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

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ClinicalTrials.gov Identifier: NCT00557362
Recruitment Status : Completed
First Posted : November 14, 2007
Results First Posted : December 19, 2013
Last Update Posted : December 19, 2013
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

November 9, 2007
November 14, 2007
June 14, 2013
December 19, 2013
December 19, 2013
November 2007
August 2008   (Final data collection date for primary outcome measure)
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.
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 ]
Complete list of historical versions of study NCT00557362 on ClinicalTrials.gov Archive Site
  • 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.
  • 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.
  • 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.
  • 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).
  • Time to Resolution of Epithelial Defect [ Time Frame: 3 months from enrollment ]
  • Size of infiltrate/scar post-treatment, using enrollment infiltrate/scar size as a covariate [ Time Frame: 3 months from enrollment ]
  • 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 ]
  • Best hard contact lens-corrected visual acuity 3 months after enrollment [ Time Frame: 3 months from enrollment ]
Not Provided
Not Provided
 
Therapeutic Exploratory Study of Comparing Natamycin and Voriconazole to Treat Fungal Corneal Ulcer
Mycotic Ulcer Treatment Trial Therapeutic Exploratory Study
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.

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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Fungal Keratitis
  • 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.
  • Active Comparator: 1
    Topical voriconazole with corneal de-epithelialization
    Interventions:
    • Drug: Voriconazole
    • Procedure: Corneal de-epithelialization
  • Active Comparator: 2
    Topical voriconazole without corneal de-epithelialization
    Intervention: Drug: Voriconazole
  • Active Comparator: 3
    Topical natamycin with corneal de-epithelialization
    Interventions:
    • Drug: Natamycin 5%
    • Procedure: Corneal de-epithelialization
  • Active Comparator: 4
    Topical natamycin without corneal de-epithelialization
    Intervention: Drug: Natamycin 5%
Prajna NV, Mascarenhas J, Krishnan T, Reddy PR, Prajna L, Srinivasan M, Vaitilingam CM, Hong KC, Lee SM, McLeod SD, Zegans ME, Porco TC, Lietman TM, Acharya NR. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch Ophthalmol. 2010 Jun;128(6):672-8. doi: 10.1001/archophthalmol.2010.102.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
120
80
August 2008
August 2008   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
16 Years and older   (Child, Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
India
 
 
NCT00557362
H9332-31301-01
No
Not Provided
Not Provided
University of California, San Francisco
University of California, San Francisco
  • That Man May See, Inc.
  • Aravind Eye Hospitals, India
  • Dartmouth-Hitchcock Medical Center
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
University of California, San Francisco
November 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP