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

This study has been completed.
Sponsor:
Collaborators:
That Man May See, Inc.
Aravind Eye Hospitals, India
Dartmouth-Hitchcock Medical Center
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00557362
First received: November 9, 2007
Last updated: November 18, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Fungal Keratitis
Drug: Natamycin 5%
Drug: Voriconazole
Procedure: Corneal de-epithelialization
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Mycotic Ulcer Treatment Trial Therapeutic Exploratory Study

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome 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 ] [ Designated as safety issue: No ]
    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:
  • Time to Resolution of Epithelial Defect [ Time Frame: 3 months from enrollment ] [ Designated as safety issue: No ]
    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. [ Time Frame: 3 months from enrollment ] [ Designated as safety issue: No ]
    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). [ Time Frame: 3 months from enrollment ] [ Designated as safety issue: No ]
    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 in a Multiple Linear Regression Model With Enrollment Hard Contact Lens-corrected Visual Acuity as a Covariate [ Time Frame: 3 months from enrollment ] [ Designated as safety issue: No ]
    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).


Enrollment: 120
Study Start Date: November 2007
Study Completion Date: August 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Topical voriconazole with corneal de-epithelialization
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.
Active Comparator: 2
Topical voriconazole without corneal de-epithelialization
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

Active Comparator: 3
Topical natamycin with corneal de-epithelialization
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
Procedure: Corneal de-epithelialization
Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications.
Active Comparator: 4
Topical natamycin without corneal de-epithelialization
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

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.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00557362

Locations
India
Aravind Eye Hospital
Madurai, Tamil Nadu, India
Aravind Eye Hospital
Pondicherry, Tamil Nadu, India
Sponsors and Collaborators
University of California, San Francisco
That Man May See, Inc.
Aravind Eye Hospitals, India
Dartmouth-Hitchcock Medical Center
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
  More Information

No publications provided by University of California, San Francisco

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00557362     History of Changes
Other Study ID Numbers: H9332-31301-01
Study First Received: November 9, 2007
Results First Received: June 14, 2013
Last Updated: November 18, 2013
Health Authority: United States: Institutional Review Board
India: Indian Council of Medical Research

Keywords provided by University of California, San Francisco:
Keratitis
Eye Infection, Fungal
Fungal Eye Infection
Ocular Infection, Fungal
Fungal Keratitis
Mycotic Infections, Ocular
Voriconazole
Natamycin

Additional relevant MeSH terms:
Keratitis
Corneal Diseases
Eye Diseases
Natamycin
Voriconazole
Anti-Infective Agents, Local
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Bacterial Agents
Antifungal Agents
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 31, 2014