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Mycotic Ulcer Treatment Trial I (MUTT I)

This study has been completed.
Sponsor:
Collaborators:
Aravind Eye Hospitals, India
Dartmouth-Hitchcock Medical Center
Information provided by (Responsible Party):
Thomas M. Lietman, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00996736
First received: October 14, 2009
Last updated: October 18, 2013
Last verified: October 2013

October 14, 2009
October 18, 2013
April 2010
July 2012   (final data collection date for primary outcome measure)
Best Spectacle-corrected logMAR Visual Acuity [ Time Frame: 3 months from enrollment ] [ Designated as safety issue: No ]
The primary analysis is best spectacle-corrected logMAR (logarithm of the Minimum Angle or Resolution) visual acuity, correcting for enrollment BSCVA and treatment arm in a multiple linear regression model. The pre-specified non-inferiority margin is less than 1.5 lines logMAR acuity. (Adjusted three-month visual acuity confidence bounds for the difference between the voriconazole and natamycin groups which meet or exceed 0.15 logMAR units would not permit noninferiority to be declared.) Note that this design also allows declaration of superiority (2-sided alpha of 0.05, corrected for an interim analysis).
Best spectacle-corrected logMAR visual acuity, correcting for enrollment BSCVA and treatment arm in a multiple linear regression model [ Time Frame: 3 months from enrollment ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00996736 on ClinicalTrials.gov Archive Site
  • Best Spectacle-corrected logMAR Visual Acuity [ Time Frame: 3 weeks after enrollment ] [ Designated as safety issue: No ]
    Best spectacle-corrected logMAR (logarithm of the Minimum Angle of Resolution) visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear regression model
  • Hard Contact Lens-corrected Visual Acuity Measured in logMAR [ Time Frame: 3 months after enrollment ] [ Designated as safety issue: No ]
    Hard contact lens-corrected visual acuity measured in logMAR (logarithm of the Minimum Angle of Resolution) 3 months after enrollment
  • Size of Infiltrate/Scar [ Time Frame: 3 weeks and 3 months after enrollment ] [ Designated as safety issue: No ]
    Size of infiltrate/scar at 3 weeks and 3 months after enrollment, using enrollment infiltrate scar/size as a covariate
  • Time to Resolution of Epithelial Defect [ Time Frame: From enrollment to the time of resolution of epithelial defect ] [ Designated as safety issue: No ]
    Time in days from enrollment to resolution of epithelial defect. For those subjects with more than 21 days to resolution, 21 days was used.
  • Minimum Inhibitory Concentration of Isolates [ Time Frame: 3 months after enrollment ] [ Designated as safety issue: No ]
    Minimum inhibitory concentration (50th percentile) of fungal isolates to natamycin and voriconazole
  • Microbiological Cure at 6 Days [ Time Frame: 7 days after enrollment ] [ Designated as safety issue: No ]
    Microbiological cure defined as no fungal growth on culture at 6 (+/-1) days from enrollment
  • Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear regression model [ Time Frame: 3 weeks after enrollment ] [ Designated as safety issue: No ]
  • Best spectacle-corrected logMAR visual acuity only in Indian sites, 3 weeks and 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear regression model [ Time Frame: 3 weeks and 3 months after enrollment ] [ Designated as safety issue: No ]
  • Hard contact-lens corrected visual acuity measured in logMAR 3 weeks and 3 months after enrollment [ Time Frame: 3 weeks and 3 months after enrollment ] [ Designated as safety issue: No ]
  • Size of infiltrate/scar at 3 weeks and 3 months after enrollment, using enrollment infiltrate scar/size as a covariate [ Time Frame: 3 weeks and 3 months after enrollment ] [ Designated as safety issue: No ]
  • Time to resolution of epithelial defect [ Time Frame: At the time of resolution of epithelial defect ] [ Designated as safety issue: No ]
  • Number of perforations and other adverse events [ Time Frame: At the time of perforation/adverse event ] [ Designated as safety issue: No ]
  • Minimum inhibitory concentration of isolates [ Time Frame: 3 months after enrollment ] [ Designated as safety issue: No ]
  • Microbiological cure at 7 days [ Time Frame: 7 days after enrollment ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Mycotic Ulcer Treatment Trial I
Mycotic Ulcer Treatment Trial

The purpose of this study is to determine if natamycin or voriconazole results in better visual outcomes in fungal corneal ulcers, especially visual acuity.

Fungal corneal ulcers tend to have very poor outcomes with commonly used treatments. There has only been a single randomized trial of anti-fungal therapy for mycotic keratitis, and no new ocular anti-fungal medications have been approved by the FDA since the 1960s. The triazole voriconazole has recently become the treatment of choice for systemic fungal infections such as pulmonary aspergillosis. The use of topical ophthalmic preparations of voriconazole has been described in numerous case reports, however there has been no systematic attempt to determine whether it is more or less clinically effective than natamycin. Additionally, there have been many case reports of the use of oral voriconazole in the treatment of fungal corneal ulcers, however there has been no systematic attempt to determine if it improves outcomes in severe ulcers.

This study is a randomized, double-masked, placebo-controlled trial to determine if the use natamycin or voriconazole results in better outcomes for fungal corneal ulcers. 368 fungal corneal ulcers with baseline visual acuity between 6/12 (20/40, logMAR 0.3) and 6/120 (20/400, logMAR 1.3) presenting to the Aravind Eye Hospitals and the UCSF Proctor Foundation will be randomized to receive either topical natamycin or topical voriconazole. The primary outcome is best spectacle-corrected logMAR visual acuity three months after enrollment, using best spectacle-corrected enrollment visual acuity as a co-variate.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Corneal Ulcer
  • Eye Infections, Fungal
  • Drug: Natamycin
    5% natamycin plus 0.02% preservative, one drop to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until 3 weeks after enrollment.
  • Drug: Voriconazole
    1% voriconazole plus 0.01% preservative, 1 drop applied to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until three weeks after enrollment.
  • Active Comparator: Topical Natamycin
    Intervention: Drug: Natamycin
  • Experimental: Topical Voriconazole
    Intervention: Drug: Voriconazole

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
323
July 2012
July 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Presence of a corneal ulcer at presentation
  • Evidence of filamentous fungus on smear (KOH wet mount, Giemsa, or Gram stain)
  • Visual acuity between 6/12 (20/40, logMAR 0.3) and 6/120 (20/400, logMAR 1.3)
  • 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 inpatient or to be treated as an outpatient and return every 3 days +/- 1 day until re-epithelialization and every week to receive fresh medication for 3 weeks
  • Appropriate consent

Exclusion Criteria:

  • 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 (2/200) in the fellow eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA 6/60 or better qualifies for enrollment)
  • Acuity worse than 6/120 (20/400) or better than 6/12 (20/40) in the study eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA can be used for enrollment)
  • Known allergy to study medications (antifungal or preservative)
  • No light perception in the affected eye
  • Not willing to participate
Both
16 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   India
 
NCT00996736
H9332-33965-02, U10-EY018573-01A1
Yes
Thomas M. Lietman, University of California, San Francisco
University of California, San Francisco
  • Aravind Eye Hospitals, India
  • Dartmouth-Hitchcock Medical Center
Principal Investigator: NV Prajna, DNB, FRC Ophth Aravind Eye Hospitals
Principal Investigator: Nisha Acharya, MD, MS Proctor Foundation, UCSF
Principal Investigator: Tom Lietman, MD Proctor Foundation, UCSF
University of California, San Francisco
October 2013

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