3-year Study in Dry Eye Disease Patients With Severe Keratitis Receiving Ikervis® (1mg/mL Ciclosporin)

Inclusion Criteria:

1. In the opinion of the investigator, the patient is capable of understanding andcomplying with protocol requirements.

2. The patient has signed and dated a written informed consent form and any requiredprivacy authorization prior to the initiation of any study procedures.

3. Male or female patient is aged 18 years or above.

4. At least 4 weeks of use of tear substitutes prior to the Baseline Visit

5. DED patients with severe keratitis defined as the following:

• CFS score of 3, 4 or 5 on the modified Oxford scale in at least one eye atBaseline Visits, AND

• Schirmer test without anaesthesia scored <10 mm/5min in the same eye atBaseline Visit, AND

• At least two moderate to very severe symptoms of dry eye disease with a score ≥2 (severity graded on a 0 to 4 grade scale), among the following symptoms:burning/stinging, foreign body sensation, eye dryness, eye pain andblurred/poor vision at Baseline Visit.

6. Patient must be willing and able to undergo and return for scheduled study-relatedexaminations.

Exclusion Criteria:

1. Active herpes keratitis or history of ocular herpes.

2. History of ocular trauma or ocular infection (viral, bacterial, fungal, protozoal)within 90 days before the Baseline Visit.

3. Any ocular diseases other than DED requiring topical ocular treatment during thecourse of the study. Patients taking preservative-free IOP lowering medications areeligible for study enrolment.

4. Concurrent ocular allergy (including seasonal conjunctivitis) or chronicconjunctivitis other than dry eye.

5. Anticipated use of temporary punctal plugs during the study. Patients with punctalplugs placed prior to the Baseline Visit are eligible for enrolment; however,punctal plugs must remain in place during the study.

6. Best corrected distance visual acuity (BCDVA) score ≤ 20/200 Snellen in each eye.

7. Presence or history of any systemic or ocular disorder, condition or disease thatcould possibly interfere with the conduct of the required study procedures or theinterpretation of study results or judged by the investigator to be incompatiblewith the study (e.g., diabetes with glycemia out of range, thyroid malfunction,uncontrolled autoimmune disease, current systemic infections, ocular infection...).

8. Known hypersensitivity to one of the components of the study or proceduralmedications (e.g., fluorescein, etc.).

9. History of ophthalmic malignancy

10. History of malignancy (other than ophthalmic) in the last 5 years.

11. Anticipated change during course of the study in the dose of systemic medicationsthat could affect a dry eye condition [mainly, estrogen-progesterone or otherestrogen derivatives (only allowed for post-menopausal women), pilocarpine,isotretinoine, tetracycline, antihistamines, tricyclic antidepressants, anxiolytics,antimuscarinics, beta-blocking agents, phenothiazines, omega-3, systemiccorticosteroids]. These treatments are allowed during the study provided they remainstable throughout the course of the study.

12. Use of topical ciclosporin in the past 3 months prior to Baseline visit.

13. Any change in systemic immunosuppressant drugs within 30 days before the BaselineVisit or anticipated change during the course of the study.

14. Pregnancy or lactation at the Baseline Visit.

15. Women of childbearing potential not using a medically acceptable, highly effectivemethod of birth control (such as hormonal implants, injectable or oralcontraceptives together with condoms, some intrauterine devices, sexual abstinenceor vasectomised partner) from the Baseline Visit throughout the conduct of the studytreatment periods and up to 2 weeks after the study end. Post-menopausal women (twoyears without menstruation) do not need to use any method of birth control.

16. Participation in a clinical trial with an investigational substance within the past 30 days prior to Baseline Visit.

17. Participation in another clinical study at the same time as the present study.