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

Fungal Keratitis Clinical Trial

— MUTT_TE  

Official title:

Mycotic Ulcer Treatment Trial Therapeutic Exploratory Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00557362
• Other study ID #: H9332-31301-01
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 2007
• Est. completion date: August 2008

Study information

• Verified date: July 2018
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: August 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Fungal Keratitis
• Keratitis

Intervention

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
• 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.

Locations

Country	Name	City	State
India	Aravind Eye Hospital	Madurai	Tamil Nadu
India	Aravind Eye Hospital	Pondicherry	Tamil Nadu

Sponsors (4)

Lead Sponsor	Collaborator
University of California, San Francisco	Aravind Eye Hospitals, India, Dartmouth-Hitchcock Medical Center, That Man May See, Inc.

Country where clinical trial is conducted

India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model	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.	3 months from enrollment
Secondary	Time to Resolution of Epithelial Defect	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.	3 months from enrollment
Secondary	Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate.	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.	3 months from enrollment
Secondary	Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp).	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.	3 months from enrollment
Secondary	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	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).	3 months from enrollment