Trial Outcomes & Findings for The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole vs Placebo (NCT NCT00997035)

NCT ID: NCT00997035

Last Updated: 2019-02-26

Results Overview

Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 240 participants
• Primary outcome timeframe: 3 months from enrollment
• Results posted on: 2019-02-26

Participant Flow

Participant milestones

Measure	Placebo 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.	Oral Voriconazole 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.
3-week Followup Visit STARTED	121	119
3-week Followup Visit COMPLETED	112	113
3-week Followup Visit NOT COMPLETED	9	6
3-month Follow-up Visit STARTED	112	113
3-month Follow-up Visit COMPLETED	100	107
3-month Follow-up Visit NOT COMPLETED	12	6

Reasons for withdrawal

Measure	Placebo 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.	Oral Voriconazole 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.
3-week Followup Visit Lost to Follow-up	9	6
3-month Follow-up Visit Lost to Follow-up	12	6

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Placebo n=121 Participants 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.	Oral Voriconazole n=119 Participants 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 n=240 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	98 Participants n=5 Participants	93 Participants n=7 Participants	191 Participants n=5 Participants
Age, Categorical >=65 years	23 Participants n=5 Participants	26 Participants n=7 Participants	49 Participants n=5 Participants
Age, Continuous	50 years n=5 Participants	54 years n=7 Participants	54 years n=5 Participants
Sex: Female, Male Female	50 Participants n=5 Participants	54 Participants n=7 Participants	104 Participants n=5 Participants
Sex: Female, Male Male	71 Participants n=5 Participants	65 Participants n=7 Participants	136 Participants n=5 Participants
Region of Enrollment Nepal	98 participants n=5 Participants	98 participants n=7 Participants	196 participants n=5 Participants
Region of Enrollment India	23 participants n=5 Participants	21 participants n=7 Participants	44 participants n=5 Participants
Weight (lbs)	108 lbs n=5 Participants	105 lbs n=7 Participants	108 lbs n=5 Participants

PRIMARY outcome

Timeframe: 3 months from enrollment

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

Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo

Outcome measures

Measure	Placebo n=119 Participants 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.	Oral Placebo n=121 Participants oral placebo plus topical antifungal agents
Incidence of Perforation or Therapeutic Penetrating Keratoplasty	0.0095562 New perforations or TPK/person-days	0.011204 New perforations or TPK/person-days

SECONDARY outcome

Timeframe: 3 months after enrollment

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

Best spectacle-corrected logMAR visual acuity at 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear

Outcome measures

Measure	Placebo n=107 Participants 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.	Oral Placebo n=100 Participants oral placebo plus topical antifungal agents
Best Spectacle-corrected logMAR Visual Acuity	.7852594 logMAR Standard Error .1083858	.787141 logMAR Standard Error .1646131

SECONDARY outcome

Timeframe: 3 weeks after enrollment

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

Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear

Outcome measures

Measure	Placebo n=113 Participants 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.	Oral Placebo n=112 Participants oral placebo plus topical antifungal agents
Best Spectacle-corrected logMAR Visual Acuity at 3-weeks	.8745454 logMAR Standard Error .1080198	.744252 logMAR Standard Error .0964871

SECONDARY outcome

Timeframe: 3 months after enrollment

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

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

Outcome measures

Measure	Placebo n=107 Participants 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.	Oral Placebo n=100 Participants oral placebo plus topical antifungal agents
Size of Infiltrate/Scar - 3 Months	.9319315 mm^2 Standard Error .06508	.697005 mm^2 Standard Error .0927

SECONDARY outcome

Timeframe: 3 weeks after enrollment

Population: Mean infiltrate scar size at three weeks.

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

Outcome measures

Measure	Placebo n=113 Participants 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.	Oral Placebo n=112 Participants oral placebo plus topical antifungal agents
Size of Infiltrate/Scar	.2192398 mm^2 Standard Error .1663	.7973467 mm^2 Standard Error .073885

SECONDARY outcome

Timeframe: Up to 21 days

Hazard Ratio of re-epithelialization comparing the treatment groups

Outcome measures

Measure	Placebo n=113 Participants 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.	Oral Placebo n=112 Participants oral placebo plus topical antifungal agents
Hazard Ratio for Re-epithelialization	.0141123 Number re-epthelialized/person-days	.0130862 Number re-epthelialized/person-days

SECONDARY outcome

Timeframe: 7 days

Population: Fungal Culture negative at 7 days post treatment

Fungal Culture negative at 7 days post treatment

Outcome measures

Measure	Placebo n=121 Participants 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.	Oral Placebo n=119 Participants oral placebo plus topical antifungal agents
Microbiological Cure at 7 Days	50 Participants	50 Participants

SECONDARY outcome

Timeframe: 3-months from enrollment

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

Outcome measures

Measure	Placebo n=119 Participants 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.	Oral Placebo n=121 Participants oral placebo plus topical antifungal agents
Number of Adverse Events	58 adverse events	28 adverse events

