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

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT00997035
• Collaborator: Aravind Eye Hospitals, India (Other), Dartmouth-Hitchcock Medical Center (Other), Lumbini Eye Institute and Hospital (Other), Bharatpur Eye Hospital (Other), National Eye Institute (NEI) (NIH)
• Enrollment: 240
• Locations: 7
• Arms: 2
• Duration (Months): 70
• Patients Per Site: 34.3
• Patients Per Site Per Month: 0.5

Study Details

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
• 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 1, 2010
• Actual Primary Completion Date: Jan 1, 2016
• Actual Study Completion Date: Mar 1, 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 [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 [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 [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 [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 [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 [Up to 21 days]

   Hazard Ratio of re-epithelialization comparing the treatment groups

6. Microbiological Cure at 7 Days [7 days]

   Fungal Culture negative at 7 days post treatment

7. Number of Adverse Events [3-months from enrollment]

   Comparing the number of serious and non-serious adverse events by treatment arm.

8. Minimum Inhibitory Concentration of Isolates - Natamycin [7 days]

   Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm

9. Minimum Inhibitory Concentration of Isolates - Voriconazole [7 days]

   Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm

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 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

	Site	City	State	Country	Postal Code
1	Proctor Foundation, UCSF	San Francisco	California	United States	94143
2	Aravind Eye Hospital	Coimbatore	Tamil Nadu	India
3	Aravind Eye Hospitals	Madurai	Tamil Nadu	India
4	Aravind Eye Hospital	Pondicherry	Tamil Nadu	India
5	Aravind Eye Hospital	Tirunelveli	Tamil Nadu	India
6	Bharatpur Eye Hospital	Bharatpur	Chitwan	Nepal
7	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• 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
• First Posted: Oct 16, 2009
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• 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

Study Results

Participant Flow

Arm/Group Title	Placebo	Oral Voriconazole
Arm/Group Description	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.	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.
Period Title: 3-week Followup Visit
STARTED	121	119
COMPLETED	112	113
NOT COMPLETED	9	6
Period Title: 3-week Followup Visit
STARTED	112	113
COMPLETED	100	107
NOT COMPLETED	12	6

Baseline Characteristics

Arm/Group Title	Placebo	Oral Voriconazole	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	121	119	240
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	98 81%	93 78.2%	191 79.6%
>=65 years	23 19%	26 21.8%	49 20.4%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	50	54	54
Sex: Female, Male (Count of Participants)
Female	50 41.3%	54 45.4%	104 43.3%
Male	71 58.7%	65 54.6%	136 56.7%
Region of Enrollment (participants) [Number]
Nepal	98 81%	98 82.4%	196 81.7%
India	23 19%	21 17.6%	44 18.3%
Weight (lbs) (lbs) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [lbs]	108	105	108

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Comparison of rate of perforation or TPK between the treatment groups (topical voriconazole with oral voriconazole vs. topical voriconazole with oral placebo)

Arm/Group Title	Oral Voriconazole	Oral Placebo
Arm/Group Description	oral voriconazole plus topical antifungal agents	oral placebo plus topical antifungal agents
Measure Participants	119	121
Number [New perforations or TPK/person-days]	0.0095562	0.011204

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Voriconazole, Oral Placebo
	Comments	The sample size was determined based on the primary end point: perforation or the need for TPK within 3 months. Simulation-based analyses estimated that a sample sizeof 240 study participants (120 per arm) would provide 80% power to detect a 15% difference in the 3-month perforation or need for TPK rate between topical antifungal plus oral voriconazole vs topical antifungal alone,with a 2-tailed α value of .05 and approximately 15%loss to follow-up.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.29
	Comments
	Method	Regression, Cox
	Comments	Cox proportional hazards regression to estimate the hazard of perforation or need for TPK.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and study site

Arm/Group Title	Oral Voriconazole	Oral Placebo
Arm/Group Description	Oral Voriconazole plus topical antifungal agents	Oral Placebo plus topical antifungal agents
Measure Participants	107	100
Mean (Standard Error) [logMAR]	.7852594 (.1083858)	.787141 (.1646131)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and study site.

