The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo

Phase 3

Completed

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	-
Oral Voriconazole	Voriconazole	-

Primary Outcome Measures

Name	Time	Method
Incidence of Perforation or Therapeutic Penetrating Keratoplasty	3 months from enrollment	Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo

Secondary Outcome Measures

Name	Time	Method
Best Spectacle-corrected logMAR Visual Acuity	3 months after enrollment	Best spectacle-corrected logMAR visual acuity at 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear
Size of Infiltrate/Scar	3 weeks after enrollment	Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate
Number of Adverse Events	3-months from enrollment	Comparing the number of serious and non-serious adverse events by treatment arm.
Size of Infiltrate/Scar - 3 Months	3 months after enrollment	Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate
Hazard Ratio for Re-epithelialization	Up to 21 days	Hazard Ratio of re-epithelialization comparing the treatment groups
Minimum Inhibitory Concentration of Isolates - Natamycin	7 days	Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm
Minimum Inhibitory Concentration of Isolates - Voriconazole	7 days	Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm
Best Spectacle-corrected logMAR Visual Acuity at 3-weeks	3 weeks after enrollment	Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear
Microbiological Cure at 7 Days	7 days	Fungal Culture negative at 7 days post treatment

Locations (5): Aravind Eye Hospitals
🇮🇳
Madurai, Tamil Nadu, India
Aravind Eye Hospital
🇮🇳
Tirunelveli, Tamil Nadu, India
Proctor Foundation, UCSF
🇺🇸
San Francisco, California, United States
Bharatpur Eye Hospital
🇳🇵
Bharatpur, Chitwan, Nepal
Lumbini Eye Institute
🇳🇵
Bhairahawa, Lumbini, Nepal