Mycotic Ulcer Treatment Trial I - Full Text View

Purpose

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

Condition	Intervention	Phase
Corneal Ulcer Eye Infections, Fungal	Drug: Natamycin Drug: Voriconazole	Phase 3


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

Resource links provided by NLM:

Genetics Home Reference related topics: keratitis-ichthyosis-deafness syndrome

MedlinePlus related topics: Eye Infections Eye Wear Molds

Drug Information available for: Natamycin Voriconazole

U.S. FDA Resources

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

Primary Outcome Measures:

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).

Secondary Outcome Measures:

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


Enrollment:	323
Study Start Date:	April 2010
Study Completion Date:	July 2012
Primary Completion Date:	July 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Topical Natamycin	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.
Experimental: Topical Voriconazole	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.

Detailed Description:

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.

Eligibility


Ages Eligible for Study:	16 Years and older (Child, Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

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: NCT00996736

Locations


United States, California
Proctor Foundation, UCSF
San Francisco, California, United States, 94143
India
Aravind Eye Hospitals
Madurai, Tamil Nadu, India
Aravind Eye Hospital
Pondicherry, Tamil Nadu, India

Sponsors and Collaborators

University of California, San Francisco

Aravind Eye Hospitals, India

Dartmouth-Hitchcock Medical Center

Investigators


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

More Information

Publications:

Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Prajna L, Srinivasan M, Raghavan A, Oldenburg CE, Ray KJ, Zegans ME, McLeod SD, Porco TC, Acharya NR, Lietman TM; Mycotic Ulcer Treatment Trial Group. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013 Apr;131(4):422-9.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rose-Nussbaumer J, Prajna NV, Krishnan KT, Mascarenhas J, Rajaraman R, Srinivasan M, Raghavan A, Oldenburg CE, O'Brien KS, Ray KJ, McLeod SD, Porco TC, Lietman TM, Acharya NR, Keenan JD; Mycotic Ulcer Treatment Trial I Group. Vision-Related Quality-of-Life Outcomes in the Mycotic Ulcer Treatment Trial I: A Randomized Clinical Trial. JAMA Ophthalmol. 2015 Jun;133(6):642-6. doi: 10.1001/jamaophthalmol.2015.0319.

Sun CQ, Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Srinivasan M, Raghavan A, O'Brien KS, Ray KJ, McLeod SD, Porco TC, Acharya NR, Lietman TM. Expert prior elicitation and Bayesian analysis of the Mycotic Ulcer Treatment Trial I. Invest Ophthalmol Vis Sci. 2013 Jun 14;54(6):4167-73. doi: 10.1167/iovs.13-11716.


Responsible Party:	Thomas M. Lietman, Professor in Residence, University of California, San Francisco
ClinicalTrials.gov Identifier:	NCT00996736 History of Changes
Other Study ID Numbers:	H9332-33965-02 U10EY018573-01A1
Study First Received:	October 14, 2009
Results First Received:	July 26, 2013
Last Updated:	March 24, 2015
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:


Fungal Infections Eye Disease Fungal Keratitis Visual Acuity

Additional relevant MeSH terms:


Ulcer Corneal Ulcer Eye Infections Mycoses Eye Infections, Fungal Pathologic Processes Infection Keratitis Corneal Diseases Eye Diseases Voriconazole Natamycin Antifungal Agents	Anti-Infective Agents 14-alpha Demethylase Inhibitors Cytochrome P-450 Enzyme Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Steroid Synthesis Inhibitors Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Cytochrome P-450 CYP3A Inhibitors Anti-Infective Agents, Local Anti-Bacterial Agents

ClinicalTrials.gov processed this record on September 30, 2016

Mycotic Ulcer Treatment Trial I (MUTT I)