- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00557362
Therapeutic Exploratory Study of Comparing Natamycin and Voriconazole to Treat Fungal Corneal Ulcer (MUTT_TE)
Mycotic Ulcer Treatment Trial Therapeutic Exploratory Study
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Tamil Nadu
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Madurai, Tamil Nadu, India
- Aravind Eye Hospital
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Pondicherry, Tamil Nadu, India
- Aravind Eye Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: 1
Topical voriconazole with corneal de-epithelialization
|
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.
|
Active Comparator: 2
Topical voriconazole without corneal de-epithelialization
|
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 |
Active Comparator: 3
Topical natamycin with corneal de-epithelialization
|
Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications.
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
|
Active Comparator: 4
Topical natamycin without corneal de-epithelialization
|
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
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to Resolution of Epithelial Defect
Time Frame: 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.
|
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.
Time Frame: 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.
|
3 months from enrollment
|
Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp).
Time Frame: 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.
|
3 months from enrollment
|
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
Time Frame: 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).
|
3 months from enrollment
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Thomas M Lietman, MD, Proctor Foundation, University of California, San Francisco
- Principal Investigator: Nisha Acharya, MD MS, Proctor Foundation, University of California, San Francisco
- Study Director: N V Prajna, MD, Aravind Eye Hospital, India
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Eye Diseases
- Corneal Diseases
- Keratitis
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents, Local
- Anti-Infective Agents
- Enzyme Inhibitors
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Anti-Bacterial Agents
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Hormone Antagonists
- Antifungal Agents
- Steroid Synthesis Inhibitors
- 14-alpha Demethylase Inhibitors
- Voriconazole
- Natamycin
Other Study ID Numbers
- H9332-31301-01
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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