Steroids and Cross-linking for Ulcer Treatment

Study Overview
=================
Brief Summary
-----------------
Steroids and Cross-linking for Ulcer Treatment (SCUT II) is an international, randomized, double-masked, clinical trial. The purpose of this study is to determine differences in 6-month visual acuity between medical antimicrobial treatments alone versus antimicrobial treatment plus collagen cross-linking (CXL), as well as to further evaluate findings from subgroup analyses of SCUT. Patients presenting to the Aravind Eye Care System (India), Kaiser Permanente Northern California (USA), or the University of California, San Francisco (USA) with smear-positive and/or culture-positive typical (i.e. non-Nocardia or Mycobacteria) bacterial corneal ulcers and moderate to severe vision loss, defined as Snellen visual acuity of 20/40 or worse, will be eligible for inclusion. Those who agree to participate will be randomized to one of three treatment groups: Group 1: Standard therapy, topical 0.5% moxifloxacin plus topical placebo plus sham CXL Group 2: Early steroids, topical 0.5% moxifloxacin plus topical difluprednate 0.05% plus sham CXL Group 3: CXL plus early steroids, topical 0.5% moxifloxacin plus topical difluprednate 0.05% plus CXL

Official Title
-----------------
Steroids and Cross-linking for Ulcer Treatment

Conditions
-----------------
Keratitis Bacterial

Intervention / Treatment
-----------------
* Drug: Moxifloxacin Ophthalmic
* Drug: Difluprednate Ophthalmic
* Drug: Riboflavin Ophthalmic
* Other: Topical Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Corneal ulcer that is smear positive and/or culture positive (within 24 hours) for typical bacteria (i.e. non-Nocardia or Mycobacteria) Moderate to severe vision loss, defined as Snellen visual acuity of 20/40 (6/12) or worse Corneal thickness ≥350 µm, as measured on AS-OCT Age over 18 years Basic understanding of the study as determined by the physician Commitment to return for follow up visits Exclusion Criteria: Evidence of concomitant infection on exam, gram stain, or confocal microscopy (i.e. herpes, both bacteria and acanthameoba on gram stain) Impending or frank perforation at recruitment Involvement of sclera at presentation Non-infectious or autoimmune keratitis History of corneal transplantation or recent intraocular surgery Pinhole visual acuity worse than 20/200 in the unaffected eye Participants who are decisionally and/or cognitively impaired

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Standard Therapy<br>Participants in this arm will receive topical 0.5% moxifloxacin plus topical placebo plus sham corneal cross-linking. | Drug: Moxifloxacin Ophthalmic<br>* Topical moxifloxacin 0.5% is a fluoroquinolone antibiotic that is used to treat bacterial infections. This is standard therapy for bacterial keratitis. Immediately after CXL/sham CXL and repeat culture, all participants will receive topical moxifloxacin drops every 1 hour for 2 days, and then every 2 hours while awake until resolution of the epithelial defect.<br>Drug: Riboflavin Ophthalmic<br>* All participants will receive a 30 minute loading dose of topical 0.1% riboflavin and 20% dextran T500 drops every 2 minutes. For participants randomized to corneal cross-linking(CXL), this will be followed by exposure to UV-A light at a wavelength of 365 nm with an irradiance of 3 mW/cm2 for 30 minutes for a total dose of 5.4 J/cm2 (UV lamp: PESCHKE Meditrade GmbH, Hueneberg, Switzerland for India; Avedro KXL System, Waltham, MA, USA for USA). During irradiation patients will continue to receive topical riboflavin at 5-minute intervals. For those randomized to sham CXL, this experience is simulated however the light will be shined adjacent to the patient, careful to avoid exposure to the cornea.<br>* Other names: Corneal Cross-Linking with Riboflavin Ophthalmic;Other: Topical Placebo<br>* Participants randomized to topical placebo will receive topical placebo on the same medication schedule as difluprednate: one drop of 0.05% difluprednate four times daily beginning 24 hours after the initiation of antibiotics for 1 week, decreased by 1 drop weekly for a total of 4 weeks of placebo therapy. Placebo will be the vehicle used in difluprednate.<br>|
| Experimental: Early Steroids<br>Participants in this arm will receive topical 0.5% moxifloxacin plus topical steroids plus sham corneal cross-linking. | Drug: Moxifloxacin Ophthalmic<br>* Topical moxifloxacin 0.5% is a fluoroquinolone antibiotic that is used to treat bacterial infections. This is standard therapy for bacterial keratitis. Immediately after CXL/sham CXL and repeat culture, all participants will receive topical moxifloxacin drops every 1 hour for 2 days, and then every 2 hours while awake until resolution of the epithelial defect.<br>Drug: Difluprednate Ophthalmic<br>* Difluprednate 0.05% is a corticosteroid used to reduce inflammation in the eye. Participants will receive one drop of 0.05% difluprednate four times daily beginning 24 hours after the initiation of antibiotics for 1 week, decreased by 1 drop weekly for a total of 4 weeks of steroid therapy.<br>|
| Experimental: Cross-Linking plus Early Steroids<br>Participants in this group will receive topical 0.5% moxifloxacin plus topical steroids plus corneal cross-linking. | Drug: Moxifloxacin Ophthalmic<br>* Topical moxifloxacin 0.5% is a fluoroquinolone antibiotic that is used to treat bacterial infections. This is standard therapy for bacterial keratitis. Immediately after CXL/sham CXL and repeat culture, all participants will receive topical moxifloxacin drops every 1 hour for 2 days, and then every 2 hours while awake until resolution of the epithelial defect.<br>Drug: Difluprednate Ophthalmic<br>* Difluprednate 0.05% is a corticosteroid used to reduce inflammation in the eye. Participants will receive one drop of 0.05% difluprednate four times daily beginning 24 hours after the initiation of antibiotics for 1 week, decreased by 1 drop weekly for a total of 4 weeks of steroid therapy.<br>Drug: Riboflavin Ophthalmic<br>* All participants will receive a 30 minute loading dose of topical 0.1% riboflavin and 20% dextran T500 drops every 2 minutes. For participants randomized to corneal cross-linking(CXL), this will be followed by exposure to UV-A light at a wavelength of 365 nm with an irradiance of 3 mW/cm2 for 30 minutes for a total dose of 5.4 J/cm2 (UV lamp: PESCHKE Meditrade GmbH, Hueneberg, Switzerland for India; Avedro KXL System, Waltham, MA, USA for USA). During irradiation patients will continue to receive topical riboflavin at 5-minute intervals. For those randomized to sham CXL, this experience is simulated however the light will be shined adjacent to the patient, careful to avoid exposure to the cornea.<br>* Other names: Corneal Cross-Linking with Riboflavin Ophthalmic;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Spectacle-Corrected Visual Acuity | Best Spectacle-Corrected Visual Acuity | 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Spectacle-Corrected Visual Acuity | Best Spectacle-Corrected Visual Acuity | 3 Weeks, 3 Months, 12 Months | 
| Number of Ulcers Testing Positive for Bacteria on Repeat Culture | Microbiological cure on repeat culture: A scraping of the corneal ulcer taken at 48 hours, then swabbed onto a culture plate and assessed for bacteria | 2 Days | 
| Scar Size | Geometric Mean | 3 Weeks, 3 Months, 6 Months 12 Months | 
| Scar Depth | Geometric Mean | 3 Weeks, 3 Months, 6 Months, 12 Months | 
| Adverse Events | Adverse Events | 12 Months |