Fungal Keratitis
Conditions
Keywords
Keratitis, Eye Infection, Fungal, Fungal Eye Infection, Ocular Infection, Fungal, Fungal Keratitis, Mycotic Infections, Ocular, Voriconazole, Natamycin
Brief summary
We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data.
Detailed description
Fungal ulcers tend to have very poor outcomes with the most common treatments, amphotericin B and natamycin. There has been only a single randomized trial of anti-fungal therapy for fungal ulcers and no new medications have been approved by the FDA since the 1960s. There are studies that indicate that the newer triazoles, such as voriconazole, are more effective in vitro against filamentous fungi such as Aspergillus spp., a common cause of fungal keratitis1-3. Despite a number of case reports and in vitro studies, there has been no systematic attempt to determine whether it is more or less effective clinically than natamycin, the only commercially available FDA-approved agent. There is little data available for physicians to make an informed, evidence-based decision on choice of antifungal. We evaluated whether voriconazole is a superior treatment to natamycin for filamentous fungal keratitis in a randomized, masked, controlled trial. This is a therapeutic exploratory study to investigate the safety and feasibility of conducting a larger study and to generate preliminary data. The primary outcome is visual acuity at 3 months from enrollment. A subset of patients will be followed at 4 years from enrollment.
Interventions
DRUGNatamycin 5%
One drop of medication will be given every one hour while awake for one week. For another 2 weeks, one drop of medication should be given every 2 hours while awake
DRUGVoriconazole
Voriconazole (VFEND® I.V., Pfizer, New York, NY) will be prepared as a 1% solution. One drop of medication should be given every one hour while awake for one week. For another 2 weeks, one drop of medication should be given every 2 hours while awake
PROCEDURECorneal de-epithelialization
Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications.
Sponsors
That Man May See, Inc.
Aravind Eye Hospitals, India
Dartmouth-Hitchcock Medical Center
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 KOH (or Giemsa or any other stain) or culture * 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 in-patient or to be treated as an out-patient and come back every 48-72 hours to receive fresh medication for 3 weeks * Appropriate consent
Exclusion criteria
* Overlying epithelial defect \< 0.5 mm at its greatest width at presentation * 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 (20/200) in the fellow eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA 6/60 or better qualifies 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 Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model | 3 months from enrollment | The primary efficacy endpoint was BSCVA at 3 months in the study eye, using a linear regression model with 3-month BSCVA measured in logMAR (logarithm of the Minimum Angle of Resolution) as the outcome variable and treatment arm (voriconazole vs natamycin) and enrollment logMAR BSCVA and corneal de-epithelialization (yes or no) as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Resolution of Epithelial Defect | 3 months from enrollment | Resolution of epithelial defect was defined as the absence of an epithelial defect with administration of fluorescein. The time to re-epithelialization was compared between the voriconazole and natamycin groups using the Cox proportional hazards model, adjusting for baseline epithelial defect size. |
| Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate. | 3 months from enrollment | Size of infiltrate/scar post-treatment was analyzed in a linear regression model using enrollment infiltrate/scar size as a covariate. No differentiation was made between infiltrate and scar when measuring infiltrate/scar size (measured in mm). For analysis, infiltrate/scar size was characterized by the geometric mean of the longest dimension and the longest perpendicular. |
| Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp). | 3 months from enrollment | Two subgroup analyses were conducted by causative organism: 1) best spectacle-corrected visual acuity (BSCVA) by treatment arm among Fusarium ulcers; 2) best spectacle-corrected visual acuity (BSCVA) by treatment arm among Aspergillus ulcers. |
| Best Hard Contact Lens-corrected Visual Acuity 3 Months After Enrollment in a Multiple Linear Regression Model With Enrollment Hard Contact Lens-corrected Visual Acuity as a Covariate | 3 months from enrollment | Best hard contact lens-corrected visual acuity 3 months after enrollment was evaluated in a multiple linear regression model with enrollment hard contact lens-corrected visual acuity as a covariate. Visual acuity is reported in logMAR (logarithm of the Minimum Angle of Resolution). |
Countries
India
Participant flow
Recruitment details
From November 27, 2007 to May 12, 2008, all patients with a corneal ulcer presenting to Aravind Eye Hospital's cornea clinics in Madurai and Pondicherry, India, were evaluated for eligibility. The Aravind Eye Care System is both a primary and tertiary care eye hospital in South India with a well-established cornea subspecialty clinic.
Pre-assignment details
All patients with a corneal ulcer had corneal scrapings using a Kimura spatula for Gram stain and potassium hydroxide wet mount and had cultures plated on blood, chocolate, and potato dextrose agar. If all inclusion criteria and no exclusion criteria were met, the patient was enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Topical Voriconazole With Corneal De-epithelialization Drug: Voriconazole Voriconazole prepared as a 1% solution. One drop of medication every one hour while awake for one week. For another 2 weeks, one drop of medication every 2 hours while awake
Procedure/Surgery: Corneal de-epithelialization Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications. | 30 |
| Topical Voriconazole Without Corneal De-epithelialization Drug: Voriconazole Voriconazole prepared as a 1% solution. One drop of medication every one hour while awake for one week. For another 2 weeks, one drop of medication every 2 hours while awake. | 30 |
| Topical Natamycin With Corneal De-epithelialization Drug: Natamycin 5% One drop of medication every one hour while awake for one week. For another 2 weeks, one drop of medication every 2 hours while awake.
Procedure/Surgery: Corneal de-epithelialization Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications. | 30 |
| Topical Natamycin Without Corneal De-epithelialization Drug: Natamycin 5% One drop of medication every one hour while awake for one week. For another 2 weeks, one drop of medication every 2 hours while awake. | 30 |
| Total | 120 |
Baseline characteristics
| Characteristic | Topical Voriconazole With Corneal De-epithelialization | Topical Voriconazole Without Corneal De-epithelialization | Topical Natamycin With Corneal De-epithelialization | Topical Natamycin Without Corneal De-epithelialization | Total |
|---|---|---|---|---|---|
| Age, Continuous | 47.0 years STANDARD_DEVIATION 14.5 | 45.0 years STANDARD_DEVIATION 14.5 | 49.8 years STANDARD_DEVIATION 11.9 | 45.9 years STANDARD_DEVIATION 13.1 | 46.93 years STANDARD_DEVIATION 13.72 |
| Enrollment logMAR BSCVA | 0.94 logMAR STANDARD_DEVIATION 0.66 | 0.96 logMAR STANDARD_DEVIATION 0.66 | 0.87 logMAR STANDARD_DEVIATION 0.67 | 0.94 logMAR STANDARD_DEVIATION 0.61 | 0.93 logMAR STANDARD_DEVIATION 0.64 |
| Region of Enrollment India | 30 participants | 30 participants | 30 participants | 30 participants | 120 participants |
| Sex: Female, Male Female | 14 Participants | 9 Participants | 7 Participants | 11 Participants | 41 Participants |
| Sex: Female, Male Male | 16 Participants | 21 Participants | 23 Participants | 19 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 30 | 5 / 30 | 2 / 30 | 2 / 30 |
| serious Total, serious adverse events | 6 / 30 | 5 / 30 | 8 / 30 | 1 / 30 |
Outcome results
Primary
Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model
The primary efficacy endpoint was BSCVA at 3 months in the study eye, using a linear regression model with 3-month BSCVA measured in logMAR (logarithm of the Minimum Angle of Resolution) as the outcome variable and treatment arm (voriconazole vs natamycin) and enrollment logMAR BSCVA and corneal de-epithelialization (yes or no) as covariates.
Time frame: 3 months from enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Voriconazole | Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model | 0.61 logMAR |
| Topical Natamycin | Best Spectacle Corrected Visual Acuity (BSCVA) 3 Months After Enrollment, Adjusting for Enrollment BSCVA in a Multiple Linear Regression Model | 0.71 logMAR |
p-value: 0.2995% CI: [-0.28, 0.083]Regression, Linear
Secondary
Best Hard Contact Lens-corrected Visual Acuity 3 Months After Enrollment in a Multiple Linear Regression Model With Enrollment Hard Contact Lens-corrected Visual Acuity as a Covariate
Best hard contact lens-corrected visual acuity 3 months after enrollment was evaluated in a multiple linear regression model with enrollment hard contact lens-corrected visual acuity as a covariate. Visual acuity is reported in logMAR (logarithm of the Minimum Angle of Resolution).
