice daily for two days followed by once daily at bedtime for 28 days. Clinical signs and symptoms were evaluated at baseline, three weeks and three months.

Inclusion/Exclusion Criteria Inclusion Criteria Age > 18 years Clinical diagnosis of blepharitis: presence of lid hyperemia, meibomian gland plugging, thickened secretions, or debris in the lashes Clinical signs and symptoms of evaporative dry eye: Tear break-up time of less than ten seconds in the worse eye, conjunctival staining score at least one out of four in each eye Exclusion Criteria Use of Azithromycin or CsA in the previous six months Allergy to either medication

Study Design Azithromycin CsA Alone Azithromycin CsA Alone +CsA +CsARandomization CsA Alone CsA Alone Visit Schedule Day 1 3 weeks 3 months Day 1 3 weeks 3 months

Safety and Efficacy Endpoints Safety Measurements Safety Measurements - Biomicroscopy and External Eye Exam - Best Corrected Visual Acuity - Best Corrected Visual Acuity - Adverse Event Monitoring - Adverse Event Monitoring - IOP - IOP Efficacy Scores for the Clinical Signs and Symptoms Efficacy Scores for the Clinical Signs and Symptoms - Fluorescein Tear Break-Up Time in seconds - Fluorescein Tear Break-Up Time in seconds - Ocular Surface Disease Index(OSDI) scores - Ocular Surface Disease Index(OSDI) scores - Conjunctival staining scores with lissamine green - Conjunctival staining scores with lissamine green - Overall patient subjective assessment of the treatment at - Overall patient subjective assessment of the treatment at the final visit the final visit

Table 1 Results - Conjunctival Staining Azithromycin + CsACsA Mean (STD)(10 subjects)(9 Subjects)p-value ObservedChange from baselineObservedChange from baseline Visit 12.4 (0.94) 2.5 (0.88) Visit 21.5 (0.77) -0.9 (0.73) 37.5%1.6 (0.59) -0.9 (0.67) 36%0.75 Visit 31.0 (0.56) -1.4 (1.06) 58.3%0.9 (0.64) -1.6 (0.98) 64 %0.74 P-Values are for the treatment difference of change from baseline of conjunctival staining using a mixed-effects linear model. These models adjusted for baseline (Visit 1) score. A random intercept is assumed for each subject to account for the correlation between eyes.

Table 2 Results – TBUT Azithromycin + CsACsA Mean (STD)(10 subjects)(9 Subjects)p-value ObservedChange from baselineObservedChange from baseline Visit 15.3 (3.05) 4.9 (2.65) Visit 28.2 (4.27) 2.9 (2.87) 54.7%7.3 (2.34) 2.4 (1.49) 49.07%0.6 Visit (4.12)5.0 (2.89) 94.3%8.3 (2.78)3.4 (1.99) 69.4%0.18 P-Values are for the treatment difference of change from baseline of conjunctival staining using a mixed-effects linear model. These models adjusted for baseline (Visit 1) score. A random intercept is assumed for each subject to account for the correlation between eyes.

Table 3 Results – OSDI Azithromycin/CsACsA Mean (STD)(10 subjects)(9 Subjects)p-value ObservedChange from baselineObservedChange from baseline Visit (25.64) 53.6 (10.59) Visit (23.75) (21.45) 56.9%33.5 (15.5) (19.67) 37.7%0.26 Visit (14.49) (19.63) 71.7%26.8 (14.95) (20.37) 50.1%0.095 P-Values are for the treatment difference of change from baseline of conjunctival staining using a mixed-effects linear model. These models adjusted for baseline (Visit 1) score. A random intercept is assumed for each subject to account for the correlation between eyes.

Table 4 Patient Overall Rating of the Treatment Overall RatingAzithromycin/CsACsA (n = 10)(n = 9) Excellent - 470%0% Good - 320%56% Fair - 210%33% Poor - 10%11% Worsening 00% Mean (SD) 3.6 (0.79) * 2.5 (0.70) * p=0.005(WRST) One patient in the CsA group rated 3.5. This was used to calculate the mean but was recorded as Good for the above table.

Safety Results Generally well tolerated Generally well tolerated - One patient removed herself from the study - One patient removed herself from the study due to burning from CsA (5%) due to burning from CsA (5%) - Three other patients removed themselves from - Three other patients removed themselves from the study for personal reasons the study for personal reasons

Conclusions For the treatment of dry eye disease associated with blepharitis, this study found: - A trend toward greater improvement in tear break-up time with combined Azithromycin and CsA treatment than CsA alone at 3 months (94% vs 69%, p=0.18) - A trend toward greater improvement in tear break-up time with combined Azithromycin and CsA treatment than CsA alone at 3 months (94% vs 69%, p=0.18) - A trend toward greater improvement in OSDI scores with combined Azithromycin and CsA treatment than CsA alone at 3 months (73% vs 50%, p=0.095) - A trend toward greater improvement in OSDI scores with combined Azithromycin and CsA treatment than CsA alone at 3 months (73% vs 50%, p=0.095) A statistically significant difference in the overall patient satisfaction rating favoring the combined Azithromycin/CsA treatment group (p=0.005). 90% of patients in the Azithromycin/CsA group rated the treatment as excellent or good, while 44% of patients in the CsA alone group rated the treatment as fair or poor.

Conclusions Both groups improved in a similar fashion in conjunctival staining. The small sample size may have limited statistical significance of the results. The trends toward greater improvement in tear break-up time and OSDI with combined therapy along with the significant difference in the patient satisfaction survey warrant further investigation and consideration for treating lid margin disease with Azithromycin simultaneously while treating dry eye disease with CsA.