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

Primary Purpose

Corneal Ulcer, Eye Infections, Fungal

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Voriconazole
Placebo
Sponsored by
University of California, San Francisco
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Corneal Ulcer focused on measuring Fungal Infections, Eye Disease, Fungal Keratitis, Visual Acuity

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Proctor Foundation, UCSF
  • Aravind Eye Hospital
  • Aravind Eye Hospitals
  • Aravind Eye Hospital
  • Aravind Eye Hospital
  • Bharatpur Eye Hospital
  • Lumbini Eye Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Oral Voriconazole

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Incidence of Perforation or Therapeutic Penetrating Keratoplasty
Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo

Secondary Outcome Measures

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
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
Size of Infiltrate/Scar - 3 Months
Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate
Size of Infiltrate/Scar
Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate
Hazard Ratio for Re-epithelialization
Hazard Ratio of re-epithelialization comparing the treatment groups
Microbiological Cure at 7 Days
Fungal Culture negative at 7 days post treatment
Number of Adverse Events
Comparing the number of serious and non-serious adverse events by treatment arm.
Minimum Inhibitory Concentration of Isolates - Natamycin
Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm
Minimum Inhibitory Concentration of Isolates - Voriconazole
Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm

Full Information

First Posted
October 14, 2009
Last Updated
February 4, 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)
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1. Study Identification

Unique Protocol Identification Number
NCT00997035
Brief Title
The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo
Acronym
MUTTII
Official Title
The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo
Study Type
Interventional

2. Study Status

Record Verification Date
February 2019
Overall Recruitment Status
Completed
Study Start Date
May 2010 (undefined)
Primary Completion Date
January 2016 (Actual)
Study Completion Date
March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the 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)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Corneal Ulcer, Eye Infections, Fungal
Keywords
Fungal Infections, Eye Disease, Fungal Keratitis, Visual Acuity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
240 (Actual)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
NV Prajna, DNB, FRC Ophth
Organizational Affiliation
Aravind Eye Hospitals
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nisha Acharya, MD, MS
Organizational Affiliation
Proctor Foundation, UCSF
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Tom Lietman, MD
Organizational Affiliation
Proctor Foundation, UCSF
Official's Role
Principal Investigator
Facility Information:
Facility Name
Proctor Foundation, UCSF
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Aravind Eye Hospital
City
Coimbatore
State/Province
Tamil Nadu
Country
India
Facility Name
Aravind Eye Hospitals
City
Madurai
State/Province
Tamil Nadu
Country
India
Facility Name
Aravind Eye Hospital
City
Pondicherry
State/Province
Tamil Nadu
Country
India
Facility Name
Aravind Eye Hospital
City
Tirunelveli
State/Province
Tamil Nadu
Country
India
Facility Name
Bharatpur Eye Hospital
City
Bharatpur
State/Province
Chitwan
Country
Nepal
Facility Name
Lumbini Eye Institute
City
Bhairahawa
State/Province
Lumbini
Country
Nepal

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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