Mycotic Antimicrobial Localized Injection for Treatment of Corneal Ulcers

Study Overview
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Brief Summary
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Mycotic Antimicrobial Localized Injection (MALIN) is a randomized, masked, two-arm clinical trial investigating intrastromal voriconazole in the treatment of fungal corneal ulcers. There is currently little evidence to guide the treatment of fungal keratitis beyond topical anti-fungal drops, though intrastromal voriconazole and oral antifungal treatments are used as well. This study will provide evidence to guide the treatment of fungal keratitis in the future. The purpose of this study is to determine differences in microbiological cure for 3-day repeat cultures between different antifungal treatments. For this study, there will be 1:1 randomization to one of these two treatment groups: 1) topical natamycin plus intrastromal voriconazole injection or 2) topical natamycin alone.

Detailed Description
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The proposed study is a randomized controlled trial to determine whether intrastromal voriconazole improves outcomes in fungal keratitis. Patients presenting to the Aravind Eye Hospitals in Pondicherry, India for treatment of fungal keratitis will be recruited for the proposed study. Approximately 70 patients will be enrolled in the study. Subjects presenting with fungal keratitis will be randomized to receive topical natamycin plus intrastromal voriconazole or to receive topical natamycin alone. Subjects may also receive oral antifungals after day 3 at the discretion of the treating clinician. All study subjects will be followed for 3 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 will 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.

Conditions
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Corneal Ulcer, Fungal Keratitis

Intervention / Treatment
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* Drug: Intrastromal voriconazole
* Drug: Natamycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Moderate to severe corneal ulcer that is smear positive for filamentous fungus Pinhole visual acuity worse than 20/70 in affected eye Basic understanding of the study as determined by the physician Commitment to return for follow up visits Exclusion Criteria: Gram stain positive for bacteria or evidence of other concomitant infection (i.e. herpes, acanthamoeba) 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 Pregnant women Participants who are decisionally and/or cognitively impaired

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intrastromal voriconazole plus natamycin<br>Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis | Drug: Intrastromal voriconazole<br>* Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis.<br>Drug: Natamycin<br>* Subjects will receive topical 5% natamycin drops hourly for 3 days.<br>|
| Active Comparator: Natamycin alone<br>Standard of care topical treatment for fungal keratitis | Drug: Natamycin<br>* Subjects will receive topical 5% natamycin drops hourly for 3 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Culture Positivity at Day 3 Using Potassium Hydroxide (KOH) Wet Mount to Test for Fungus | Number of of participants with positive fungal cultures at 3 days | 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist | Best spectacle-corrected visual acuity using calibrated Original Series Early Treatment Diabetic Retinopathy Study eye charts and recorded as number of letter read. | 3 weeks and 3 months | 
| Scar Size | Scar size, geometric mean | 3 weeks and 3 months | 
| Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | Number of participants with scar depth at the anterior third (0-33% depth), middle third (>33-67% depth), and posterior third (>67-100% depth) of the cornea, as measured on slit lamp exam. | 3 weeks and 3 months | 
| Corneal Thinning, as Measured by Pachymetry and OCT |  | 6 months | 
| Corneal Topography, as Measured by a Non-contact Imaging Topographer |  | 6 months | 
| Change in Quality of Life, Measured by the Indian Vision Function Questionnaire (IND-VFQ) |  | 3 months | 
| Corneal Neovascularization |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cornea, ulcer, fungal, keratitis