The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo

Study Overview
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Brief Summary
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The purpose of this study is to determine if the addition of oral voriconazole to topical treatment regimens results in lower rates of perforation in severe fungal corneal ulcers.

Detailed Description
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Fungal corneal ulcers tend to have very poor outcomes with commonly used treatments. There has only been a single randomized trial of anti-fungal therapy for mycotic keratitis, and no new ocular anti-fungal medications have been approved by the FDA since the 1960s. The triazole voriconazole has recently become the treatment of choice for systemic fungal infections such as pulmonary aspergillosis. The use of topical ophthalmic preparations of voriconazole has been described in numerous case reports, however there has been no systematic attempt to determine whether it is more or less clinically effective than natamycin. Additionally, there have been many case reports of the use of oral voriconazole in the treatment of fungal corneal ulcers, however there has been no systematic attempt to determine if it improves outcomes in severe ulcers. This study is a randomized, double-masked, placebo-controlled trial to determine if the use of oral voriconazole in severe ulcers reduces the rate of perforations. 240 fungal corneal ulcers with baseline visual acuity worse than 6/120 presenting to the Aravind Eye Hospitals and the UCSF Proctor Foundation will be randomized to receive oral voriconazole plus topical voriconazole and topical natamycin, or oral placebo plus topical voriconazole and topical natamycin. The primary outcome is the rate of perforation over the three month follow-up period.

Official Title
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The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo

Conditions
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Corneal Ulcer, Eye Infections, Fungal

Intervention / Treatment
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* Drug: Voriconazole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of a corneal ulcer at presentation Evidence of filamentous fungus on smear (KOH wet mount, Giemsa, or Gram stain) Visual acuity worse than 6/120 (20/400, logMAR 1.3) The patient must be able to verbalize a basic understanding of the study after it is explained to the patient, as determined by physician examiner. This understanding must include a commitment to return for follow-up visits. Willingness to be treated as an inpatient or to be treated as an outpatient and return every 3 days +/- 1 day until re-epithelialization and every week to receive fresh medication for 3 weeks Appropriate consent Exclusion Criteria: Evidence of bacteria on Gram stain at the time of enrollment Evidence of acanthamoeba by stain Evidence of herpetic keratitis by history or exam Corneal scar not easily distinguishable from current ulcer Age less than 16 years (before 16th birthday) Bilateral ulcers Previous penetrating keratoplasty in the affected eye Pregnancy (by history or urine test) or breast feeding (by history) Known liver disease, including hepatitis or cirrhosis (Child-Pugh A-C) Acuity worse than 6/60 (2/200) in the fellow eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA 6/60 or better qualifies for enrollment) Acuity better than 6/120 (20/400) in the study eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA can be used for enrollment) Currently on rifampin, rifabutin, ritonavir, long acting barbiturates, phenytoin, carbamazepine, or other drugs known to interact with voriconazole Known allergy to study medications (antifungal or preservative) No light perception in the affected eye Not willing to participate

Ages Eligible for Study
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Minimum Age: 16 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral Voriconazole<br> | Drug: Voriconazole<br>* 1% voriconazole (topical) plus 0.01% preservative, 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment. 5% natamycin (topical), 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment. 400 mg BID PO on study day one (loading dose), then 200 mg BID PO until 3 weeks from enrollment for patients weighing greater than 50 kg. For patients 40-50 kg, the loading dose is 300 mg BID PO on study day 1, then 150 mg BID PO until 3 weeks from enrollment. For patients weighing <40 kg, the loading dose is 200 mg BID PO, then 100 mg BID PO until 3 weeks after enrollment.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 1% voriconazole (topical) plus 0.01% preservative, 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment. 5% natamycin (topical), 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment. Two tablets BID PO on study day one, then one tablet BID PO until 3 weeks from enrollment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Perforation or Therapeutic Penetrating Keratoplasty | Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo | 3 months from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Spectacle-corrected logMAR Visual Acuity | Best spectacle-corrected logMAR visual acuity at 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear | 3 months after enrollment | 
| Best Spectacle-corrected logMAR Visual Acuity at 3-weeks | Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear | 3 weeks after enrollment | 
| Size of Infiltrate/Scar - 3 Months | Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate | 3 months after enrollment | 
| Size of Infiltrate/Scar | Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate | 3 weeks after enrollment | 
| Hazard Ratio for Re-epithelialization | Hazard Ratio of re-epithelialization comparing the treatment groups | Up to 21 days | 
| Microbiological Cure at 7 Days | Fungal Culture negative at 7 days post treatment | 7 days | 
| Number of Adverse Events | Comparing the number of serious and non-serious adverse events by treatment arm. | 3-months from enrollment | 
| Minimum Inhibitory Concentration of Isolates - Natamycin | Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm | 7 days | 
| Minimum Inhibitory Concentration of Isolates - Voriconazole | Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fungal Infections, Eye Disease, Fungal Keratitis, Visual Acuity