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| Name | Class |
|---|---|
| That Man May See, Inc. | OTHER |
| Aravind Eye Hospitals, India | OTHER |
| Dartmouth-Hitchcock Medical Center | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Active Comparator | Topical voriconazole with corneal de-epithelialization |
|
| 2 | Active Comparator | Topical voriconazole without corneal de-epithelialization |
|
| 3 | Active Comparator | Topical natamycin with corneal de-epithelialization |
|
| 4 | Active Comparator | Topical natamycin without corneal de-epithelialization |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Natamycin 5% | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 3 months from enrollment |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 3 months from enrollment |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Thomas M Lietman, MD | Proctor Foundation, University of California, San Francisco | Principal Investigator |
| Nisha Acharya, MD MS | Proctor Foundation, University of California, San Francisco | Principal Investigator |
| N V Prajna, MD | Aravind Eye Hospital, India | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Aravind Eye Hospital | Madurai | Tamil Nadu | India | |||
| Aravind Eye Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20547942 | Derived | Prajna NV, Mascarenhas J, Krishnan T, Reddy PR, Prajna L, Srinivasan M, Vaitilingam CM, Hong KC, Lee SM, McLeod SD, Zegans ME, Porco TC, Lietman TM, Acharya NR. Comparison of natamycin and voriconazole for the treatment of fungal keratitis. Arch Ophthalmol. 2010 Jun;128(6):672-8. doi: 10.1001/archophthalmol.2010.102. |
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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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Topical Natamycin With Corneal De-epithelialization | 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. |
| FG001 | Topical Natamycin Without Corneal De-epithelialization | 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. |
| FG002 | Topical Voriconazole With Corneal De-epithelialization | 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. |
| FG003 | Topical Voriconazole Without Corneal De-epithelialization | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | 95% Confidence Interval | logMAR | 3 months from enrollment |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Corneal perforation | Eye disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Local allergic reaction | Eye disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Tom M/ Lietman | University of California San Francisco Proctor Foundation | 4155022662 | tom.lietman@ucsf.edu |
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| ID | Term |
|---|---|
| D007634 | Keratitis |
| D015821 | Eye Infections, Fungal |
| ID | Term |
|---|---|
| D003316 | Corneal Diseases |
| D005128 | Eye Diseases |
| D009181 | Mycoses |
| D001423 | Bacterial Infections and Mycoses |
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| ID | Term |
|---|---|
| D065819 | Voriconazole |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Voriconazole | Drug | 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 |
|
| Corneal de-epithelialization | Procedure | Corneal de-epithelialization at 1 week and 2 weeks from enrollment to increase epithelial penetration of antifungal medications. |
|
| 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. | 3 months from enrollment |
| 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. | 3 months from enrollment |
| 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). | 3 months from enrollment |
| Pondicherry |
| Tamil Nadu |
| India |
| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Enrollment logMAR BSCVA | Best spectacle-corrected visual acuity at time of enrollment measured in logMAR | Mean | Standard Deviation | logMAR |
|
| Topical Natamycin |
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. |
|
|
|
| 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. | Posted | Mean | Standard Deviation | days | 3 months from enrollment |
|
|
|
|
| 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. | Posted | Mean | 95% Confidence Interval | mm | 3 months from enrollment |
|
|
|
|
| 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. | 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. | Posted | Mean | 95% Confidence Interval | logMAR | 3 months from enrollment |
|
|
|
|
| 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). | Posted | Mean | 95% Confidence Interval | logMAR | 3 months from enrollment |
|
|
|
|
| 6 |
| 30 |
| 2 |
| 30 |
| EG001 | 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. | 5 | 30 | 5 | 30 |
| EG002 | 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. | 8 | 30 | 2 | 30 |
| EG003 | 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. | 1 | 30 | 2 | 30 |
| Death | General disorders | Non-systematic Assessment |
|
| Increase in hypopyon | Eye disorders | Non-systematic Assessment |
|
| Increase in infiltrate | Eye disorders | Non-systematic Assessment |
|
| No resolution of epithelial defect by 21 days | Eye disorders | Systematic Assessment | Reepithelialization was defined as an epithelial defect of less than 0.5 mm with administration of fluorescein. |
|
| Progressive corneal thinning | Eye disorders | Non-systematic Assessment |
|
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| D007239 |
| Infections |
| D015817 | Eye Infections |
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.
| Regression, Linear |
| 0.26 |
| Mean Difference (Net) |
| -0.20 |
| 2-Sided |
| 95 |
| -0.57 |
| 0.17 |
| Superiority or Other |