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Mycotic Ulcer Treatment Trial I (MUTT I)

Primary Purpose

Corneal Ulcer, Eye Infections, Fungal

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Natamycin
Voriconazole
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 between 6/12 (20/40, logMAR 0.3) and 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:

  • Impending perforation
  • 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)
  • 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 worse than 6/120 (20/400) or better than 6/12 (20/40) in the study eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA can be used for enrollment)
  • 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 Hospitals
  • Aravind Eye Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Topical Natamycin

Topical Voriconazole

Arm Description

Outcomes

Primary Outcome Measures

Best Spectacle-corrected logMAR Visual Acuity
The primary analysis is best spectacle-corrected logMAR (logarithm of the Minimum Angle or Resolution) visual acuity, correcting for enrollment BSCVA and treatment arm in a multiple linear regression model. The pre-specified non-inferiority margin is less than 1.5 lines logMAR acuity. (Adjusted three-month visual acuity confidence bounds for the difference between the voriconazole and natamycin groups which meet or exceed 0.15 logMAR units would not permit noninferiority to be declared.) Note that this design also allows declaration of superiority (2-sided alpha of 0.05, corrected for an interim analysis).

Secondary Outcome Measures

Best Spectacle-corrected logMAR Visual Acuity
Best spectacle-corrected logMAR (logarithm of the Minimum Angle of Resolution) visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear regression model
Hard Contact Lens-corrected Visual Acuity Measured in logMAR
Hard contact lens-corrected visual acuity measured in logMAR (logarithm of the Minimum Angle of Resolution) 3 months after enrollment
Size of Infiltrate/Scar
Size of infiltrate/scar at 3 weeks and 3 months after enrollment, using enrollment infiltrate scar/size as a covariate
Time to Resolution of Epithelial Defect
Time in days from enrollment to resolution of epithelial defect. For those subjects with more than 21 days to resolution, 21 days was used.
Minimum Inhibitory Concentration of Isolates
Minimum inhibitory concentration (50th percentile) of fungal isolates to natamycin and voriconazole
Microbiological Cure at 6 Days
Microbiological cure defined as no fungal growth on culture at 6 (+/-1) days from enrollment

Full Information

First Posted
October 14, 2009
Last Updated
July 6, 2018
Sponsor
University of California, San Francisco
Collaborators
Aravind Eye Hospitals, India, Dartmouth-Hitchcock Medical Center, National Eye Institute (NEI)
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1. Study Identification

Unique Protocol Identification Number
NCT00996736
Brief Title
Mycotic Ulcer Treatment Trial I
Acronym
MUTT I
Official Title
Mycotic Ulcer Treatment Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2018
Overall Recruitment Status
Completed
Study Start Date
April 2010 (undefined)
Primary Completion Date
July 2012 (Actual)
Study Completion Date
July 2012 (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, National Eye Institute (NEI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine if natamycin or voriconazole results in better visual outcomes in fungal corneal ulcers, especially visual acuity.
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 natamycin or voriconazole results in better outcomes for fungal corneal ulcers. 368 fungal corneal ulcers with baseline visual acuity between 6/12 (20/40, logMAR 0.3) and 6/120 (20/400, logMAR 1.3) presenting to the Aravind Eye Hospitals and the UCSF Proctor Foundation will be randomized to receive either topical natamycin or topical voriconazole. The primary outcome is best spectacle-corrected logMAR visual acuity three months after enrollment, using best spectacle-corrected enrollment visual acuity as a co-variate.

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
323 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Topical Natamycin
Arm Type
Active Comparator
Arm Title
Topical Voriconazole
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Natamycin
Intervention Description
5% natamycin plus 0.02% preservative, one drop to the affected eye every one hour while awake for 1 week, then every 2 hours while awake until 3 weeks after enrollment.
Intervention Type
Drug
Intervention Name(s)
Voriconazole
Intervention Description
1% voriconazole 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.
Primary Outcome Measure Information:
Title
Best Spectacle-corrected logMAR Visual Acuity
Description
The primary analysis is best spectacle-corrected logMAR (logarithm of the Minimum Angle or Resolution) visual acuity, correcting for enrollment BSCVA and treatment arm in a multiple linear regression model. The pre-specified non-inferiority margin is less than 1.5 lines logMAR acuity. (Adjusted three-month visual acuity confidence bounds for the difference between the voriconazole and natamycin groups which meet or exceed 0.15 logMAR units would not permit noninferiority to be declared.) Note that this design also allows declaration of superiority (2-sided alpha of 0.05, corrected for an interim analysis).
Time Frame
3 months from enrollment
Secondary Outcome Measure Information:
Title
Best Spectacle-corrected logMAR Visual Acuity
Description
Best spectacle-corrected logMAR (logarithm of the Minimum Angle of Resolution) visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear regression model
Time Frame
3 weeks after enrollment
Title
Hard Contact Lens-corrected Visual Acuity Measured in logMAR
Description
Hard contact lens-corrected visual acuity measured in logMAR (logarithm of the Minimum Angle of Resolution) 3 months after enrollment
Time Frame
3 months after enrollment
Title
Size of Infiltrate/Scar
Description
Size of infiltrate/scar at 3 weeks and 3 months after enrollment, using enrollment infiltrate scar/size as a covariate
Time Frame
3 weeks and 3 months after enrollment
Title
Time to Resolution of Epithelial Defect
Description
Time in days from enrollment to resolution of epithelial defect. For those subjects with more than 21 days to resolution, 21 days was used.
Time Frame
From enrollment to the time of resolution of epithelial defect
Title
Minimum Inhibitory Concentration of Isolates
Description
Minimum inhibitory concentration (50th percentile) of fungal isolates to natamycin and voriconazole
Time Frame
3 months after enrollment
Title
Microbiological Cure at 6 Days
Description
Microbiological cure defined as no fungal growth on culture at 6 (+/-1) days from enrollment
Time Frame
7 days after enrollment

