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

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.

Study Overview

• Status: Completed
• Conditions: Corneal Ulcer; Eye Infections, Fungal
• Intervention / Treatment: Drug: Voriconazole; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 240
• Phase: Phase 3

Contacts and Locations

Study Locations

• India
  • Tamil Nadu
    • Coimbatore, Tamil Nadu, India
      • Aravind Eye Hospital
    • Madurai, Tamil Nadu, India
      • Aravind Eye Hospitals
    • Pondicherry, Tamil Nadu, India
      • Aravind Eye Hospital
    • Tirunelveli, Tamil Nadu, India
      • Aravind Eye Hospital
• Nepal
  • Chitwan
    • Bharatpur, Chitwan, Nepal
      • Bharatpur Eye Hospital
  • Lumbini
    • Bhairahawa, Lumbini, Nepal
      • Lumbini Eye Institute
• United States
  • California
    • San Francisco, California, United States, 94143
      • Proctor Foundation, UCSF

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: 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.
Active Comparator: Oral Voriconazole	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
Hazard Ratio for Re-epithelialization	Hazard Ratio of re-epithelialization comparing the treatment groups	Up to 21 days
Microbiological Cure at 7 Days	Fungal Culture negative at 7 days post treatment	7 days
Number of Adverse Events	Comparing the number of serious and non-serious adverse events by treatment arm.	3-months from enrollment
Minimum Inhibitory Concentration of Isolates - Natamycin	Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm	7 days
Minimum Inhibitory Concentration of Isolates - Voriconazole	Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm	7 days

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: October 14, 2009
• First Submitted That Met QC Criteria: October 15, 2009
• First Posted (Estimate): October 16, 2009

Study Record Updates

• Last Update Posted (Actual): February 26, 2019
• Last Update Submitted That Met QC Criteria: February 4, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Visual Acuity; Eye Disease; Fungal Infections; Fungal Keratitis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Eye Diseases; Bacterial Infections and Mycoses; Keratitis; Corneal Diseases; Ulcer; Mycoses; Eye Infections; Corneal Ulcer; Eye Infections, Fungal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Voriconazole
• Other Study ID Numbers: H9332-33965-02_2; U10EY018573 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided