Corneal Ulcer, Eye Infections, Fungal
Conditions
Keywords
Fungal Infections, Eye Disease, Fungal Keratitis, Visual Acuity
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.
Interventions
DRUGNatamycin
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.
DRUGVoriconazole
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.
Sponsors
Aravind Eye Hospitals, India
Dartmouth-Hitchcock Medical Center
National Eye Institute (NEI)
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| Minimum Inhibitory Concentration of Isolates | 3 months after enrollment | Minimum inhibitory concentration (50th percentile) of fungal isolates to natamycin and voriconazole |
| Microbiological Cure at 6 Days | 7 days after enrollment | Microbiological cure defined as no fungal growth on culture at 6 (+/-1) days from enrollment |
| 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. |
Countries
India, United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Topical Natamycin | 162 |
| Topical Voriconazole | 161 |
| Total | 323 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 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
| Characteristic | Topical Natamycin | Topical Voriconazole | Total |
|---|---|---|---|
| Age, Continuous | 48 years | 45 years | 47 years |
| Region of Enrollment India | 162 participants | 161 participants | 323 participants |
| Sex: Female, Male Female | 73 Participants | 67 Participants | 140 Participants |
| Sex: Female, Male Male | 89 Participants | 94 Participants | 183 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 162 | 27 / 161 |
| serious Total, serious adverse events | 42 / 162 | 82 / 161 |
Outcome results
Primary
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).
Time frame: 3 months from enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Natamycin | Best Spectacle-corrected logMAR Visual Acuity | 0.39 logMAR |
| Topical Voriconazole | Best Spectacle-corrected logMAR Visual Acuity | 0.57 logMAR |
p-value: 0.00695% CI: [-0.3, -0.05]Regression, Linear
Secondary
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
Time frame: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Natamycin | Best Spectacle-corrected logMAR Visual Acuity | 0.49 logMAR |
| Topical Voriconazole | Best Spectacle-corrected logMAR Visual Acuity | 0.63 logMAR |
Secondary
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
Time frame: 3 months after enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Natamycin | Hard Contact Lens-corrected Visual Acuity Measured in logMAR | 0.18 logMAR |
| Topical Voriconazole | Hard Contact Lens-corrected Visual Acuity Measured in logMAR | 0.30 logMAR |
Secondary
Microbiological Cure at 6 Days
Microbiological cure defined as no fungal growth on culture at 6 (+/-1) days from enrollment
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Topical Natamycin | Microbiological Cure at 6 Days | 23 participants |
| Topical Voriconazole | Microbiological Cure at 6 Days | 69 participants |
Secondary
Minimum Inhibitory Concentration of Isolates
Minimum inhibitory concentration (50th percentile) of fungal isolates to natamycin and voriconazole
Time frame: 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).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Natamycin | Minimum Inhibitory Concentration of Isolates | 4 μg/ml |
| Topical Voriconazole | Minimum Inhibitory Concentration of Isolates | 2 μg/ml |
Secondary
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 frame: 3 weeks and 3 months after enrollment
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Topical Natamycin | Size of Infiltrate/Scar | 3 weeks from enrollment | 3.30 mm |
| Topical Natamycin | Size of Infiltrate/Scar | 3 months from enrollment | 3.31 mm |
| Topical Voriconazole | Size of Infiltrate/Scar | 3 weeks from enrollment | 3.44 mm |
| Topical Voriconazole | Size of Infiltrate/Scar | 3 months from enrollment | 3.52 mm |
Secondary
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.
Time frame: From enrollment to the time of resolution of epithelial defect
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topical Natamycin | Time to Resolution of Epithelial Defect | 11.50 days | Standard Deviation 7.6 |
| Topical Voriconazole | Time to Resolution of Epithelial Defect | 11.50 days | Standard Deviation 7.9 |