Mycotic Ulcer Treatment Trial I

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if natamycin or voriconazole results in better visual outcomes in fungal corneal ulcers, especially visual acuity.

Detailed Description
-----------------
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 natamycin or voriconazole results in better outcomes for fungal corneal ulcers. 368 fungal corneal ulcers with baseline visual acuity between 6/12 (20/40, logMAR 0.3) and 6/120 (20/400, logMAR 1.3) presenting to the Aravind Eye Hospitals and the UCSF Proctor Foundation will be randomized to receive either topical natamycin or topical voriconazole. The primary outcome is best spectacle-corrected logMAR visual acuity three months after enrollment, using best spectacle-corrected enrollment visual acuity as a co-variate.

Official Title
-----------------
Mycotic Ulcer Treatment Trial

Conditions
-----------------
Corneal Ulcer, Eye Infections, Fungal

Intervention / Treatment
-----------------
* Drug: Natamycin
* Drug: Voriconazole


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Presence of a corneal ulcer at presentation Evidence of filamentous fungus on smear (KOH wet mount, Giemsa, or Gram stain) Visual acuity between 6/12 (20/40, logMAR 0.3) and 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: Impending perforation 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) 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 worse than 6/120 (20/400) or better than 6/12 (20/40) in the study eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA can be used for enrollment) Known allergy to study medications (antifungal or preservative) No light perception in the affected eye Not willing to participate

Ages Eligible for Study
-----------------
Minimum Age: 16 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 |
| --- | --- |
| Active Comparator: Topical Natamycin<br> | Drug: Natamycin<br>* 5% natamycin plus 0.02% preservative, one drop to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until 3 weeks after enrollment.<br>|
| Experimental: Topical Voriconazole<br> | Drug: Voriconazole<br>* 1% voriconazole 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.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Spectacle-corrected logMAR Visual Acuity | The primary analysis is best spectacle-corrected logMAR (logarithm of the Minimum Angle or Resolution) visual acuity, correcting for enrollment BSCVA and treatment arm in a multiple linear regression model. The pre-specified non-inferiority margin is less than 1.5 lines logMAR acuity. (Adjusted three-month visual acuity confidence bounds for the difference between the voriconazole and natamycin groups which meet or exceed 0.15 logMAR units would not permit noninferiority to be declared.) Note that this design also allows declaration of superiority (2-sided alpha of 0.05, corrected for an interim analysis). | 3 months from enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Spectacle-corrected logMAR Visual Acuity | Best spectacle-corrected logMAR (logarithm of the Minimum Angle of Resolution) visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear regression model | 3 weeks after enrollment | 
| Hard Contact Lens-corrected Visual Acuity Measured in logMAR | Hard contact lens-corrected visual acuity measured in logMAR (logarithm of the Minimum Angle of Resolution) 3 months after enrollment | 3 months after enrollment | 
| Size of Infiltrate/Scar | Size of infiltrate/scar at 3 weeks and 3 months after enrollment, using enrollment infiltrate scar/size as a covariate | 3 weeks and 3 months after enrollment | 
| Time to Resolution of Epithelial Defect | Time in days from enrollment to resolution of epithelial defect. For those subjects with more than 21 days to resolution, 21 days was used. | From enrollment to the time of resolution of epithelial defect | 
| Minimum Inhibitory Concentration of Isolates | Minimum inhibitory concentration (50th percentile) of fungal isolates to natamycin and voriconazole | 3 months after enrollment | 
| Microbiological Cure at 6 Days | Microbiological cure defined as no fungal growth on culture at 6 (+/-1) days from enrollment | 7 days after enrollment | 

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