Clinical trial NCT00997035: The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo
Official title: The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo
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: Lumbini Eye Institute and Hospital
name: Bharatpur Eye Hospital
name: National Eye Institute (NEI)
First posted: 2009-10-16
Enrollment: 240
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 the addition of oral voriconazole to topical treatment regimens results in lower rates of perforation in severe fungal corneal ulcers.

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 of oral voriconazole in severe ulcers reduces the rate of perforations. 240 fungal corneal ulcers with baseline visual acuity worse than 6/120 presenting to the Aravind Eye Hospitals and the UCSF Proctor Foundation will be randomized to receive oral voriconazole plus topical voriconazole and topical natamycin, or oral placebo plus topical voriconazole and topical natamycin. The primary outcome is the rate of perforation over the three month follow-up period.

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 worse than 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:

* 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)
* Known liver disease, including hepatitis or cirrhosis (Child-Pugh A-C)
* 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 better than 6/120 (20/400) in the study eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA can be used for enrollment)
* Currently on rifampin, rifabutin, ritonavir, long acting barbiturates, phenytoin, carbamazepine, or other drugs known to interact with voriconazole
* Known allergy to study medications (antifungal or preservative)
* No light perception in the affected eye
* Not willing to participate

Primary outcomes:
measure: Incidence of Perforation or Therapeutic Penetrating Keratoplasty
timeFrame: 3 months from enrollment
Secondary outcomes:
measure: Best Spectacle-corrected logMAR Visual Acuity
timeFrame: 3 months after enrollment
measure: Best Spectacle-corrected logMAR Visual Acuity at 3-weeks
timeFrame: 3 weeks after enrollment
measure: Size of Infiltrate/Scar - 3 Months
timeFrame: 3 months after enrollment
measure: Size of Infiltrate/Scar
timeFrame: 3 weeks after enrollment
measure: Hazard Ratio for Re-epithelialization
timeFrame: Up to 21 days
measure: Microbiological Cure at 7 Days
timeFrame: 7 days
measure: Number of Adverse Events
timeFrame: 3-months from enrollment
measure: Minimum Inhibitory Concentration of Isolates - Natamycin
timeFrame: 7 days
measure: Minimum Inhibitory Concentration of Isolates - Voriconazole
timeFrame: 7 days
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Proctor Foundation, UCSF
state: California
city: Coimbatore
country: India
facility: Aravind Eye Hospital
state: Tamil Nadu
city: Madurai
country: India
facility: Aravind Eye Hospitals
state: Tamil Nadu
city: Pondicherry
country: India
facility: Aravind Eye Hospital
state: Tamil Nadu
city: Tirunelveli
country: India
facility: Aravind Eye Hospital
state: Tamil Nadu
city: Bharatpur
country: Nepal
facility: Bharatpur Eye Hospital
state: Chitwan
city: Bhairahawa
country: Nepal
facility: Lumbini Eye Institute
state: Lumbini
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: