Steroids and Cross-linking for Ulcer Treatment (SCUT II)

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

Study Overview

• Status: Active, not recruiting
• Conditions: Keratitis Bacterial
• Intervention / Treatment: Drug: Moxifloxacin Ophthalmic; Drug: Riboflavin Ophthalmic; Other: Topical Placebo; Drug: Difluprednate Ophthalmic

• Study Type: Interventional
• Enrollment (Actual): 279
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Tom Lietman, MD; Phone Number: 415-502-2662; Email: tom.lietman@ucsf.edu
• Study Contact Backup: Name: Nicole Varnado, MPH; Email: nvarnado@stanford.edu

Study Locations

• India
  • Tamil Nadu
    • Madurai, Tamil Nadu, India
      • Aravind Eye Care System
• United States
  • California
    • San Francisco, California, United States, 94143
      • Francis I. Proctor Foundaiton
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Standard Therapy; Participants in this arm will receive topical 0.5% moxifloxacin plus topical placebo plus sham corneal cross-linking.	Drug: Moxifloxacin Ophthalmic; 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.; Drug: Riboflavin Ophthalmic; 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.; Other Names: Corneal Cross-Linking with Riboflavin Ophthalmic; Other: Topical Placebo; 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.
Experimental: Early Steroids; Participants in this arm will receive topical 0.5% moxifloxacin plus topical steroids plus sham corneal cross-linking.	Drug: Moxifloxacin Ophthalmic; 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.; Drug: Difluprednate Ophthalmic; 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.
Experimental: Cross-Linking plus Early Steroids; Participants in this group will receive topical 0.5% moxifloxacin plus topical steroids plus corneal cross-linking.	Drug: Moxifloxacin Ophthalmic; 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.; Drug: Riboflavin Ophthalmic; 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.; Other Names: Corneal Cross-Linking with Riboflavin Ophthalmic; Drug: Difluprednate Ophthalmic; 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.

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

Collaborators and Investigators

• Sponsor: Thomas M. Lietman
• Collaborators: University of Miami; National Eye Institute (NEI); Stanford University; Aravind Eye Care System
• Investigators: Principal Investigator: Jennifer Rose-Nussbaumer, MD, Stanford University; Study Director: Nicole Varnado, MPH, Stanford University; Principal Investigator: Tom Lietman, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Radhakrishnan N, Prajna VN, Prajna LS, Venugopal A, Narayana S, Rajaraman R, Amescua G, Porco TC, Lietman TM, Rose-Nussbaumer J. Double-masked, sham and placebo-controlled trial of corneal cross-linking and topical difluprednate in the treatment of bacterial keratitis: Steroids and Cross-linking for Ulcer Treatment Trial (SCUT II) study protocol. BMJ Open Ophthalmol. 2021 Nov 29;6(1):e000811. doi: 10.1136/bmjophth-2021-000811. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): September 24, 2020
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): November 30, 2024

Study Registration Dates

• First Submitted: September 12, 2019
• First Submitted That Met QC Criteria: September 18, 2019
• First Posted (Actual): September 20, 2019

Study Record Updates

• Last Update Posted (Estimated): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Corneal Diseases; Keratitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Photosensitizing Agents; Dermatologic Agents; Micronutrients; Anti-Bacterial Agents; Vitamins; Vitamin B Complex; Moxifloxacin; Riboflavin; Difluprednate
• Other Study ID Numbers: 18-26045; UG1EY028518 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No