Cross-linking for Corneal Ulcers Treatment Trial

Study Overview
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Brief Summary
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The primary purpose of this study is to determine if patients randomized to corneal collagen cross-linking plus medical therapy will have a lower prevalence of positive bacterial or fungal cultures immediately after the procedure than patients who received medical therapy alone. The secondary purpose of this study is to determine if patients randomized to corneal collagen cross-linking will have a better visual acuity at 3 and 12 months than patients who receive medical therapy alone.

Detailed Description
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The proposed study is a randomized controlled trial to determine whether collagen cross-linking improves outcomes in microbial keratitis. Patients presenting to the Aravind Eye Hospitals in Madurai, India for treatment of microbial keratitis will be recruited for the proposed study. Approximately 266 patients will be enrolled in the study. Subjects presenting with bacterial keratitis will be randomized to receive medical therapy plus corneal collagen cross-linking at presentation or to receive medical therapy alone. All subjects with bacterial ulcers will receive standard topical antibiotic medications as required after the procedure. Subjects with fungal keratitis will be randomized into one of four groups: collagen cross-linking + amphotericin; collagen cross-linking + natamycin; amphotericin alone; natamycin alone. All study subjects will be followed for 12 months to evaluate response to treatment. Investigators from the University of California, San Francisco (UCSF) will assist Aravind Eye Hospital with the study design, implementation, and analysis of the research, and will help fund the study. The investigators plan to visit Aravind to help with the study implementation. UCSF will play an important role in this study by assisting with the study design, implementation, analysis, and funding.

Official Title
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Cross-linking for Corneal Ulcers Treatment Trial

Conditions
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Corneal Ulcer, Infectious Keratitis, Bacterial Ulcer, Fungal Ulcer

Intervention / Treatment
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* Procedure: Bacterial ulcer cross-linking
* Procedure: Bacterial ulcer control
* Procedure: Fungal ulcer cross-linking
* Procedure: Fungal ulcer control


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Corneal ulcer that is smear positive for either bacteria or filamentous fungus Pinhole visual acuity worse than 20/70 in the affected eye Not treated already with antimicrobial medications at presentation 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 or gram stain (i.e. herpes, both bacteria and acanthamoeba 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 No light perception in the affected eye Pinhole visual acuity worse than 20/200 in the unaffected eye Participants who are decisionally and/or cognitively impaired

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bacterial ulcer cross-linking<br>Standard of care topical treatment for bacterial ulcer plus cross-linking | Procedure: Bacterial ulcer cross-linking<br>* For those subjects randomized to receive collagen cross-linking, the procedure will be performed as per the routine at the hospital (UV-X machine; strict aseptic precautions; corneal epithelium debrided and 0.1% riboflavin applied for 30 minutes, then UV-A radiation applied for 30 minutes at 370nm with 3mW/cm2). Corneal cross-linking is a routine procedure performed by Aravind Eye Hospital for infectious keratitis.<br>|
| Active Comparator: Bacterial ulcer control<br>Standard of care topical treatment for bacterial ulcer | Procedure: Bacterial ulcer control<br>* For those bacterial ulcer subjects randomized to the control group, they will receive the standard of care topical treatment for bacterial ulcers. This group will have their eyes irrigated with a balanced salt solution.<br>|
| Experimental: Fungal ulcer cross-linking plus natamycin<br>Standard of care topical treatment for fungal ulcer with natamycin plus cross-linking | Procedure: Fungal ulcer cross-linking<br>* Prior to receiving cross-linking, topical amphotericin B or topical natamycin antifungal therapy will be started as per routine at the hospital; a loading dose of amphotericin B or natamycin every 5 minutes x 6 will be followed by dosing every 30 minutes. Amphotericin B and natamycin are routinely used therapies for fungal keratitis at Aravind Eye Hospital. For those subjects randomized to receive collagen cross-linking, the procedure will be performed as per the routine at the hospital (UV-X machine; strict aseptic precautions; corneal epithelium debrided and 0.1% riboflavin applied for 30 minutes, then UV-A radiation applied for 30 minutes at 370nm with 3mW/cm2). Corneal cross-linking is a routine procedure performed by Aravind Eye Hospital for infectious keratitis.<br>|
| Active Comparator: Fungal ulcer control with natamycin<br>Standard of care topical treatment for fungal ulcer with natamycin | Procedure: Fungal ulcer control<br>* Prior to receiving sham cross-linking, topical amphotericin B or topical natamycin antifungal therapy will be started as per routine at the hospital; a loading dose of amphotericin B or natamycin every 5 minutes x 6 will be followed by dosing every 30 minutes. Amphotericin B and natamycin are routinely used therapies for fungal keratitis at Aravind Eye Hospital. For those fungal ulcer subjects randomized to the control group, they will receive the standard of care topical treatment for fungal ulcers. This group will have their eyes irrigated with a balanced salt solution.<br>|
| Experimental: Fungal ulcer cross-linking plus amphotericin<br>Standard of care topical treatment for fungal ulcer with amphotericin plus cross-linking | Procedure: Fungal ulcer cross-linking<br>* Prior to receiving cross-linking, topical amphotericin B or topical natamycin antifungal therapy will be started as per routine at the hospital; a loading dose of amphotericin B or natamycin every 5 minutes x 6 will be followed by dosing every 30 minutes. Amphotericin B and natamycin are routinely used therapies for fungal keratitis at Aravind Eye Hospital. For those subjects randomized to receive collagen cross-linking, the procedure will be performed as per the routine at the hospital (UV-X machine; strict aseptic precautions; corneal epithelium debrided and 0.1% riboflavin applied for 30 minutes, then UV-A radiation applied for 30 minutes at 370nm with 3mW/cm2). Corneal cross-linking is a routine procedure performed by Aravind Eye Hospital for infectious keratitis.<br>|
| Active Comparator: Fungal ulcer control with amphotericin<br>Standard of care topical treatment for fungal ulcer with amphotericin | Procedure: Fungal ulcer control<br>* Prior to receiving sham cross-linking, topical amphotericin B or topical natamycin antifungal therapy will be started as per routine at the hospital; a loading dose of amphotericin B or natamycin every 5 minutes x 6 will be followed by dosing every 30 minutes. Amphotericin B and natamycin are routinely used therapies for fungal keratitis at Aravind Eye Hospital. For those fungal ulcer subjects randomized to the control group, they will receive the standard of care topical treatment for fungal ulcers. This group will have their eyes irrigated with a balanced salt solution.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiological cure on repeat culture |  | 4 to 24 hours after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best spectacle-corrected visual acuity |  | 12 months | 
| Scar size | Measured by clinical exam | 12 months | 
| Adverse events including rate of perforation/need for therapeutic penetrating keratoplasty |  | 12 months | 
| Corneal thinning | As measured on Pentacam | 12 months | 
| Topography | As measured on Pentacam | 12 months | 
| Corneal Higher Order Aberrations | As measured on Pentacam | 12 months | 
| Vision related quality of life | As measured by the Indian Visual Function Questionnaire | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infectious keratitis, Cornea, Ulcer, Bacterial, Fungal