Targeting Reactive Oxygen Species Production as a Novel Therapeutic in Fuch's Endothelial Corneal Dystrophy

Study Overview
=================
Brief Summary
-----------------
This protocol will investigate whether topical application of N-acetyl cysteine (NAC) eye drops decreases oxidative stress and confers cytoprotection in patients with FECD.

Detailed Description
-----------------
Fuchs Endothelial Corneal Dystrophy (FECD) is the most common corneal endothelial disorder and has been estimated to affect approximately 4% of the US population over the age of 40. Corneal transplantation is currently the primary treatment modality available to treat FECD, and there are no medical therapies that treat the disease or stall its progression. Therefore, there is an unmet need to identify pharmacotherapeutic interventions that would prevent the endothelial cell loss in early through late stages of FECD, as well as after corneal transplantation, aiding in the survival of the corneal grafts. The investigators know that cell loss in FECD is caused by increased oxidative stress in the CEC and aqueous humor of FECD. The investigators have in vitro and in vivo data showing that the processes involved in the development of FECD can be arrested with administration of N-acetyl cysteine (NAC). Currently topical solutions of NAC are already used in ophthalmology for application in keratoconjunctivitis sicca (using 20% weight/volume solution or 10%), meibomian gland dysfunction (using 5%) and Sjögren's dry eye syndrome (also using 5%). This is a single center, double-blind, placebo-controlled, randomized trial. Adult participants with advanced FECD and cataracts who qualify for the standard treatment (combined Descemet Membrane Endothelial Keratoplasty (DMEK) and cataract surgery) will be enrolled at Massachusetts Eye and Ear. After meeting eligibility criteria and completing informed consent, 30 eyes from up to 30 participants with advanced FECD and cataracts with indication for combined DMEK and cataract surgery will be initially enrolled. (NOTE: Some participants may be enrolled twice if they elect to have both eyes treated within the study.) Eyes will be randomized 1:1 to NAC 10% and the placebo, Visine Tears Dry Eye Relief artificial tears ophthalmic solution. Each participant will self-administer 1 drop of study drug four times a day in the planned operative eye for 28 days prior to planned surgery. After interim analysis of the study with 30 eyes, if a significant difference in the primary endpoint between NAC 10% and placebo is not found, an additional 15 eyes from up to 15 participants will be enrolled and assigned to 20% NAC. Prior to and after using the study medication, participants will complete patient-reported visual disability questionnaires and have corneal measurements and images taken. Participants additionally will complete a tolerability and medication adherence questionnaire after using the study medication. In the operating room, a standard incision will be made to collect the fluid from the anterior part of the eye and replaced with a salt solution or viscous agent routinely used during the surgery. This procedure is routinely performed during this type of surgery, however, some of the aqueous fluid will be collected and analyzed rather than being discarded. Additionally, corneal tissue which is normally removed during corneal transplantation surgery and discarded will be kept for further research on FECD.

Official Title
-----------------
Targeting Reactive Oxygen Species Production as a Novel Therapeutic in Fuch's Endothelial Corneal Dystrophy

Conditions
-----------------
Fuchs Endothelial Corneal Dystrophy

Intervention / Treatment
-----------------
* Drug: N-acetyl cysteine (NAC) 10% solution
* Drug: N-acetyl cysteine (NAC) 20% solution
* Drug: Visine Dry Eye Relief eye drops


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female ≥21 years of age at time of surgical evaluation. Diagnosis of advanced FECD and visually significant cataract Indication for DMEK (Descemet Membrane Endothelial Keratoplasty) with concurrent cataract surgery Written informed consent obtained from subject and ability for subject to comply with the requirements of the study. Willingness and ability to adhere to medication regimen Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. History of prior intraocular surgery in study eye including cataract, glaucoma and/or retina surgery History of other corneal diseases, such as severe dry eye, corneal scars, pseudophakic bullous keratopathy, corneal degenerations, corneal infections Use of ocular prescription medications except for lubricants, hyperosmotic agents, or ocular hypotensive agents History of ocular surface infection within the past 30 days Use of systemic, inhalational, or topical N-Acetylcysteine within the past 30 days History of intolerance to topical N-Acetylcysteine Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. -

