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

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 (DED) who are under chronic treatment with topical Cyclosporine A (CsA).

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 CsA and commercially available preservative free artificial tears provided by Sponsor for a period of 7 days and 9 days. At the end of the washout 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. In addition to topical CsA eye drops (both groups will continue 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 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 Cenegermin (Oxervate®) 20 mcg/mL Ophthalmic Solution Versus Vehicle, in Patients With Severe Sjogren's Dry Eye Disease Under Treatment With Cyclosporine A (PROTEGO-2 Study).

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female aged ≥ 18 years Patients with a confirmed diagnosis of Sjogren syndrome or other autoimmune disease known to induce Sjogren's DED. Patients with severe Sjogren's DED characterized by the following clinical features: Corneal and/or conjunctival staining with fluorescein using National Eye Institute (NEI) grading system ≥3 Symptom assessment in dry eye (SANDE) questionnaire global score >25 mm Schirmer test I (without anaesthesia) between 2 and 5mm/5min, inclusive The same eye (eligible eye) must fulfill all the above criteria Diagnosis of severe Sjogren's DED at least 3 months before enrolment (current use or recommended use of artificial tears for the treatment of Sjogren's related dry eye) 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 with childbearing potential, have a negative pregnancy test Patients who have given written informed consent before any study-related procedures not part of standard medical care are performed. Patients must have the ability and willingness to comply with study procedures. 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: 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 due to dry eye (DE) 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 with a history of serious adverse reaction or significant hypersensitivity to any drug or chemically related compounds or clinically significant allergy to 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 postmenopausal 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 period 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 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 googles, 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 within the last year 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 prior of screening 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
Interventional Model Description: multicenter, double-masked, vehicle-controlled study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxervate<br>Oxervate®, an ophthalmic solution containing cenegermin 20 mcg/mL, which is a recombinant human Nerve Growth Factor (rhNGF). in this arm one drop of cenegermin 20 mcg/mL will be instilled in both eyes TID for 28 consecutive days. | Drug: Oxervate<br>* One drop of the test product will be instilled in both eyes TID<br>* Other names: Cenegermin;|
| Placebo Comparator: Vehicle<br>In this arm one drop of vehicle will be instilled in both eyes TID for 28 consecutive days. | Other: Vehicle<br>* One drop of the placebo will be instilled in both eyes TID<br>* Other names: Placebo;|

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 | The Schirmer test is used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye. Without previously instilling anesthetic drops, the Schirmer strip is inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. The patients will be instructed to close their eyes gently. After 5 minutes have elapsed, the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured (millimeters/5 minutes) Cutoff values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion | at week 4 | 
| Change from baseline in SANDE global score | The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both the severity and frequency of symptoms. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms. | At week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Schirmer I test (without anesthesia) | The Schirmer test is used in ophthalmic examination to measure tear production for the diagnosis of conditions such as keratoconjunctivitis sicca and dry eye. Without previously instilling anesthetic drops, the Schirmer strip is inserted into the lower conjunctival sac at the junction of the lateral and middle thirds, avoiding touching the cornea, and the length of wetting strips in millimeters is recorded after 5 minutes. The patients will be instructed to close their eyes gently. After 5 minutes have elapsed, the Schirmer test strip will be removed and the length of the tear absorption on the strip will be measured (millimeters/5 minutes) Cutoff values: <5 mm - pathologic dry eye 5-10 mm - marginal dry eye >10 and <30 mm - normal secretion | At weeks 4, 8, 12 and 16 | 
| Change from baseline in Cornea and conjunctiva vital staining with fluorescein (National Eye Institute [NEI] scales | The NEI/Industry Workshop guidelines are used for grading the scale of corneal and conjunctival damage. The cornea is divided into five sectors (central, superior, inferior, nasal and temporal), each of which is scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva is divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18). Briefly, grade 0 reflects normal/healthy situation, whereas grade 3 reflects a severe damage in the considered sector. | At weeks 4, 8, 12 and 16 | 
| Change from baseline in Tear Film Break-Up Time (TFBUT) | Tear film break-up time (TFBUT) is the time taken to appear first dry spot on cornea after a complete blinking. TFBUT measurement is an easy and fast method used to assess the stability of tear film. It is a standard diagnostic procedure in the dry eye clinics. TFBUT is measured by determining the time to tear break-up. The TFBUT is performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient is instructed to blink several times to thoroughly mix the fluorescein with the tear film. A TFBUT greater than 15 seconds is considered normal, while a break time of less than 10 seconds is to be considered pathological. | At weeks 4, 8, 12 and 16 | 
| Change from baseline in SANDE scores for severity and frequency | The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both the severity and frequency of symptoms. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms. | At weeks 8, 12 and 16 | 
| Number of patients experiencing a worsening in SANDE and/or NEI score ≥ 50% | The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale (VAS). The patient symptoms of ocular dryness and/or irritation were quantified on the scale based on two questions that assessed both the severity and frequency of symptoms. The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms. | At week 4 | 
| Quality of life (IDEEL) questionnaire | IDEEL assesses quality of life, symptoms and treatment effects on patients with dry eye. The IDEEL contains 3 modules (Daily Activities, Treatment Satisfaction, and Symptom Bother) with a total of 57 questions. The Daily Activities Module is the quality of life instrument. It is comprised of 27 items. The IDEEL Treatment Satisfaction and Bother Module is divided into 2 sections, Treatment - In General and Treatment - Eye Drops. The Symptom Bother Module consists of 20 items in a single content domain, Symptom Bother. Scores for each dimensions ranged from 0 to 100. Higher scores for: dimension of the Dry Eye Impact on Daily Life module indicates less impact on daily activities; symptom-bother dimension indicates greater bother due to symptoms; satisfaction with Treatment Effectiveness dimension indicates greater satisfaction with treatment effectiveness; treatment-related bother/inconvenience indicates less treatment-related bother or inconvenience. | At weeks 4, 8, 12 and 16 | 
| Incidence and frequency of Adverse Events (AEs) and Treatment-emergent adverse events (TEAEs), | An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment emergent adverse events (TEAE) are undesirable events not present prior to medical treatment, or an already present event that worsens either in intensity or frequency following the treatment. | From Screening day ( Day 8) up to Follow-up week 24 (day 168 +/-7days) | 

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