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

This study has been completed.
Sponsor:
Collaborators:
Aravind Eye Hospitals, India
Dartmouth-Hitchcock Medical Center
Lumbini Eye Institute and Hospital
Bharatpur Eye Hospital, Nepal
National Eye Institute (NEI)
Information provided by (Responsible Party):
Thomas M. Lietman, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00997035
First received: October 14, 2009
Last updated: May 17, 2017
Last verified: May 2017
  Purpose
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 Intervention Phase
Corneal Ulcer Eye Infections, Fungal Drug: Voriconazole Drug: Placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Thomas M. Lietman, University of California, San Francisco:

Primary Outcome Measures:
  • 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:
  • 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

  • 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

  • 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

  • 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

  • Hazard Ratio for Re-epithelialization [ Time Frame: Up to 21 days ]
    Hazard Ratio of re-epithelialization comparing the treatment groups

  • Microbiological Cure at 7 Days [ Time Frame: 7 days ]
    Fungal Culture negative at 7 days post treatment

  • Number of Adverse Events [ Time Frame: 3-months from enrollment ]
    Comparing the number of serious and non-serious adverse events by treatment arm.

  • Minimum Inhibitory Concentration of Isolates [ Time Frame: 3 months after enrollment ]
    Comparing Minimum inhibitory concentration of isolates by treatment arm


Enrollment: 240
Study Start Date: May 2010
Study Completion Date: March 2016
Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.


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

Ages Eligible for Study:   16 Years and older   (Child, Adult, Senior)
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00997035

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, Nepal
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     History of Changes
Other Study ID Numbers: H9332-33965-02_2
U10EY018573 ( U.S. NIH Grant/Contract )
Study First Received: October 14, 2009
Results First Received: June 9, 2016
Last Updated: May 17, 2017
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:
Ulcer
Corneal Ulcer
Eye Infections
Mycoses
Eye Infections, Fungal
Pathologic Processes
Infection
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

ClinicalTrials.gov processed this record on July 21, 2017