Clinical trial NCT00996736: Mycotic Ulcer Treatment Trial I
Official title: Mycotic Ulcer Treatment Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Corneal Ulcer
Eye Infections, Fungal
Keywords: Fungal Infections
Eye Disease
Fungal Keratitis
Visual Acuity
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Aravind Eye Hospitals, India
name: Dartmouth-Hitchcock Medical Center
name: National Eye Institute (NEI)
First posted: 2009-10-16
Enrollment: 323
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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 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

Primary outcomes:
measure: Best Spectacle-corrected logMAR Visual Acuity
timeFrame: 3 months from enrollment
Secondary outcomes:
measure: Best Spectacle-corrected logMAR Visual Acuity
timeFrame: 3 weeks after enrollment
measure: Hard Contact Lens-corrected Visual Acuity Measured in logMAR
timeFrame: 3 months after enrollment
measure: Size of Infiltrate/Scar
timeFrame: 3 weeks and 3 months after enrollment
measure: Time to Resolution of Epithelial Defect
timeFrame: From enrollment to the time of resolution of epithelial defect
measure: Minimum Inhibitory Concentration of Isolates
timeFrame: 3 months after enrollment
measure: Microbiological Cure at 6 Days
timeFrame: 7 days after enrollment
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Proctor Foundation, UCSF
state: California
city: Madurai
country: India
facility: Aravind Eye Hospitals
state: Tamil Nadu
city: Pondicherry
country: India
facility: Aravind Eye Hospital
state: Tamil Nadu
Study officials:
affiliation: Aravind Eye Hospitals
name: NV Prajna, DNB, FRC Ophth
role: PRINCIPAL_INVESTIGATOR
affiliation: Proctor Foundation, UCSF
name: Nisha Acharya, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Proctor Foundation, UCSF
name: Tom Lietman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1001/jamaophthalmol.2013.1497.
citation: Prajna NV, Lalitha P, Krishnan T, Rajaraman R, Radnakrishnan N, Srinivasan M, Devi L, Das M, Liu Z, Zegans ME, Acharya NR, Porco TC, Lietman TM, Rose-Nussbaumer J. Patterns of Antifungal Resistance in Adult Patients With Fungal Keratitis in South India: A Post Hoc Analysis of 3 Randomized Clinical Trials. JAMA Ophthalmol. 2022 Feb 1;140(2):179-184. doi: 10.1001/jamaophthalmol.2021.5765.
citation: Prajna NV, Krishnan T, Rajaraman R, Patel S, Shah R, Srinivasan M, Das M, Ray KJ, Oldenburg CE, McLeod SD, Zegans ME, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. Predictors of Corneal Perforation or Need for Therapeutic Keratoplasty in Severe Fungal Keratitis: A Secondary Analysis of the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol. 2017 Sep 1;135(9):987-991. doi: 10.1001/jamaophthalmol.2017.2914.
citation: Prajna NV, Krishnan T, Rajaraman R, Patel S, Shah R, Srinivasan M, Devi L, Das M, Ray KJ, O'Brien KS, Oldenburg CE, McLeod SD, Zegans ME, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis: A Secondary Analysis From the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol. 2017 Jun 1;135(6):520-525. doi: 10.1001/jamaophthalmol.2017.0616.
citation: Prajna NV, Krishnan T, Rajaraman R, Patel S, Srinivasan M, Das M, Ray KJ, O'Brien KS, Oldenburg CE, McLeod SD, Zegans ME, Porco TC, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial II Group. Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial. JAMA Ophthalmol. 2016 Dec 1;134(12):1365-1372. doi: 10.1001/jamaophthalmol.2016.4096.
citation: Prajna NV, Lalitha P, Rajaraman R, Krishnan T, Raghavan A, Srinivasan M, O'Brien KS, Zegans M, McLeod SD, Acharya NR, Keenan JD, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial. JAMA Ophthalmol. 2016 Jun 1;134(6):693-6. doi: 10.1001/jamaophthalmol.2016.0530.
citation: Rose-Nussbaumer J, Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Srinivasan M, Raghavan A, Oldenburg CE, O'Brien KS, Ray KJ, Porco TC, McLeod SD, Acharya NR, Keenan JD, Lietman TM; Mycotic Ulcer Treatment Trial Group. Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole. Br J Ophthalmol. 2016 Jul;100(7):929-932. doi: 10.1136/bjophthalmol-2015-306828. Epub 2015 Nov 3.
citation: 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.
citation: 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.