Title
Therapeutic Exploratory Study of Comparing Natamycin and Voriconazole to Treat Fungal Corneal Ulcer
Mycotic Ulcer Treatment Trial Therapeutic Exploratory Study
Phase
Phase 1/Phase 2Lead Sponsor
University of California, San FranciscoStudy Type
InterventionalStatus
Completed Results PostedIndication/Condition
Fungal KeratitisIntervention/Treatment
natamycin voriconazole ...Study Participants
120We 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.
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.
One drop of medication will be given every one hour while awake for one week. For another 2 weeks, one drop of medication should be given every 2 hours while awake
Voriconazole (VFEND® I.V., Pfizer, New York, NY) will be prepared as a 1% solution. One drop of medication should be given every one hour while awake for one week. For another 2 weeks, one drop of medication should be given every 2 hours while awake
Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications.
Topical voriconazole with corneal de-epithelialization
Topical natamycin with corneal de-epithelialization
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
| Event Type | Organ System | Event Term | Topical Voriconazole With Corneal De-epithelialization | Topical Voriconazole Without Corneal De-epithelialization | Topical Natamycin With Corneal De-epithelialization | Topical Natamycin Without Corneal De-epithelialization |
|---|
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.
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. 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.
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.
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).
