Assessing the Safety and Efficacy of AVX-012 in Subjects With Mild-to-moderate Dry Eye Syndrome

Study Overview
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Brief Summary
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This is a first-in-human phase I/II randomized, double-blind, placebo (vehicle)-controlled, multicenter study to assess the Safety and Efficacy of AVX-012 Ophthalmic Solution in subjects with Mild-to-Moderate Dry Eye Syndrome. The study consists of two parts (part A and part B):

Detailed Description
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The study part A will be an early safety assessment of AVX-012 ophthalmic solution (Low dose and High dose AVX-012) administered three times per day (TID) when compared with the vehicle (placebo). Approximately 24 patients will be randomized 1:1:1 to study groups (Low dose AVX-012, High dose AVX-012, or placebo [vehicle]). An independent safety committee will be in charge of assessing the safety of study treatments to proceed to part B. The study part B will be an efficacy and safety assessment of the dose of AVX-012 ophthalmic solution selected in the study part A (Low dose or High dose AVX-012) administered three times a day (TID) and twice a day (BID) when compared with the vehicle (placebo). Approximately 148 patients will be randomized 1:1:1:1 to study groups (Low dose or High dose AVX-012 and placebo [vehicle], TID and BID).

Official Title
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A Phase I/II, Double-blind, Placebo-controlled Study Assessing the Safety and Efficacy of AVX-012 Ophthalmic Solution in Subjects With Mild-to-moderate Dry Eye Syndrome

Conditions
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Dry Eye Syndrome

Intervention / Treatment
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* Drug: AVX012 Ophthalmic Solution Low dose
* Drug: AVX012 Ophthalmic Solution High dose
* Drug: Placebo (vehicle)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects of at least 18 years of age. Diagnosis of dry eye (by a health care professional) for at least 3 months prior to screening visit. Normal lid anatomy. Intraocular pressure less than 22 mmHg (inclusive) in each eye. Best-corrected visual acuity measured by ETDRS in each eye of 20/200 (logMAR 1.0) or better. Schirmer I test score of ≥ 3 mm to ≤ 9 mm/ 5 min (with anesthesia). SANDE symptom score of 50 or more. Total ocular staining of minimum 1 in Oxford scale with fluorescein and/or green lissamine. Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements. Exclusion Criteria: History of other than dry eye, ocular surface of moderate to severe Meibomian gland disease (grades +++ to ++++ [moderately to severely altered expressibility and secretion quality]: moderate symptoms with mild to moderate corneal staining, mainly peripheral; or marked symptoms with marked corneal staining, central in addition), chronic, or acute ophthalmic disease in either eye, including glaucoma, macular degeneration, clinically significant cataract (primary or secondary). Best-corrected visual acuity score of 55 letters read or lower in each eye as measured by ETDRS (letters read method). Previous history of drug or any ingredient hypersensitivity. Intraocular or strabismus surgery or glaucoma laser surgery within the previous 6 months. History of refractive surgery in either eye (e.g., radial keratotomy, PRK, LASIK, etc.). Ocular trauma within the past 6 months. Relevant ocular pathology judged by the investigator such as; eyelid anomalies, corneal disorders, metaplasia of the ocular surface, current filamentous keratitis, or corneal neovascularization. Any history of herpes simplex or herpes zoster keratitis. Ocular infection (bacterial, viral, or fungal) Ocular medication of any kind, with the exception of artificial tears/gels/lubricants within the past 2 weeks of screening. Cyclosporine treatment during the 6 months prior to enrolment. Use of systemic medication that might cause dryness in the eye as a secondary effect (such as antihistaminics, hormone replacing therapies, etc.). Use of contact lens Use of additional artificial tears (other than study treatments) throughout the study, starting at screening visit. Participation in an investigational drug or device trial within the 30 days previous to screening visit. Any abnormality preventing reliable applanation tonometry of either eye. Central corneal thickness greater than 600 μm by conventional pachymetry. Signs of severe ocular surface diseases including corneal or conjunctival staining judged as severe by the investigator. Clinically significant systemic disease including uncontrolled diabetes, myasthenia gravis, hepatic, renal, cardiovascular, endocrine disorders, previous cerebrovascular accident with a significant residual motor or sensory defect, progressive neurologic disorders (Parkinsonism, dementias, multiple sclerosis, unstable acquired seizure disorders) which might interfere with the study as judged by the investigator. Any systemic disease or medication that might course with known dryness in the eye. Changes of systemic medication that could have a substantial effect on intraocular pressure within 30 days prior to screening or anticipated during the study. Any medical condition (systemic or ophthalmic) that may, in the opinion of the investigator, preclude the safe administration of the investigational product or safe participation in this study. Pregnant or breastfeeding females or those with a positive pregnancy test. All females of childbearing potential must have a negative urine pregnancy test result at screening, and also agree to abstain from sexual intercourse with a male partner or agree to use a medically acceptable method of birth control (such as condom, diaphragm or cervical/vault cap with spermicide) until 28 days post-treatment. Males should also agree to abstain from sexual intercourse with a female partner or agree to use a condom with spermicide until 28 days post-treatment.

