Trial Outcomes & Findings for Mycotic Ulcer Treatment Trial I (NCT NCT00996736)

NCT ID: NCT00996736

Last Updated: 2018-08-01

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 323 participants
• Primary outcome timeframe: 3 months from enrollment
• Results posted on: 2018-08-01

Participant Flow

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.

Participant milestones

Measure	Topical Natamycin	Topical Voriconazole
Overall Study STARTED	162	161
Overall Study 3-week Visit	155	151
Overall Study 3-month Visit	146	146
Overall Study COMPLETED	141	143
Overall Study NOT COMPLETED	21	18

Reasons for withdrawal

Measure	Topical Natamycin	Topical Voriconazole
Overall Study Death	1	1
Overall Study Lost to Follow-up	15	14
Overall Study Visit not within 3-month window	5	3

Baseline Characteristics

Mycotic Ulcer Treatment Trial I

Baseline characteristics by cohort

Measure	Topical Natamycin n=162 Participants	Topical Voriconazole n=161 Participants	Total n=323 Participants Total of all reporting groups
Age, Continuous	48 years n=5 Participants	45 years n=7 Participants	47 years n=5 Participants
Sex: Female, Male Female	73 Participants n=5 Participants	67 Participants n=7 Participants	140 Participants n=5 Participants
Sex: Female, Male Male	89 Participants n=5 Participants	94 Participants n=7 Participants	183 Participants n=5 Participants
Region of Enrollment India	162 participants n=5 Participants	161 participants n=7 Participants	323 participants n=5 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Topical Natamycin n=141 Participants	Topical Voriconazole n=143 Participants
Best Spectacle-corrected logMAR Visual Acuity	0.39 logMAR Interval 0.3 to 0.48	0.57 logMAR Interval 0.48 to 0.65

SECONDARY outcome

Timeframe: 3 weeks after enrollment

Population: 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.

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

Outcome measures

Measure	Topical Natamycin n=149 Participants	Topical Voriconazole n=144 Participants
Best Spectacle-corrected logMAR Visual Acuity	0.49 logMAR Interval 0.42 to 0.57	0.63 logMAR Interval 0.56 to 0.7

SECONDARY outcome

Timeframe: 3 months after enrollment

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

Outcome measures

Measure	Topical Natamycin n=141 Participants	Topical Voriconazole n=143 Participants
Hard Contact Lens-corrected Visual Acuity Measured in logMAR	0.18 logMAR Interval 0.11 to 0.26	0.30 logMAR Interval 0.22 to 0.38

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Topical Natamycin n=141 Participants	Topical Voriconazole n=143 Participants
Size of Infiltrate/Scar 3 weeks from enrollment	3.30 mm Interval 3.15 to 3.48	3.44 mm Interval 3.29 to 3.6
Size of Infiltrate/Scar 3 months from enrollment	3.31 mm Interval 3.15 to 3.48	3.52 mm Interval 3.35 to 3.68

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Topical Natamycin n=162 Participants	Topical Voriconazole n=161 Participants
Time to Resolution of Epithelial Defect	11.50 days Standard Deviation 7.60	11.50 days Standard Deviation 7.90

SECONDARY outcome

Timeframe: 3 months after enrollment

Population: 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).

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

Outcome measures

Measure	Topical Natamycin n=108 Participants	Topical Voriconazole n=113 Participants
Minimum Inhibitory Concentration of Isolates	4 μg/ml Interval 4.0 to 4.0	2 μg/ml Interval 1.0 to 2.0

SECONDARY outcome

Timeframe: 7 days after enrollment

Population: 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.

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

Outcome measures

Measure	Topical Natamycin n=155 Participants	Topical Voriconazole n=144 Participants
Microbiological Cure at 6 Days	23 participants	69 participants

Adverse Events

Topical Natamycin

Serious events: 42 serious events

Other events: 10 other events

Deaths: 0 deaths

Topical Voriconazole

Serious events: 82 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Measure	Topical Natamycin n=162 participants at risk	Topical Voriconazole n=161 participants at risk
Eye disorders Corneal perforation	6.2% 10/162	9.3% 15/161
Eye disorders Therapeutic penetrating keratoplasty	8.0% 13/162	18.0% 29/161
Eye disorders Endophthalmitis	0.00% 0/162	1.2% 2/161
Eye disorders Death	0.62% 1/162	0.62% 1/161
Cardiac disorders Myocardial infarction or stroke	0.00% 0/162	0.62% 1/161
Eye disorders Corneal perforation and/or TPK	11.1% 18/162	21.1% 34/161

Other adverse events

Measure	Topical Natamycin n=162 participants at risk	Topical Voriconazole n=161 participants at risk
Eye disorders Increase in hypopyon (>2mm)	3.1% 5/162	7.5% 12/161
Eye disorders Increase in infiltrate size > 50%	3.1% 5/162	8.1% 13/161
Eye disorders Progressive corneal thinning, <=50% of enrollment thickness	0.00% 0/162	1.2% 2/161

Additional Information

Dr. Thomas Lietman

F.I. Proctor Foundation, University of Califonia, San Francisco

Phone: 415-502-2662

Email: tom.lietman@ucsf.edu

Results disclosure agreements

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