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

Primary Purpose

Fungal Keratitis

Status
Completed
Phase
Phase 1
Locations
India
Study Type
Interventional
Intervention
Natamycin 5%
Voriconazole
Corneal de-epithelialization
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fungal Keratitis focused on measuring Keratitis, Eye Infection, Fungal, Fungal Eye Infection, Ocular Infection, Fungal, Fungal Keratitis, Mycotic Infections, Ocular, Voriconazole, Natamycin

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Aravind Eye Hospital
  • Aravind Eye Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

1

2

3

4

Arm Description

Topical voriconazole with corneal de-epithelialization

Topical voriconazole without corneal de-epithelialization

Topical natamycin with corneal de-epithelialization

Topical natamycin without corneal de-epithelialization

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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).

Full Information

First Posted
November 9, 2007
Last Updated
July 9, 2018
Sponsor
University of California, San Francisco
Collaborators
That Man May See, Inc., Aravind Eye Hospitals, India, Dartmouth-Hitchcock Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT00557362
Brief Title
Therapeutic Exploratory Study of Comparing Natamycin and Voriconazole to Treat Fungal Corneal Ulcer
Acronym
MUTT_TE
Official Title
Mycotic Ulcer Treatment Trial Therapeutic Exploratory Study
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
November 2007 (undefined)
Primary Completion Date
August 2008 (Actual)
Study Completion Date
August 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of California, San Francisco
Collaborators
That Man May See, Inc., Aravind Eye Hospitals, India, Dartmouth-Hitchcock Medical Center

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fungal Keratitis
Keywords
Keratitis, Eye Infection, Fungal, Fungal Eye Infection, Ocular Infection, Fungal, Fungal Keratitis, Mycotic Infections, Ocular, Voriconazole, Natamycin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
120 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
Topical voriconazole with corneal de-epithelialization
Arm Title
2
Arm Type
Active Comparator
Arm Description
Topical voriconazole without corneal de-epithelialization
Arm Title
3
Arm Type
Active Comparator
Arm Description
Topical natamycin with corneal de-epithelialization
Arm Title
4
Arm Type
Active Comparator
Arm Description
Topical natamycin without corneal de-epithelialization
Intervention Type
Drug
Intervention Name(s)
Natamycin 5%
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Voriconazole
Intervention Description
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
Intervention Type
Procedure
Intervention Name(s)
Corneal de-epithelialization
Intervention Description
Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications.
Primary Outcome Measure Information:
Title
Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model
Description
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.
Time Frame
3 months from enrollment
Secondary Outcome Measure Information:
Title
Time to Resolution of Epithelial Defect
Description
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.
Time Frame
3 months from enrollment
Title
Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate.
Description
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.
Time Frame
3 months from enrollment
Title
Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp).
Description
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.
Time Frame
3 months from enrollment
Title
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
Description
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 Frame
3 months from enrollment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Thomas M Lietman, MD
Organizational Affiliation
Proctor Foundation, University of California, San Francisco
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nisha Acharya, MD MS
Organizational Affiliation
Proctor Foundation, University of California, San Francisco
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
N V Prajna, MD
Organizational Affiliation
Aravind Eye Hospital, India
Official's Role
Study Director
Facility Information:
Facility Name
Aravind Eye Hospital
City
Madurai
State/Province
Tamil Nadu
Country
India
Facility Name
Aravind Eye Hospital
City
Pondicherry
State/Province
Tamil Nadu
Country
India

12. IPD Sharing Statement

Citations:
PubMed Identifier
20547942
Citation
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.
Results Reference
derived

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

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