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 between 6/12 (20/40, logMAR 0.3) and 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: Impending perforation 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) 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 worse than 6/120 (20/400) or better than 6/12 (20/40) in the study eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA can be used for enrollment) 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 Hospitals
City
Madurai
State/Province
Tamil Nadu
Country
India
Facility Name
Aravind Eye Hospital
City
Pondicherry
State/Province
Tamil Nadu
Country
India

12. IPD Sharing Statement

Citations:
PubMed Identifier
23710492
Citation
Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Prajna L, Srinivasan M, Raghavan A, Oldenburg CE, Ray KJ, Zegans ME, McLeod SD, Porco TC, Acharya NR, Lietman TM; Mycotic Ulcer Treatment Trial Group. The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013 Apr;131(4):422-9. doi: 10.1001/jamaophthalmol.2013.1497.
Results Reference
background
PubMed Identifier
35024776
Citation
Prajna NV, Lalitha P, Krishnan T, Rajaraman R, Radnakrishnan N, Srinivasan M, Devi L, Das M, Liu Z, Zegans ME, Acharya NR, Porco TC, Lietman TM, Rose-Nussbaumer J. Patterns of Antifungal Resistance in Adult Patients With Fungal Keratitis in South India: A Post Hoc Analysis of 3 Randomized Clinical Trials. JAMA Ophthalmol. 2022 Feb 1;140(2):179-184. doi: 10.1001/jamaophthalmol.2021.5765.
Results Reference
derived
PubMed Identifier
28817744
Citation
Prajna NV, Krishnan T, Rajaraman R, Patel S, Shah R, Srinivasan M, Das M, Ray KJ, Oldenburg CE, McLeod SD, Zegans ME, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. Predictors of Corneal Perforation or Need for Therapeutic Keratoplasty in Severe Fungal Keratitis: A Secondary Analysis of the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol. 2017 Sep 1;135(9):987-991. doi: 10.1001/jamaophthalmol.2017.2914.
Results Reference
derived
PubMed Identifier
28426856
Citation
Prajna NV, Krishnan T, Rajaraman R, Patel S, Shah R, Srinivasan M, Devi L, Das M, Ray KJ, O'Brien KS, Oldenburg CE, McLeod SD, Zegans ME, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis: A Secondary Analysis From the Mycotic Ulcer Treatment Trial II. JAMA Ophthalmol. 2017 Jun 1;135(6):520-525. doi: 10.1001/jamaophthalmol.2017.0616.
Results Reference
derived
PubMed Identifier
27787540
Citation
Prajna NV, Krishnan T, Rajaraman R, Patel S, Srinivasan M, Das M, Ray KJ, O'Brien KS, Oldenburg CE, McLeod SD, Zegans ME, Porco TC, Acharya NR, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial II Group. Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial. JAMA Ophthalmol. 2016 Dec 1;134(12):1365-1372. doi: 10.1001/jamaophthalmol.2016.4096.
Results Reference
derived
PubMed Identifier
27054515
Citation
Prajna NV, Lalitha P, Rajaraman R, Krishnan T, Raghavan A, Srinivasan M, O'Brien KS, Zegans M, McLeod SD, Acharya NR, Keenan JD, Lietman TM, Rose-Nussbaumer J; Mycotic Ulcer Treatment Trial Group. Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial. JAMA Ophthalmol. 2016 Jun 1;134(6):693-6. doi: 10.1001/jamaophthalmol.2016.0530.
Results Reference
derived
PubMed Identifier
26531051
Citation
Rose-Nussbaumer J, Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Srinivasan M, Raghavan A, Oldenburg CE, O'Brien KS, Ray KJ, Porco TC, McLeod SD, Acharya NR, Keenan JD, Lietman TM; Mycotic Ulcer Treatment Trial Group. Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole. Br J Ophthalmol. 2016 Jul;100(7):929-932. doi: 10.1136/bjophthalmol-2015-306828. Epub 2015 Nov 3.
Results Reference
derived
PubMed Identifier
25764482
Citation
Rose-Nussbaumer J, Prajna NV, Krishnan KT, Mascarenhas J, Rajaraman R, Srinivasan M, Raghavan A, Oldenburg CE, O'Brien KS, Ray KJ, McLeod SD, Porco TC, Lietman TM, Acharya NR, Keenan JD; Mycotic Ulcer Treatment Trial I Group. Vision-Related Quality-of-Life Outcomes in the Mycotic Ulcer Treatment Trial I: A Randomized Clinical Trial. JAMA Ophthalmol. 2015 Jun;133(6):642-6. doi: 10.1001/jamaophthalmol.2015.0319.
Results Reference
derived
PubMed Identifier
23702779
Citation
Sun CQ, Prajna NV, Krishnan T, Mascarenhas J, Rajaraman R, Srinivasan M, Raghavan A, O'Brien KS, Ray KJ, McLeod SD, Porco TC, Acharya NR, Lietman TM. Expert prior elicitation and Bayesian analysis of the Mycotic Ulcer Treatment Trial I. Invest Ophthalmol Vis Sci. 2013 Jun 14;54(6):4167-73. doi: 10.1167/iovs.13-11716.
Results Reference
derived

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Mycotic Ulcer Treatment Trial I

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