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
Interventional Model Description: Phase I: patient will be included on 3 arms of treatment ( Placebo, Low dose or High dose AVX-012) TID Phase II: Patient will be included on 4 arms of treatment (Placebo/Dose) BID/TID
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AVX-012 Opthalmic Solution Low dose<br>Phase I: AVX-012 ophthalmic solution Low dose administration three times per day (TID) for 7 days Phase II: If the low dose of AVX012 is selected on phase I, AVX-012 ophthalmic solution Low dose administration three times per day (TID) and two times per day (BID) for 28 days | Drug: AVX012 Ophthalmic Solution Low dose<br>* Ocular topical administration of AVX Ophthalmic Solution Low dose<br>|
| Experimental: AVX-012 Opthalmic Solution High dose<br>Phase I: AVX-012 ophthalmic solution High dose administration three times per day (TID) for 7 days Phase II: If the high dose of AVX012 is selected on phase I, AVX-012 ophthalmic solution High dose administration three times per day (TID) and two times per day (BID) for 28 days | Drug: AVX012 Ophthalmic Solution High dose<br>* Ocular topical administration of AVX Ophthalmic Solution High dose<br>|
| Placebo Comparator: Placebo (Vehicle) Opthalmic Solution<br>Phase I: Placebo ophthalmic solution administration three times per day (TID) for 7 days Phase II: Placebo ophthalmic solution administration three times per day (TID) and two times per day (BID) for 28 days | Drug: Placebo (vehicle)<br>* Ocular topical administration of placebo (vehicle Ophthalmic Solution)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The objective of part A is to evaluate the safety of AVX-012 ophthalmic solution in subjects with dry eye syndrome. | Evaluation of vital signs (blood pressure and heart rate), laboratory analyses (haematology, biochemistry, and urine pregnancy test), best-corrected visual acuity (ETDRS), corneal anaesthesia (Cochet-Bonnet), intraocular pressure, biomicroscopy/staining (fluorescein), and ophthalmoscopy (dilated). | 7 days (+1 day) | 
| The objective of part B is to evaluate the efficacy of AVX-012 ophthalmic solution in treating symptoms of dry eye. | Percentage of patients achieving an improvement ≥ 20 points in the Symptom Assessment in Dry Eye (SANDE) questionnaire according to the different dosing frequencies (TID and BID). | 28 days (+7 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirm the safety of AVX-012 ophthalmic solution in subjects with dry eye syndrome. | Percentage of patients with adverse events from baseline (treatment period and post-treatment safety follow-up) according to the different dosing frequencies (TID and BID). | 28 days (+7 days) | 
| Change from baseline in corneal staining score |  | 28 days (+7 days) | 
| Change from baseline in Schirmer I test score |  | 28 days (+7 days) | 
| Change from baseline in tear film break up time score |  | 28 days (+7 days) | 
| Change from baseline in conjunctival staining score |  | 28 days (+7 days) |