Study to Evaluate Safety and Efficacy of Cenegermin (Oxervate®) vs Vehicle in Severe Sjogren's Dry Eye Disease (NGF0121 - PROTEGO-1 Study)

Study Overview
=================
Brief Summary
-----------------
The study objective is to assess the efficacy and safety of cenegermin (rhNGF) ophthalmic solution at 20 mcg/mL concentration administered three times daily for 4 weeks in patients with severe Sjogren's dry eye disease.

Detailed Description
-----------------
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 will be performed. From the day of screening the patients will stop 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 will be 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 is allowed. During the follow up period, the patient can administer additional artificial tear eye drops, provided by Sponsor, only if strictly needed, and must document in the patient's diary the number of additional drops administered for each eye. Patients will then be followed up for efficacy and safety endpoints until week 16 and for safety endpoints until week 24. The total duration of the study is 25 weeks including 1 week of screening.

Official Title
-----------------
A 4-week, Phase III, Multicenter, Double-masked, Vehicle-controlled Clinical Study to Evaluate Safety and Efficacy of Oxervate® (Cenegermin) 20 mcg/mL Ophthalmic Solution Versus Vehicle, in Patients With Severe Sjogren's Dry Eye Disease (PROTEGO-1 Study)

Conditions
-----------------
Dry Eye

Intervention / Treatment
-----------------
* Drug: Oxervate
* Other: Vehicle


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female aged ≥ 18 years Patients with a confirmed diagnosis of Sjögren's syndrome or other autoimmune disease known to induce Sjögren's Dry Eye Disease (DED). Patients with severe Sjögren's dry eye disease characterized by the following clinical features: Corneal and/or conjunctival staining with fluorescein using National Eye Institute (NEI) grading system ≥3 SANDE questionnaire >25 mm Schirmer test I (without anaesthesia) ≥2 ≤5mm/5min The same eye (eligible eye) must fulfill all the above criteria Patients diagnosed with severe Sjögren's dry eye disease at least 3 months before enrolment 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 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. 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 Patients must have the ability and willingness to comply with study procedures. Exclusion Criteria: 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 Evidence of an active ocular infection, in either eye Presence of any other ocular disorder or condition requiring topical medication during the entire duration of study in either eye History of severe systemic allergy or of ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis and/or keratitis other than dry eye Intraocular inflammation defined as Tyndall score >0 History of malignancy in the last 5 years 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 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). 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: are currently pregnant or, have a positive result at the urine pregnancy test (Baseline/Day 1) or, intend to become pregnant during the study treatment period or, are breast-feeding or, are not willing to use highly effective birth control measures During the entire course of and 30 days after the study treatment periods 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 Use of topical cyclosporine, or topical ophthalmic treatments of the same class, within 14 days of screening visit (day -8) 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) 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) History of drug addiction or alcohol abuse in the last 2 years Any prior ocular surgery (including refractive, palpebral and cataract surgery) if within 90 days before the screening visit Participation in a clinical trial with a new active substance during the past 3 months Participation in another clinical trial study at the same time as the present study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxervate<br>one drop of cenegermin 20 mcg/mL will be instilled in both eyes three times daily. | Drug: Oxervate<br>* Oxervate®, an ophthalmic solution containing cenegermin 20 mcg/mL, which is a recombinant human Nerve Growth Factor (rhNGF); one drop of the test product will be instilled in both eyes three times daily (TID).<br>* Other names: Cenegermin;|
| Placebo Comparator: Vehicle<br>vehicle eye one drop will be instilled in both eyes three times daily. | Other: Vehicle<br>* Vehicle will be instilled with the same scheme of the test product<br>* Other names: Reference product;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Schirmer I test (without anesthesia) >10mm/5min | in the eligible eye | at week 4 | 
| Change from baseline in Symptoms questionnaire (SANDE) global score |  | at week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Schirmer I test (without anesthesia) |  | At weeks 4, 8, 12 and 16 | 
| Change from baseline in Cornea and conjunctiva vital staining with fluorescein(National Eye Institute [NEI] scales) |  | At weeks 4, 8, 12 and 16 | 
| Change from baseline in Tear Film Break-Up Time (TFBUT) |  | At weeks 4, 8, 12 and 16 | 
| Change from baseline in Symptoms questionnaire (SANDE) scores for severity and frequency |  | At weeks 8, 12 and 16 | 
| Number of patients experienced a worsening in symptom scores (SANDE) and/or NEI score ≥ 50% |  | At week 4 | 
| Quality of life (IDEEL) questionnaire |  | At weeks 4, 8, 12 and 16 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sjorgen's dry eye