MUTT I: Mycotic Ulcer Treatment Trial I

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00996736
• Collaborator: Aravind Eye Hospitals, India (Other), Dartmouth-Hitchcock Medical Center (Other), National Eye Institute (NEI) (NIH)
• Enrollment: 323
• Locations: 3
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 107.7
• Patients Per Site Per Month: 4

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Corneal Ulcer; Eye Infections, Fungal	Drug: Natamycin; Drug: Voriconazole	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 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 323 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Mycotic Ulcer Treatment Trial
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Topical Natamycin	Drug: Natamycin; 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.
Experimental: Topical Voriconazole	Drug: Voriconazole; 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.

Outcome Measures

Primary Outcome Measures

1. Best Spectacle-corrected logMAR Visual Acuity [3 months from enrollment]

   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

1. Best Spectacle-corrected logMAR Visual Acuity [3 weeks after enrollment]

   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

2. Hard Contact Lens-corrected Visual Acuity Measured in logMAR [3 months after enrollment]

   Hard contact lens-corrected visual acuity measured in logMAR (logarithm of the Minimum Angle of Resolution) 3 months after enrollment

3. Size of Infiltrate/Scar [3 weeks and 3 months after enrollment]

   Size of infiltrate/scar at 3 weeks and 3 months after enrollment, using enrollment infiltrate scar/size as a covariate

4. Time to Resolution of Epithelial Defect [From enrollment to the time of 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.

5. Minimum Inhibitory Concentration of Isolates [3 months after enrollment]

   Minimum inhibitory concentration (50th percentile) of fungal isolates to natamycin and voriconazole

6. Microbiological Cure at 6 Days [7 days after enrollment]

   Microbiological cure defined as no fungal growth on culture at 6 (+/-1) days from enrollment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Proctor Foundation, UCSF	San Francisco	California	United States	94143
2	Aravind Eye Hospitals	Madurai	Tamil Nadu	India
3	Aravind Eye Hospital	Pondicherry	Tamil Nadu	India

Sponsors and Collaborators

• University of California, San Francisco
• Aravind Eye Hospitals, India
• Dartmouth-Hitchcock Medical Center
• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.

• Responsible Party: Thomas M. Lietman, Professor in Residence, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT00996736
• Other Study ID Numbers: H9332-33965-02; U10EY018573-01A1
• First Posted: Oct 16, 2009
• Last Update Posted: Aug 1, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Thomas M. Lietman, Professor in Residence, 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; Voriconazole; Natamycin

Study Results

Participant Flow

Recruitment Details	Between April 3, 2010, and December 31, 2011, patients were recruited from the Cornea Clinics at the Aravind Eye Care Hospitals in Madurai, Pondicherry, and Coimbatore in Tamil Nadu, India.

Arm/Group Title	Topical Natamycin	Topical Voriconazole
Arm/Group Description
Period Title: Overall Study
STARTED	162	161
3-week Visit	155	151
3-month Visit	146	146
COMPLETED	141	143
NOT COMPLETED	21	18

Baseline Characteristics

Arm/Group Title	Topical Natamycin	Topical Voriconazole	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	162	161	323
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	48	45	47
Sex: Female, Male (Count of Participants)
Female	73 45.1%	67 41.6%	140 43.3%
Male	89 54.9%	94 58.4%	183 56.7%
Region of Enrollment (participants) [Number]
India	162 100%	161 100%	323 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Topical Natamycin	Topical Voriconazole
Arm/Group Description
Measure Participants	141	143
Mean (95% Confidence Interval) [logMAR]	0.39	0.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Topical Natamycin, Topical Voriconazole
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	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).
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.30 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

306 total subjects (155 in natamycin arm, 151 in voriconazole arm) returned after enrollment for a second visit, but only 293 of those (149 in natamycin arm and 144 in voriconazole arm) visited within the 3-week window (2.5-5 weeks). Only those who visited within the window were included in the analysis.

Arm/Group Title	Topical Natamycin	Topical Voriconazole
Arm/Group Description
Measure Participants	149	144
Mean (95% Confidence Interval) [logMAR]	0.49	0.63

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Topical Natamycin	Topical Voriconazole
Arm/Group Description
Measure Participants	141	143
Mean (95% Confidence Interval) [logMAR]	0.18	0.30

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Topical Natamycin	Topical Voriconazole
Arm/Group Description
Measure Participants	141	143
3 weeks from enrollment	3.30	3.44
3 months from enrollment	3.31	3.52

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Topical Natamycin	Topical Voriconazole
Arm/Group Description
Measure Participants	162	161
Mean (Standard Deviation) [days]	11.50 (7.60)	11.50 (7.90)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The population for analysis included only those subjects with positive fungal cultures and for whom Minimum Inhibitory Concentrations were available (108 subjects who were randomized to natamycin and 113 who were randomized to voriconazole).

Arm/Group Title	Topical Natamycin	Topical Voriconazole
Arm/Group Description
Measure Participants	108	113
Mean (95% Confidence Interval) [μg/ml]	4	2

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Of the 323 participants with smear-positive ulcers enrolled in the trial, 299 (92.6%) were scraped and cultured 6 days after enrollment - 155 in the natamycin arm, and 144 in the voriconazole arm.

Arm/Group Title	Topical Natamycin	Topical Voriconazole
Arm/Group Description
Measure Participants	155	144
Number [participants]	23 14.2%	69 42.9%

Adverse Events

Arm/Group Title	Topical Natamycin		Topical Voriconazole
Arm/Group Description
All Cause Mortality
	Topical Natamycin		Topical Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Topical Natamycin		Topical Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/162 (25.9%)		82/161 (50.9%)
Cardiac disorders
Myocardial infarction or stroke	0/162 (0%)		1/161 (0.6%)
Eye disorders
Corneal perforation	10/162 (6.2%)		15/161 (9.3%)
Therapeutic penetrating keratoplasty	13/162 (8%)		29/161 (18%)
Endophthalmitis	0/162 (0%)		2/161 (1.2%)
Death	1/162 (0.6%)		1/161 (0.6%)
Corneal perforation and/or TPK	18/162 (11.1%)		34/161 (21.1%)
Other (Not Including Serious) Adverse Events
	Topical Natamycin		Topical Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/162 (6.2%)		27/161 (16.8%)
Eye disorders
Increase in hypopyon (>2mm)	5/162 (3.1%)		12/161 (7.5%)
Increase in infiltrate size > 50%	5/162 (3.1%)		13/161 (8.1%)
Progressive corneal thinning, <=50% of enrollment thickness	0/162 (0%)		2/161 (1.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.