SECONDARY outcome

Timeframe: 7 days

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

Outcome measures

Measure	Placebo n=62 Participants 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.	Oral Placebo n=64 Participants oral placebo plus topical antifungal agents
Minimum Inhibitory Concentration of Isolates - Natamycin	12 mg/L Interval 4.0 to 32.0	4 mg/L Interval 4.0 to 16.0

SECONDARY outcome

Timeframe: 7 days

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

Outcome measures

Measure	Placebo n=62 Participants 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.	Oral Placebo n=64 Participants oral placebo plus topical antifungal agents
Minimum Inhibitory Concentration of Isolates - Voriconazole	1 mg/L Interval 0.5 to 4.0	2 mg/L Interval 0.5 to 4.0

Adverse Events

Placebo

Serious events: 1 serious events

Other events: 27 other events

Deaths: 0 deaths

Oral Voriconazole

Serious events: 7 serious events

Other events: 52 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=121 participants at risk 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.	Oral Voriconazole n=119 participants at risk 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.
Eye disorders Endophthalmitis	0.83% 1/121 • Over the entire course of the trial. (June, 2010-December 2015)	2.5% 3/119 • Over the entire course of the trial. (June, 2010-December 2015)
Eye disorders Evisceration	0.00% 0/121 • Over the entire course of the trial. (June, 2010-December 2015)	0.84% 1/119 • Over the entire course of the trial. (June, 2010-December 2015)
Cardiac disorders Myocardial infarction or stroke	0.00% 0/121 • Over the entire course of the trial. (June, 2010-December 2015)	0.84% 1/119 • Over the entire course of the trial. (June, 2010-December 2015)
Hepatobiliary disorders AST or ALT elevated to five times the upper limit of normal	0.00% 0/121 • Over the entire course of the trial. (June, 2010-December 2015)	1.7% 2/119 • Over the entire course of the trial. (June, 2010-December 2015)

Other adverse events

Measure	Placebo n=121 participants at risk 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.	Oral Voriconazole n=119 participants at risk 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.
Eye disorders Ulcer not healing after 6 weeks of therapy	1.7% 2/121 • Over the entire course of the trial. (June, 2010-December 2015)	4.2% 5/119 • Over the entire course of the trial. (June, 2010-December 2015)
Eye disorders Increase in hypopyon (increase>2mm)	6.6% 8/121 • Over the entire course of the trial. (June, 2010-December 2015)	4.2% 5/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Headache	6.6% 8/121 • Over the entire course of the trial. (June, 2010-December 2015)	5.9% 7/119 • Over the entire course of the trial. (June, 2010-December 2015)
Hepatobiliary disorders AST or ALT elevated to twice upper limit of normal	0.00% 0/121 • Over the entire course of the trial. (June, 2010-December 2015)	6.7% 8/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Dizziness	0.83% 1/121 • Over the entire course of the trial. (June, 2010-December 2015)	4.2% 5/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Vomiting	1.7% 2/121 • Over the entire course of the trial. (June, 2010-December 2015)	3.4% 4/119 • Over the entire course of the trial. (June, 2010-December 2015)
Psychiatric disorders Visual disturbances	0.00% 0/121 • Over the entire course of the trial. (June, 2010-December 2015)	4.2% 5/119 • Over the entire course of the trial. (June, 2010-December 2015)
Gastrointestinal disorders Diarrhea	0.83% 1/121 • Over the entire course of the trial. (June, 2010-December 2015)	2.5% 3/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Fever	1.7% 2/121 • Over the entire course of the trial. (June, 2010-December 2015)	1.7% 2/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Lethargy	0.83% 1/121 • Over the entire course of the trial. (June, 2010-December 2015)	1.7% 2/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Nausea	0.83% 1/121 • Over the entire course of the trial. (June, 2010-December 2015)	1.7% 2/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Local allergic reaction	0.83% 1/121 • Over the entire course of the trial. (June, 2010-December 2015)	0.84% 1/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Other systemic event thought to be related to study drug	0.00% 0/121 • Over the entire course of the trial. (June, 2010-December 2015)	0.84% 1/119 • Over the entire course of the trial. (June, 2010-December 2015)
General disorders Dermatologic reaction	0.00% 0/121 • Over the entire course of the trial. (June, 2010-December 2015)	0.84% 1/119 • Over the entire course of the trial. (June, 2010-December 2015)
Gastrointestinal disorders Stomach pain	0.00% 0/121 • Over the entire course of the trial. (June, 2010-December 2015)	0.84% 1/119 • Over the entire course of the trial. (June, 2010-December 2015)

Additional Information

Kathryn Ray

University of California, San Francisco

Phone: 415-514-3227

Email: kathryn.ray@ucsf.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place