Arm/Group Title	Oral Voriconazole	Oral Placebo
Arm/Group Description	Oral Voriconazole plus topical antifungal agents	Oral Placebo plus topical antifungal agents
Measure Participants	113	112
Mean (Standard Error) [logMAR]	.8745454 (.1080198)	.744252 (.0964871)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Mean infiltrate scar size at three months correcting for baseline scar size and site

Arm/Group Title	Oral Voriconazole	Oral Placebo
Arm/Group Description	Oral voriconazole treated participants	Oral Placebo plus topical antifungal agents
Measure Participants	107	100
Mean (Standard Error) [mm^2]	.9319315 (.06508)	.697005 (.0927)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Mean infiltrate scar size at three weeks.

Arm/Group Title	Oral Voriconazole	Oral Placebo
Arm/Group Description	Oral voriconazole treated participants	Oral Placebo plus topical antifungal agent
Measure Participants	113	112
Mean (Standard Error) [mm^2]	.2192398 (.1663)	.7973467 (.073885)

6. Secondary Outcome

Title	Hazard Ratio for Re-epithelialization
Description	Hazard Ratio of re-epithelialization comparing the treatment groups
Time Frame	Up to 21 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Voriconazole	Oral Placebo
Arm/Group Description	oral voriconazole plus topical antifungal	oral placebo plus topical antifungal
Measure Participants	113	112
Number [Number re-epthelialized/person-days]	.0141123	.0130862

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Voriconazole, Oral Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.65
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; .49 to 1.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Microbiological Cure at 7 Days
Description	Fungal Culture negative at 7 days post treatment
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Fungal Culture negative at 7 days post treatment

Arm/Group Title	Placebo	Oral Voriconazole
Arm/Group Description	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.	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.
Measure Participants	121	119
Count of Participants [Participants]	50 41.3%	50 42%

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Voriconazole	Placebo
Arm/Group Description	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: 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.
Measure Participants	119	121
Number [adverse events]	58	28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Oral Voriconazole, Oral Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Statistically significant after Holms-Šidák correction for multiple comparisons.
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Minimum Inhibitory Concentration of Isolates - Natamycin
Description	Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Voriconazole	Placebo
Arm/Group Description	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: 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.
Measure Participants	62	64
Median (Inter-Quartile Range) [mg/L]	12	4

10. Secondary Outcome

Title	Minimum Inhibitory Concentration of Isolates - Voriconazole
Description	Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Voriconazole	Placebo
Arm/Group Description	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: 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.
Measure Participants	62	64
Median (Inter-Quartile Range) [mg/L]	1	2

Adverse Events

Time Frame	Over the entire course of the trial. (June, 2010-December 2015)
Arm/Group Title	Placebo		Oral Voriconazole
Arm/Group Description	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.		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.
All Cause Mortality
	Placebo		Oral Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Oral Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/121 (0.8%)		7/119 (5.9%)
Cardiac disorders
Myocardial infarction or stroke	0/121 (0%)		1/119 (0.8%)
Eye disorders
Endophthalmitis	1/121 (0.8%)		3/119 (2.5%)
Evisceration	0/121 (0%)		1/119 (0.8%)
Hepatobiliary disorders
AST or ALT elevated to five times the upper limit of normal	0/121 (0%)		2/119 (1.7%)
Other (Not Including Serious) Adverse Events
	Placebo		Oral Voriconazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/121 (22.3%)		52/119 (43.7%)
Eye disorders
Ulcer not healing after 6 weeks of therapy	2/121 (1.7%)		5/119 (4.2%)
Increase in hypopyon (increase>2mm)	8/121 (6.6%)		5/119 (4.2%)
Gastrointestinal disorders
Diarrhea	1/121 (0.8%)		3/119 (2.5%)
Stomach pain	0/121 (0%)		1/119 (0.8%)
General disorders
Headache	8/121 (6.6%)		7/119 (5.9%)
Dizziness	1/121 (0.8%)		5/119 (4.2%)
Vomiting	2/121 (1.7%)		4/119 (3.4%)
Fever	2/121 (1.7%)		2/119 (1.7%)
Lethargy	1/121 (0.8%)		2/119 (1.7%)
Nausea	1/121 (0.8%)		2/119 (1.7%)
Local allergic reaction	1/121 (0.8%)		1/119 (0.8%)
Other systemic event thought to be related to study drug	0/121 (0%)		1/119 (0.8%)
Dermatologic reaction	0/121 (0%)		1/119 (0.8%)
Hepatobiliary disorders
AST or ALT elevated to twice upper limit of normal	0/121 (0%)		8/119 (6.7%)
Psychiatric disorders
Visual disturbances	0/121 (0%)		5/119 (4.2%)

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.