Study to Evaluate Safety and Efficacy of Cenegermin (Oxervate®) vs Vehicle in Severe Sjogren's Dry Eye Disease

Primary Objectives:

* To compare the efficacy of cenegermin vs vehicle in Schirmer I test (without anaesthesia) \> 10 mm/5 min 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 was 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 under treatment with Ciclosporine A (or other drugs of the same class).

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 CsA and commercially available preservative-free artificial tears provided by the Sponsor for a period of 8 days and 10 days as maximum. At the end of the washout period, patients still meeting the entry criteria for this study were randomized 1:1 and treated for 4 weeks with either cenegermin ophthalmic solution 20 mcg/mL three times a day (TID) or vehicle TID.

In addition to topical CsA eye drops (both groups continued with topical CsA eye drops, or other topical ophthalmic treatment of the same class), during the 4 weeks of masked treatment, only the administration of investigational medicinal product (IMP) was allowed.

During the follow up period, the patient could administer additional preservative-free artificial tear eye drops, provided by the Sponsor, only if strictly needed, and had to 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 DED.
3. Patients with severe Sjögren's DED 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 ≤ 5 mm/5 min.
4. The same eye (eligible eye) must fulfil all the above criteria.
5. Patients diagnosed with severe Sjögren's DED at least 3 months before enrolment (current use or recommended use of artificial tears for the treatment of Sjögren's related DE).
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. Patients who have given written informed consent before any study-related procedures not part of standard medical care are performed.
9. Patients must have the ability and willingness to comply with study procedures.
10. Patients under treatment with topical cyclosporine (CsA), or topical ophthalmic treatments of the same class for at least 30 days before Screening Visit (Day -8).

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 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) were excluded from participation in the study if they met any one of the following conditions:

   1. were currently pregnant or,
   2. had a positive result at the urine pregnancy test (Baseline/Day 1) or,
   3. intended to become pregnant during the study treatment period or,
   4. were breast-feeding or,
   5. were not willing to use highly effective birth control measures, such as: combined (oestrogen and progesterone containing) hormonal contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, implantable, injectable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence - during the entire course of and 30 days after the study treatment period.
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 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).
12. 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).
13. History of drug addiction or alcohol abuse in the last 2 years.
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 3 months.
16. Participation in another clinical trial study at the same time as the present study.