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

• ClinicalTrials.gov Identifier: NCT00997035
• Recruitment Status: Completed
• First Posted: October 16, 2009
• Results First Posted: June 14, 2017
• Last Update Posted: February 26, 2019
• Sponsor: University of California, San Francisco
• Collaborators: Aravind Eye Hospitals, India; Dartmouth-Hitchcock Medical Center; Lumbini Eye Institute and Hospital; Bharatpur Eye Hospital; National Eye Institute (NEI)
• Information provided by (Responsible Party): Thomas M. Lietman, University of California, San Francisco

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Corneal Ulcer; Eye Infections, Fungal	Drug: Voriconazole; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 240 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo
• Study Start Date: May 2010
• Actual Primary Completion Date: January 2016
• Actual Study Completion Date: March 2016

Arms and Interventions

Arm	Intervention/treatment
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.
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.

Outcome Measures

Primary Outcome Measures :

1. Incidence of Perforation or Therapeutic Penetrating Keratoplasty [ Time Frame: 3 months from enrollment ]
   Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo

Secondary Outcome Measures :

1. Best Spectacle-corrected logMAR Visual Acuity [ Time Frame: 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
2. Best Spectacle-corrected logMAR Visual Acuity at 3-weeks [ Time Frame: 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
3. Size of Infiltrate/Scar - 3 Months [ Time Frame: 3 months after enrollment ]
   Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate
4. Size of Infiltrate/Scar [ Time Frame: 3 weeks after enrollment ]
   Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate
5. Hazard Ratio for Re-epithelialization [ Time Frame: Up to 21 days ]
   Hazard Ratio of re-epithelialization comparing the treatment groups
6. Microbiological Cure at 7 Days [ Time Frame: 7 days ]
   Fungal Culture negative at 7 days post treatment
7. Number of Adverse Events [ Time Frame: 3-months from enrollment ]
   Comparing the number of serious and non-serious adverse events by treatment arm.
8. Minimum Inhibitory Concentration of Isolates - Natamycin [ Time Frame: 7 days ]
   Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm
9. Minimum Inhibitory Concentration of Isolates - Voriconazole [ Time Frame: 7 days ]
   Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, California

Proctor Foundation, UCSF

San Francisco, California, United States, 94143

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, India

Nepal

Bharatpur Eye Hospital

Bharatpur, Chitwan, Nepal

Lumbini Eye Institute

Bhairahawa, Lumbini, Nepal

Sponsors and Collaborators

University of California, San Francisco

Aravind Eye Hospitals, India

Dartmouth-Hitchcock Medical Center

Lumbini Eye Institute and Hospital

Bharatpur Eye Hospital

National Eye Institute (NEI)

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

More Information

• Responsible Party: Thomas M. Lietman, Professor in Residence, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00997035
• Other Study ID Numbers: H9332-33965-02_2; U10EY018573 ( U.S. NIH Grant/Contract )
• First Posted: October 16, 2009
• Results First Posted: June 14, 2017
• Last Update Posted: February 26, 2019
• Last Verified: February 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Thomas M. Lietman, University of California, San Francisco:

Fungal Infections; Eye Disease; Fungal Keratitis; Visual Acuity

Additional relevant MeSH terms:

Corneal Ulcer; Eye Infections; Mycoses; Eye Infections, Fungal; Ulcer; Infection; Pathologic Processes; Keratitis; Corneal Diseases; Eye Diseases; Voriconazole; Antifungal Agents; Anti-Infective Agents; 14-alpha Demethylase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Cytochrome P-450 CYP3A Inhibitors