Therapeutic Exploratory Study of Comparing Natamycin and Voriconazole to Treat Fungal Corneal Ulcer

Phase 1

Completed

Conditions: Fungal Keratitis

Interventions: Drug: Voriconazole
Drug: Natamycin 5%
Procedure: Corneal de-epithelialization

Registration Number: NCT00557362

Lead Sponsor: University of California, San Francisco

Brief Summary: We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data.

Detailed Description: Fungal ulcers tend to have very poor outcomes with the most common treatments, amphotericin B and natamycin. There has been only a single randomized trial of anti-fungal therapy for fungal ulcers and no new medications have been approved by the FDA since the 1960s. There are studies that indicate that the newer triazoles, such as voriconazole, are more effective in vitro against filamentous fungi such as Aspergillus spp., a common cause of fungal keratitis1-3. Despite a number of case reports and in vitro studies, there has been no systematic attempt to determine whether it is more or less effective clinically than natamycin, the only commercially available FDA-approved agent. There is little data available for physicians to make an informed, evidence-based decision on choice of antifungal.

We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data. The primary outcome is visual acuity at 3 months from enrollment. A subset of patients will be followed at 4 years from enrollment.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 120

Inclusion Criteria

Presence of a corneal ulcer at presentation
Evidence of filamentous fungus on KOH (or Giemsa or any other stain) or culture
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 in-patient or to be treated as an out-patient and come back every 48-72 hours to receive fresh medication for 3 weeks
Appropriate consent

Exclusion Criteria

Overlying epithelial defect < 0.5 mm at its greatest width at presentation
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 (20/200) in the fellow eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA 6/60 or better qualifies for enrollment)
Known allergy to study medications (antifungal or preservative)
No light perception in the affected eye
Not willing to participate

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	Voriconazole	Topical voriconazole with corneal de-epithelialization
3	Corneal de-epithelialization	Topical natamycin with corneal de-epithelialization
4	Natamycin 5%	Topical natamycin without corneal de-epithelialization
1	Corneal de-epithelialization	Topical voriconazole with corneal de-epithelialization
3	Natamycin 5%	Topical natamycin with corneal de-epithelialization
2	Voriconazole	Topical voriconazole without corneal de-epithelialization

Primary Outcome Measures

Name	Time	Method
Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model	3 months from enrollment	The primary efficacy endpoint was BSCVA at 3 months in the study eye, using a linear regression model with 3-month BSCVA measured in logMAR (logarithm of the Minimum Angle of Resolution) as the outcome variable and treatment arm (voriconazole vs natamycin) and enrollment logMAR BSCVA and corneal de-epithelialization (yes or no) as covariates.

Secondary Outcome Measures

Name	Time	Method
Best Hard Contact Lens-corrected Visual Acuity 3 Months After Enrollment in a Multiple Linear Regression Model With Enrollment Hard Contact Lens-corrected Visual Acuity as a Covariate	3 months from enrollment	Best hard contact lens-corrected visual acuity 3 months after enrollment was evaluated in a multiple linear regression model with enrollment hard contact lens-corrected visual acuity as a covariate. Visual acuity is reported in logMAR (logarithm of the Minimum Angle of Resolution).
Time to Resolution of Epithelial Defect	3 months from enrollment	Resolution of epithelial defect was defined as the absence of an epithelial defect with administration of fluorescein. The time to re-epithelialization was compared between the voriconazole and natamycin groups using the Cox proportional hazards model, adjusting for baseline epithelial defect size.
Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate.	3 months from enrollment	Size of infiltrate/scar post-treatment was analyzed in a linear regression model using enrollment infiltrate/scar size as a covariate. No differentiation was made between infiltrate and scar when measuring infiltrate/scar size (measured in mm). For analysis, infiltrate/scar size was characterized by the geometric mean of the longest dimension and the longest perpendicular.
Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp).	3 months from enrollment	Two subgroup analyses were conducted by causative organism: 1) best spectacle-corrected visual acuity (BSCVA) by treatment arm among Fusarium ulcers; 2) best spectacle-corrected visual acuity (BSCVA) by treatment arm among Aspergillus ulcers.