An 8-week Study to Evaluate Safety and Efficacy of NGF Eye Drops Solution Versus Vehicle in Patients With Dry Eye

Study Overview
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Brief Summary
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The primary objective of this study was to assess the efficacy and safety of rhNGF when administered as eye drops to patients with dry eye The secondary objectives of this study were: To assess change from baseline in Symptom Assessment In Dry Eye (SANDE) scores (without imputation), corneal and conjunctival staining according to National Eye Institute (NEI) scale, and in Tear Film Break-up Time (TFBUT) and Schirmer test I, following 4 and 8 weeks of treatment. To assess change in levels of inflammatory biomarker matrix metallopeptidase 9 (MMP-9) in tears following 8 weeks of treatment. To assess the incidence and frequency of treatment-emergent adverse events (TEAEs) following 8 weeks of treatment.

Detailed Description
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The proposed phase II study is a single-center, randomized, double-masked, parallel-arm, vehicle-controlled trial, designed to evaluate the safety and efficacy of Recombinant Human Nerve Growth Factor (rhNGF) eye drops at 20 μg/ml concentration administered six times daily for 8 weeks in patients with dry eye. After confirmation of inclusion and exclusion criteria all eligible patients will be randomized at 2:1 ratio to rhNGF or vehicle control treatment with 8 weeks of study treatments administration with 4 weeks Follow-up.

Official Title
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An 8-week, Phase II, Single-center, Randomized, Double-masked, Vehicle-controlled, Parallel-group Study With 4 Weeks of Follow-up to Evaluate Safety and Efficacy of rhNGF Eye Drops Solution vs Vehicle in Patients With Dry Eye

Conditions
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Dry Eye

Intervention / Treatment
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* Drug: NGF
* Other: Vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients (male or female) must be ≥ 18 years of age. Patients must be diagnosed with any type of dry eye (e.g. Meibomian Gland Dysfunction, Blepharitis, Keratoconjunctivitis sicca etc) at least 3 months before enrollment. Patients must present dry eye pathology characterized by the following clinical features: Corneal and/or conjunctival staining with fluorescein and lissamine green using National Eye Institute (NEI) grading system > 3 Mean Symptom Assessment in Dry Eye (SANDE) questionnaire ≥30 Schirmer test without anesthesia < 10 mm/5 minutes and/or tear film break-up time (TFBUT) < 10 seconds in the study eye The same eye (study eye) must fulfill all the above criteria. Patients must have best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes at the time of study enrollment. Female patients must have negative pregnancy test if at childbirth potential. Only patients who satisfy all requirements for informed consent may be included in the study. Written Informed Consent must be obtained before the initiation of any study specific procedures. Patients must have the ability and willingness to comply with study procedures. Exclusion Criteria: Best corrected distance visual acuity (BCDVA) score of < 0.1 decimal units in either eye. Evidence of an active ocular infection in either eye. Presence or history of any ocular disorder or condition, including ocular surgery, trauma, or disease that could possibly interfere with the interpretation of study results in the opinion of the Investigator. Intraocular inflammation defined as Tyndall score >0. Active or recent diagnosis of malignancy (i.e., currently under chemo/radiotherapy). Systemic disease not stabilized within 1 month before baseline visit (e.g., uncontrolled diabetes; 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. Patients who have 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 containing carboxymethylcellulose (CMC) (in the opinion of the Investigator). Use of topical cyclosporine, topical corticosteroids, or any other topical medication for the treatment of dry eye in either eye until the day of study enrollment. Contact lenses or punctal plug use during the study (previous use not an exclusion criteria, but must be discontinued at the baseline visit. An anticipated need of additional systemic treatments for dry eye during the study (all prior treatment must be continued for the entire duration of the study). 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 0) 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, 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 a intrauterine device (IUD) - during the entire course of and 30 days after the study treatment periods. History of drug addiction or alcohol abuse. 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 30 days. Participation in another clinical trial study at the same time as the present study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhNGF 20μg/mL<br>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily | Drug: NGF<br>* Eye Drop 20 μg/mL<br>* Other names: cenegermin;|
| Placebo Comparator: Vehicle<br>vehicle eye drops six times daily | Other: Vehicle<br>* Vehicle Eye Drop<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom Assessment in Dry Eye (SANDE) Scores | Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts. 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. | week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SANDE Scores | Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts. 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. | Week 4, week 8, week 12 | 
| Cornea Vital Staining | Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva was 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 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector. | week 4, week 8, week 12 | 
| Conjunctival Vital Staining | Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15. Both nasally and temporally, the conjunctiva was 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 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector. | week 4, week 8, week 12 | 
| Change in Tear Film Break-up Time (TFBUT) | TFBUT was measured by determining the time to tear break-up. The TFBUT was 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 was instructed to blink several times to thoroughly mix the fluorescein with the tear film. | week 4, week 8, week 12 | 
| Change From Baseline in Wetting Distance | The Schirmer test without anesthesia was performed to measure aqueous tear secretion prior to the instillation of any dilating or eye drops | week 8 |