Official Title: “Mycotic Ulcer Treatment Trial Pilot Study”

We are planning to evaluate whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. The study being proposed in this application is a pilot study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: August 2008

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 are planning to evaluate whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. The study being proposed in this application is a pilot study to investigate the safety and feasibility of conducting the main study and to generate preliminary data.

Intervention(s) in this Clinical Trial

• Drug: Natamycin 5%
  • 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
• Drug: Voriconazole
  • 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
• Procedure: Corneal de-epithelialization
  • Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Topical voriconazole with corneal de-epithelialization
• Active Comparator: 2
  • Topical voriconazole without corneal de-epithelialization
• Active Comparator: 3
  • Topical natamycin with corneal de-epithelialization
• Active Comparator: 4
  • Topical natamycin without corneal de-epithelialization

Primary Measures

• Best spectacle corrected visual acuity (BSCVA) 3 months after enrollment, adjusting for enrollment BSCVA in a multiple linear regression model
  • Time Frame: 3 months from enrollment
    Safety Issue?: No

Secondary Measures

• Time to resolution of epithelial defect
  • Time Frame: 3 months from enrollment
    Safety Issue?: No
• Size of infiltrate/scar post-treatment, using enrollment infiltrate/scar size as a covariate
  • Time Frame: 3 months from enrollment
    Safety Issue?: No
• Subgroup analysis - It will be determined if voriconazole or natamycin results in better clinical outcomes in subgroups of fungal ulcers (Fusarium spp and Aspergillus spp).
  • Time Frame: 3 months from enrollment
    Safety Issue?: No
• Best hard contact lens-corrected visual acuity 3 months after enrollment
  • Time Frame: 3 months from enrollment
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 16 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of California, San Francisco

Overall Clinical Trial Officials and Contacts

Thomas M Lietman, MD Principal Investigator Proctor Foundation, University of California, San Francisco  

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00557362

Study ID Number: H9332-31301-01

ClinicalTrials.gov Identifier: NCT00557362

Health Authority: United States: Institutional Review Board