A Study to Evaluate Safety and Efficacy of rhNGF Eye Solution vs Vehicle in Patients With Moderate to Severe Dry Eye

The objective of this study is to assess the efficacy and safety of rhNGF eye drops at 20 μg/ml concentration administered two or three times daily for 4 weeks in patients with moderate to severe dry eye.

This is a 4 weeks, Phase II, multicenter, randomized, double-masked, vehicle-controlled, parallel group study with 12 weeks of follow-up, designed to perform dose-ranging and to evaluate safety and efficacy of recombinant human Nerve Growth Factor (rhNGF) eye drops solution versus vehicle, in patients with moderate to severe dry eye (DE).

Test product is rhNGF 20 μg/ml; reference product is vehicle. Test and reference will be instilled in both eyes according to the following scheme:

Group 1: one drop of rhNGF 20 μg/ml is instilled in both eyes three times daily (every 6-8 hours, e.g. 7:00 am, 02:00 pm; 09:00 pm).

Group 2: one drop of rhNGF 20 μg/ml is instilled in both eyes two times daily (in the morning and in the evening) plus one drop (40 μL) of vehicle (placebo) is instilled in both eyes once daily in the afternoon.

Group 3: one drop (40 μL) of vehicle (placebo) is instilled in both eyes three times daily (every 6-8 hours, e.g. 7:00 am, 02:00 pm; 09:00 pm).

Approximate randomization 1:1:1 of 261 patients to rhNGF eye drops solution 20 μg/ml TID (87 patients) or rhNGF eye drops solution 20 μg/ml BID + vehicle eye drop SID (86 patients) or vehicle eye drops solution (88 patients) TID for 4 weeks was applied.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female aged ≥ 18 years
2. Patients with moderate to severe dry eye characterized by the following clinical features:

   1. Corneal and/or conjunctival staining with fluorescein using National Eye Institute (NEI) grading system \> 3
   2. SANDE questionnaire \>25 mm
   3. Schirmer test I (without anaesthesia) \>2mm \<10 mm/5 minutes
   4. Tear film break-up time (TFBUT) \< 10 seconds in the worse eye
3. The same eye (eligible eye) must fulfill all the above criteria
4. Patients diagnosed with dry eye at least 6 months before enrolment (current use or recommended use of artificial tears for the treatment of Dry Eye)
5. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 Snellen value) in both eyes at the time of study enrolment
6. If a female of childbearing potential, have a negative pregnancy test
7. Only patients who satisfy all Informed Consent requirements may be included in the study. The patient and/or his/her legal representative must read, sign and date the Informed Consent document before any study-related procedures are performed. The Informed Consent form signed by patients and/or legal representative must have been approved by the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) for the current study
8. Patients must have the ability and willingness to comply with study procedures.

Exclusion Criteria:

1. Inability to speak and understand the local language sufficiently to understand the nature of the study, to provide written informed consent, and to allow the completion of all study assessments;
2. Evidence of an active ocular infection, in either eye
3. Presence of any other ocular disorder or condition requiring topical medication during the entire duration of study
4. History of severe systemic allergy or of ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis and/or keratitis other than dry eye
5. Intraocular inflammation defined as Tyndall score \>0
6. History of malignancy in the last 5 years
7. Systemic disease not stabilized within 1 month before Screening Visit (e.g. diabetes with glycemia out of range, thyroid malfunction..) or judged by the investigator to be incompatible with the study (e.g. current systemic infections) or with a condition incompatible with the frequent assessment required by the study
8. Patient had a serious adverse reaction or significant hypersensitivity to any drug or chemically related compounds or had a clinically significant allergy to drugs, foods, amide local anaesthetics or other materials including commercial artificial tears (in the opinion of the investigator)
9. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study if they meet any one of the following conditions:

   1. are currently pregnant or,
   2. have a positive result at the urine pregnancy test (Baseline/Day 0) or,
   3. intend to become pregnant during the study treatment period or,
   4. are breast-feeding or,
   5. are not willing to use highly effective birth control measures, such as: hormonal contraceptives - oral, implanted, transdermal, or injected - and/or mechanical barrier methods - spermicide in conjunction with a barrier such as a condom or diaphragm or Intra Uterine Device (IUD) - during the entire course of and 30 days after the study treatment periods
10. Any concurrent medical condition, that in the judgment of the PI, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient's well-being
11. Use of topical cyclosporine, topical corticosteroids or any other topical drug for the treatment of dry eye in either eye within 30 days of study enrolment.
12. Contact lenses or punctum plug use during the study (previous use not an exclusion criteria but must be discontinued at the screening visit)
13. History of drug addiction or alcohol abuse
14. Any prior ocular surgery (including refractive palpebral and cataract surgery) if within 90 days before the screening visit
15. Participation in a clinical trial with a new active substance during the past 6 months
16. Participation in another clinical trial study at the same time as the present study.