Ages Eligible for Study
-----------------
Minimum Age: 21 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: Initially, 30 eyes from up to 30 participants will be randomized 1:1 to one of two groups, a group administering N-acetyl cysteine (NAC) 10% and a group administering Visine Tears Dry Eye Relief artificial tears ophthalmic solution (the placebo). After interim analysis of the study with 30 eyes, if a significant difference in the primary endpoint between NAC 10% and placebo is not found, an additional 15 eyes from up to 15 participants will be enrolled to investigate 20% NAC.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NAC 10% group<br>Subjects in this group will be treated with eye drops containing a 10% solution of N-acetyl cysteine. Topical NAC is a well-tolerated medication that has many applications in ophthalmology including dry eye disease and meibomian gland dysfunction. | Drug: N-acetyl cysteine (NAC) 10% solution<br>* N-acetyl cysteine is a sterile, unpreserved eye drop containing 10% (100 mg/mL) of acetylcysteine.<br>* Other names: acetylcysteine;|
| Active Comparator: NAC 20% group<br>Subjects in this group will be treated with eye drops containing a 20% solution of N-acetyl cysteine. Topical NAC is a well-tolerated medication that has many applications in ophthalmology including dry eye disease and meibomian gland dysfunction. | Drug: N-acetyl cysteine (NAC) 20% solution<br>* N-acetyl cysteine is a sterile, unpreserved eye drop containing 20% (200 mg/mL) of acetylcysteine.<br>* Other names: acetylcysteine;|
| Placebo Comparator: Placebo group<br>Subjects in this group will be treated with a placebo (Visine Tears Dry Eye Relief artificial tears ophthalmic solution.) | Drug: Visine Dry Eye Relief eye drops<br>* Visine Tears Dry Eye Relief artificial tears ophthalmic solution<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of H2O2 in the aqueous humor | The primary endpoint is the level of H2O2 in the aqueous humor obtained at time of DMEK surgery. | DMEK Surgery occurs 28 to 42 days after participant enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of safety of NAC eye drops in patients with FECD by documenting the number and severity of adverse events. | Safety assessment will be ongoing for the entire 28 days that study participants take study drug (prior to surgery) and in all post surgical follow-up visits. Assessment will be based on the number and severity of adverse events, with specific scrutiny for evidence of severe ocular adverse reactions such as ocular chemosis, severe injection, presence or worsening of corneal epithelial staining and/or epithelial defects. | Ongoing safety assessment will occur starting on the first day when subjects receive the study drug, through the pre-operative visit, surgery and post-surgical follow-up visits, a period of approximately 6-7 weeks. | 
| Assessment of tolerability of N-acetyl cysteine drops in patients with FECD by documenting participants' reports of irritation, burning, itchiness or redness in their eyes while taking the study drug | Participants will be asked to fill out a tolerability and medication adherence questionnaire where they will rate the irritation, burning, itchiness and redness they experience after using the medication on a scale of 1 to 100. | Tolerability will be assessed after participants have taken study drug for 28 days or earlier, if the participants report difficulties tolerating the drug. | 
| Change in patient-reported visual disability after NAC administration | Change in patient-reported visual disability will be obtained using the previously validated questionnaire, V-FUCHS instrument 10 before and after the study drug is administered. Participants will be asked how often they experience specific visual difficulties selecting from the following choices: never, rarely, sometimes, most of the time or all of the time. Participants will also be asked how much difficulty they have performing certain visual tasks. Options for the answers are: No difficulty, a little difficulty, moderate difficulty, a lot of difficulty or extreme difficulty. | Assessed when subject starts study drug and again, 21 to 28 days later. | 
| Change in central corneal thickness after NAC administration | Change in central corneal thickness as measured by CCT; decrease by >30 µm before and after NAC drop administration period. | Assessed when subject starts study drug and again, 21 to 28 days later. | 
| Change in corneal endothelial cell counts after NAC administration | Change in the number of corneal endothelial cells as determined by HRT3 with Rostock Corneal Module (Heidelberg Engineering, Heidelberg, Germany) before and after NAC drop administration period. If central counts are unattainable due to end-stage of FECD, then peripheral counts will be obtained. | Assessed when subject starts study drug and again, 21 to 28 days later. | 
| Changes in corneal tomography after NAC administration | Corneal tomography is a three-dimensional imaging technique that characterizes the anterior/posterior corneal surfaces. Participants will have corneal tomography twice: first before they start the study drug, and then again, 28 to 42 days later when the drug treatment has concluded. Change in corneal tomography imaging will be assessed qualitatively. | Assessed when subject starts study drug and again, 21 to 28 days later. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
DMEK, Fuchs, Fuchs Endothelial Corneal Dystrophy, oxidative stress, N-Acetylcysteine ophthalmic drops, Descemet Membrane Endothelial Keratoplasty