Kenneth A. Beckman, M.D., F.A.C.S.

1. 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.

2. 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.

3. 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 Inclusion/Exclusion Criteria

4. Study Design Azithromycin CsA Alone +CsA Randomization CsA Alone Visit Schedule Day 1 3 weeks 3 months

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

6. Table 1 • 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.

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

11. 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 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.

12. 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.