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

Corneal Ulcer Clinical Trial

— MUTTII  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00997035
• Other study ID #: H9332-33965-02_2
• Secondary ID: U10EY018573
• Status: Completed
• Phase: Phase 3
• Start date: May 2010
• Est. completion date: March 2016

Study information

• Verified date: February 2019
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 240
• Est. completion date: March 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

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

Related Conditions & MeSH terms

• Corneal Ulcer
• Eye Infections
• Eye Infections, Fungal
• Mycoses
• Ulcer

Intervention

Drug:
• Voriconazole
1% voriconazole (topical) 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. 5% natamycin (topical), 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. 400 mg BID PO on study day one (loading dose), then 200 mg BID PO until 3 weeks from enrollment for patients weighing greater than 50 kg. For patients 40-50 kg, the loading dose is 300 mg BID PO on study day 1, then 150 mg BID PO until 3 weeks from enrollment. For patients weighing <40 kg, the loading dose is 200 mg BID PO, then 100 mg BID PO until 3 weeks after enrollment.
• Placebo
1% voriconazole (topical) 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. 5% natamycin (topical), 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. Two tablets BID PO on study day one, then one tablet BID PO until 3 weeks from enrollment.

Locations

Country	Name	City	State
India	Aravind Eye Hospital	Coimbatore	Tamil Nadu
India	Aravind Eye Hospitals	Madurai	Tamil Nadu
India	Aravind Eye Hospital	Pondicherry	Tamil Nadu
India	Aravind Eye Hospital	Tirunelveli	Tamil Nadu
Nepal	Lumbini Eye Institute	Bhairahawa	Lumbini
Nepal	Bharatpur Eye Hospital	Bharatpur	Chitwan
United States	Proctor Foundation, UCSF	San Francisco	California

Sponsors (6)

Lead Sponsor	Collaborator
University of California, San Francisco	Aravind Eye Hospitals, India, Bharatpur Eye Hospital, Dartmouth-Hitchcock Medical Center, Lumbini Eye Institute and Hospital, National Eye Institute (NEI)

Countries where clinical trial is conducted

United States,  India,  Nepal, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Perforation or Therapeutic Penetrating Keratoplasty	Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo	3 months from enrollment
Secondary	Best Spectacle-corrected logMAR Visual Acuity	Best spectacle-corrected logMAR visual acuity at 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear	3 months after enrollment
Secondary	Best Spectacle-corrected logMAR Visual Acuity at 3-weeks	Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear	3 weeks after enrollment
Secondary	Size of Infiltrate/Scar - 3 Months	Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate	3 months after enrollment
Secondary	Size of Infiltrate/Scar	Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate	3 weeks after enrollment
Secondary	Hazard Ratio for Re-epithelialization	Hazard Ratio of re-epithelialization comparing the treatment groups	Up to 21 days
Secondary	Microbiological Cure at 7 Days	Fungal Culture negative at 7 days post treatment	7 days
Secondary	Number of Adverse Events	Comparing the number of serious and non-serious adverse events by treatment arm.	3-months from enrollment
Secondary	Minimum Inhibitory Concentration of Isolates - Natamycin	Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm	7 days
Secondary	Minimum Inhibitory Concentration of Isolates - Voriconazole	Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm	7 days