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

Primary Purpose

Fuchs Endothelial Corneal Dystrophy

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
N-acetyl cysteine (NAC) 10% solution
N-acetyl cysteine (NAC) 20% solution
Visine Dry Eye Relief eye drops
Sponsored by
Massachusetts Eye and Ear Infirmary
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fuchs Endothelial Corneal Dystrophy focused on measuring Fuchs, Fuchs Endothelial Corneal Dystrophy, oxidative stress, N-Acetylcysteine ophthalmic drops, Descemet Membrane Endothelial Keratoplasty, DMEK

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male or female ≥21 years of age at time of surgical evaluation.
  2. Diagnosis of advanced FECD and visually significant cataract
  3. Indication for DMEK (Descemet Membrane Endothelial Keratoplasty) with concurrent cataract surgery
  4. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study.
  5. Willingness and ability to adhere to medication regimen

Exclusion Criteria:

  1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
  2. History of prior intraocular surgery in study eye including cataract, glaucoma and/or retina surgery
  3. History of other corneal diseases, such as severe dry eye, corneal scars, pseudophakic bullous keratopathy, corneal degenerations, corneal infections
  4. Use of ocular prescription medications except for lubricants, hyperosmotic agents, or ocular hypotensive agents
  5. History of ocular surface infection within the past 30 days
  6. Use of systemic, inhalational, or topical N-Acetylcysteine within the past 30 days
  7. History of intolerance to topical N-Acetylcysteine
  8. 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.

    -

Sites / Locations

  • Massachusetts Eye and Ear InfirmaryRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

NAC 10% group

NAC 20% group

Placebo group

Arm Description

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.

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.

Subjects in this group will be treated with a placebo (Visine Tears Dry Eye Relief artificial tears ophthalmic solution.)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.

Full Information

First Posted
June 11, 2020
Last Updated
January 25, 2023
Sponsor
Massachusetts Eye and Ear Infirmary
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1. Study Identification

Unique Protocol Identification Number
NCT04440280
Brief Title
Targeting Reactive Oxygen Species Production as a Novel Therapeutic in Fuch's Endothelial Corneal Dystrophy
Official Title
Targeting Reactive Oxygen Species Production as a Novel Therapeutic in Fuch's Endothelial Corneal Dystrophy
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 16, 2020 (Actual)
Primary Completion Date
May 1, 2024 (Anticipated)
Study Completion Date
April 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts Eye and Ear Infirmary

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fuchs Endothelial Corneal Dystrophy
Keywords
Fuchs, Fuchs Endothelial Corneal Dystrophy, oxidative stress, N-Acetylcysteine ophthalmic drops, Descemet Membrane Endothelial Keratoplasty, DMEK

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantInvestigator
Masking Description
This is a double-blind trial, where neither the study participant nor the investigators will know to which treatment group the study participant has been assigned.
Allocation
Randomized
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
NAC 10% group
Arm Type
Active Comparator
Arm Description
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.
Arm Title
NAC 20% group
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo group
Arm Type
Placebo Comparator
Arm Description
Subjects in this group will be treated with a placebo (Visine Tears Dry Eye Relief artificial tears ophthalmic solution.)
Intervention Type
Drug
Intervention Name(s)
N-acetyl cysteine (NAC) 10% solution
Other Intervention Name(s)
acetylcysteine
Intervention Description
N-acetyl cysteine is a sterile, unpreserved eye drop containing 10% (100 mg/mL) of acetylcysteine.
Intervention Type
Drug
Intervention Name(s)
N-acetyl cysteine (NAC) 20% solution
Other Intervention Name(s)
acetylcysteine
Intervention Description
N-acetyl cysteine is a sterile, unpreserved eye drop containing 20% (200 mg/mL) of acetylcysteine.
Intervention Type
Drug
Intervention Name(s)
Visine Dry Eye Relief eye drops
Intervention Description
Visine Tears Dry Eye Relief artificial tears ophthalmic solution
Primary Outcome Measure Information:
Title
Level of H2O2 in the aqueous humor
Description
The primary endpoint is the level of H2O2 in the aqueous humor obtained at time of DMEK surgery.
Time Frame
DMEK Surgery occurs 28 to 42 days after participant enrollment
Secondary Outcome Measure Information:
Title
Assessment of safety of NAC eye drops in patients with FECD by documenting the number and severity of adverse events.
Description
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.
Time Frame
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.
Title
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
Description
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.
Time Frame
Tolerability will be assessed after participants have taken study drug for 28 days or earlier, if the participants report difficulties tolerating the drug.
Title
Change in patient-reported visual disability after NAC administration
Description
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.
Time Frame
Assessed when subject starts study drug and again, 21 to 28 days later.
Title
Change in central corneal thickness after NAC administration
Description
Change in central corneal thickness as measured by CCT; decrease by >30 µm before and after NAC drop administration period.
Time Frame
Assessed when subject starts study drug and again, 21 to 28 days later.
Title
Change in corneal endothelial cell counts after NAC administration
Description
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.
Time Frame
Assessed when subject starts study drug and again, 21 to 28 days later.
Title
Changes in corneal tomography after NAC administration
Description
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.
Time Frame
Assessed when subject starts study drug and again, 21 to 28 days later.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
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. -
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kevin Ma, MD
Phone
6175737900
Email
kevin_ma@meei.harvard.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Stacey Ellender, PhD
Phone
857-231-1593
Email
stacey_ellender@meei.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ula Jurkunas, MD
Organizational Affiliation
Massachusetts Eye and Ear
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts Eye and Ear Infirmary
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stacey Ellender
Phone
857-231-1593
Email
stacey_ellender@meei.harvard.edu
First Name & Middle Initial & Last Name & Degree
Ula Jurkunas, MD
Phone
6175734330
Ext
Jurkunas
Email
Ula_Jurkunas@meei.harvard.edu
First Name & Middle Initial & Last Name & Degree
Ula Jurkunas, MD

12. IPD Sharing Statement

Learn more about this trial

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

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