Safety and Efficacy Study on Cenegermin (Oxervate®) vs Vehicle in Severe Sjogren's Dry Eye Disease (PROTEGO-1 Study)

Primary objectives

* To compare the efficacy of cenegermin vs vehicle in Schirmer I test (without anaesthesia) \>10mm/5min at Week 4 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in Symptom Assessment in Dry Eye questionnaire (SANDE) global score at Week 12 by testing the superiority.

Secondary objectives

* To compare the efficacy of cenegermin vs vehicle in Schirmer I test at Week 4, 8, 12 and 16 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in Cornea and conjunctiva vital staining with fluorescein (National Eye Institute \[NEI\] scales) at Week 4, 8, 12 and 16 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in Tear Film Break-Up Time (TFBUT) at Week 4, 8, 12 and 16 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in SANDE scores at Week 8, 12 and 16 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in worsening in symptom scores (SANDE) and/or NEI score at Week 4 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in impact of dry eye on everyday life (IDEEL) questionnaire at Week 4, 8, 12 and 16 by testing the superiority.

This is a 4 week phase III, multicenter, double-masked, vehicle-controlled study to evaluate safety and efficacy of cenegermin ophthalmic solution at 20 mcg/mL solution versus vehicle, in patients with severe Sjogren's dry eye disease.

During the screening all procedures for inclusion and exclusion were performed. From the day of screening the patients stopped any kind of further treatment, except commercially available preservative free artificial tears provided by Sponsor.

At the end of the wash out period, patients meeting the entry criteria for this study were randomized 1:1 and treated for 4 weeks with either cenegermin ophthalmic solution 20 mcg/mL TID or vehicle TID.

During the 4 weeks of masked treatment only the administration of IMP was allowed.

During the follow up period, the patient could administer additional artificial tear eye drops, provided by Sponsor, only if strictly needed, and should document in the patient's diary the number of additional drops administered for each eye.

Patients were then followed up for efficacy and safety endpoints until week 16 and for safety endpoints until week 24.

The total duration of the study was 25 weeks including 1 week of screening.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female aged ≥ 18 years
2. Patients with a confirmed diagnosis of Sjögren's syndrome or other autoimmune disease known to induce Sjögren's Dry Eye Disease (DED).
3. Patients with severe Sjögren's dry eye disease 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) ≥2 ≤5mm/5min
4. The same eye (eligible eye) must fulfill all the above criteria
5. Patients diagnosed with severe Sjögren's dry eye disease at least 3 months before enrolment
6. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 Snellen value) in each eye at the time of study enrolment
7. If a female of childbearing potential, have a negative urine pregnancy test and use a highly effective method to avoid pregnancy for the duration of the trial and 30 days after the study treatment period. Males of reproductive potential should use effective contraception during treatment and 30 days after the study treatment period.
8. 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 IRB/IEC for the current study
9. 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 in either eye
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 anesthetics 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 1) 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

   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, or topical ophthalmic treatments of the same class, within 14 days of screening visit (day -8)
12. Use of topical corticosteroids, lifitegrast, autologous serum tears in either eye during the study (previous use not an exclusion criteria but must be discontinued at the screening visit)
13. Contact lenses, True Tear device, moisture goggles, sutureless amniotic membrane or punctum plug use during the study (previous use not an exclusion criteria but must be discontinued at the screening visit)
14. History of drug addiction or alcohol abuse in the last 2 years
15. Any prior ocular surgery (including refractive, palpebral and cataract surgery) if within 90 days before the screening visit
16. Participation in a clinical trial with a new active substance during the past 3 months
17. Participation in another clinical trial study at the same time as the present study.