Phase 2/3 Dose-Ranging Study of the Safety and Efficacy of OTX-101 in the Treatment of Keratoconjunctivitis Sicca

Inclusion Criteria:

1. Subjects age 18 years or older on the date of informed consent.
2. All subjects must provide signed written consent prior to participation in anystudy-related procedures.
3. Patient-reported history of KCS for a period of at least 6 months.
4. Clinical diagnosis of bilateral KCS supported by OTX-101-2014-001 study assessments.
5. Lissamine green conjunctival staining sum score of ≥ 3 to ≤ 9 out of a total possiblescore of 12 (scoring excludes superior zones 2 and 4) in the same eye at Screening andBaseline.
6. Global symptom score ≥ 40 at both Screening and Baseline.
7. Corrected Snellen VA of better than 20/200 in each eye.
8. Willing to discontinue use of current dry eye therapy (including artificial tears orocular lubricants) during the study as of the run-in period.
9. Female subjects of childbearing potential must have a negative urine pregnancy test atScreening. Women of childbearing potential (ie, women who are not eitherpostmenopausal for one year or surgically sterile) must use an acceptable form ofcontraception throughout the study.

Exclusion Criteria:

1. Use of cyclosporine ophthalmic emulsion 0.05% (Restasis®) within 3 months prior toScreening.
2. Previous treatment failure (lack of efficacy) on cyclosporine ophthalmic emulsion 0.05% (Restasis).
3. Diagnosed with Sjögren's disease ˃5 years prior to Screening.
4. Clinical diagnosis of seasonal and perennial allergic conjunctivitis.
5. Use of systemic and topical medications that are known to cause dry eye within 7 daysprior to Screening and throughout the study period. These include the followingmedications:

• Immunomodulators (permitted if dose is stable for 3 months prior to screening anddoes not change during the study period)
• Antihistamines (including over-the counter (OTC))
• Cholinergics
• Antimuscarinics
• Tricyclic antidepressants
• Phenothiazines
• Retinoids

6. Oral omega-3 fatty acids (permitted if dose is stable for 3 months prior to Screeningand does not change during the study period)
7. Use of any topical ophthalmic medications, prescription (including antiglaucomamedications) or OTC (including artificial tears), other than the assigned studymedication during the study period.
8. Current active eye disease other than KCS (i.e., any disease for which topical orsystemic ophthalmic medication is necessary).
9. History of herpes keratitis.
10. Unstable macular disease (e.g., age-related macular degeneration, diabeticmaculopathy). Stable macular disease is defined as no reduction in central VA within 6months prior to Screening.
11. Diagnosis of chronic uveitis.
12. Corneal transplant (e.g., penetrating keratoplasty, lamellar keratoplasty, Descemet'sstripping endothelial keratoplasty (DSEK) ).
13. Corneal refractive surgery (e.g., laser-assisted in situ keratomileusis (LASIK]) photorefractive keratectomy (PRK), limbal relaxing incision (LRI) ) within 6 months priorto screening or postoperative refractive surgery symptoms of dryness that have notresolved.
14. Cataract surgery within 3 months prior to Screening.
15. Non-laser glaucoma surgery at any time; glaucoma laser procedures within 3 monthsprior to Screening.
16. Presence of punctal plugs or past history of permanent punctal occlusion (e.g.,cautery).
17. Lagophthalmos or clinically significant eyelid margin irregularity of the study eyewhether congenital or acquired.
18. Presence of conjunctivochalasis (i.e., mechanical blockage of the lower lid punctum byredundant conjunctiva).
19. Presence of pterygium in the study eye.
20. Unwilling to discontinue use of contact lenses during the duration of the study.
21. Preplanned elective surgery or hospitalization during the study period.
22. HIV-positive.
23. Unable to reliably report symptoms and history.
24. Has known hypersensitivity or contraindication to the study medication(s) or theircomponents.
25. Has a history or presence of chronic generalized systemic disease that theInvestigator feels might increase the risk to the subject or confound the result(s) ofthe study.
26. Has a severe/serious ocular condition, or any other unstable medical condition that,in the Investigator's opinion, may preclude study treatment or follow-up.
27. Women who are pregnant or breastfeeding.
28. Participation in any drug or device clinical investigation within 30 days prior toentry into this study and/or during the period of study participation.
29. Previous randomization into this study.