Time frame: 3 months from enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Voriconazole | Best Hard Contact Lens-corrected Visual Acuity 3 Months After Enrollment in a Multiple Linear Regression Model With Enrollment Hard Contact Lens-corrected Visual Acuity as a Covariate | 0.39 logMAR |
| Topical Natamycin | Best Hard Contact Lens-corrected Visual Acuity 3 Months After Enrollment in a Multiple Linear Regression Model With Enrollment Hard Contact Lens-corrected Visual Acuity as a Covariate | 0.46 logMAR |
p-value: 0.5395% CI: [-0.26, 0.14]Regression, Linear
Secondary
Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate.
Size of infiltrate/scar post-treatment was analyzed in a linear regression model using enrollment infiltrate/scar size as a covariate. No differentiation was made between infiltrate and scar when measuring infiltrate/scar size (measured in mm). For analysis, infiltrate/scar size was characterized by the geometric mean of the longest dimension and the longest perpendicular.
Time frame: 3 months from enrollment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Topical Voriconazole | Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate. | 4.21 mm |
| Topical Natamycin | Size of Infiltrate/Scar Post-treatment Was Analyzed in a Linear Regression Model Using Enrollment Infiltrate/Scar Size as a Covariate. | 4.08 mm |
p-value: 0.3795% CI: [-0.2, 0.53]Regression, Linear
Secondary
Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp).
Two subgroup analyses were conducted by causative organism: 1) best spectacle-corrected visual acuity (BSCVA) by treatment arm among Fusarium ulcers; 2) best spectacle-corrected visual acuity (BSCVA) by treatment arm among Aspergillus ulcers.
Time frame: 3 months from enrollment
Population: This analysis looks at two different subgroups - Fusarium ulcers and Aspergillus ulcers. There were 44 Fusaruim ulcers enrolled in this trial and analyzed here, 23 of which were randomized to voriconazole and 21 to natamycin. There were 19 Aspergillus ulcers analyzed here, 8 of which were randomized to voriconazole and 11 to natamycin.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Topical Voriconazole | Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp). | BSCVA Fusarium ulcers (n=23 vori; n=21 nata) | 0.58 logMAR |
| Topical Voriconazole | Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp). | BSCVA Aspergillus ulcers (n=8 vori; n=11 nata) | 0.48 logMAR |
| Topical Natamycin | Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp). | BSCVA Fusarium ulcers (n=23 vori; n=21 nata) | 0.50 logMAR |
| Topical Natamycin | Subgroup Analysis - Best Spectacle-corrected Visual Acuity Examined by Voriconazole and Natamycin Treatment Arms in Subgroups of Fungal Ulcers (Fusarium Spp and Aspergillus Spp). | BSCVA Aspergillus ulcers (n=8 vori; n=11 nata) | 0.68 logMAR |
Comparison: Best spectacle-corrected visual acuity (BSCVA) was examined in a linear regression model with enrollment BSCVA and treatment arm as covariates among a subgroup of ulcers caused by Fusarium spp.p-value: 0.6295% CI: [-0.25, 0.41]Regression, Linear
Comparison: Best spectacle-corrected visual acuity (BSCVA) was evaluated in a linear regression model with enrollment BSCVA and treatment arm as covariates in a subgroup of ulcers caused by Aspergillus spp.p-value: 0.2695% CI: [-0.57, 0.17]Regression, Linear
Secondary
Time to Resolution of Epithelial Defect
Resolution of epithelial defect was defined as the absence of an epithelial defect with administration of fluorescein. The time to re-epithelialization was compared between the voriconazole and natamycin groups using the Cox proportional hazards model, adjusting for baseline epithelial defect size.
Time frame: 3 months from enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topical Voriconazole | Time to Resolution of Epithelial Defect | 13.07 days | Standard Deviation 7.71 |
| Topical Natamycin | Time to Resolution of Epithelial Defect | 15.2 days | Standard Deviation 7.03 |
p-value: 0.495% CI: [0.76, 2.02]Regression, Cox