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| ID | Type | Description | Link |
|---|---|---|---|
| U10EY018573 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Aravind Eye Hospitals, India | OTHER |
| Dartmouth-Hitchcock Medical Center | OTHER |
| Lumbini Eye Institute and Research Centre | OTHER |
| Bharatpur Eye Hospital |
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The purpose of this study is to determine if the addition of oral voriconazole to topical treatment regimens results in lower rates of perforation in severe fungal corneal ulcers.
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 of oral voriconazole in severe ulcers reduces the rate of perforations. 240 fungal corneal ulcers with baseline visual acuity worse than 6/120 presenting to the Aravind Eye Hospitals and the UCSF Proctor Foundation will be randomized to receive oral voriconazole plus topical voriconazole and topical natamycin, or oral placebo plus topical voriconazole and topical natamycin. The primary outcome is the rate of perforation over the three month follow-up period.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Oral Voriconazole | Active Comparator |
| |
| Placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Voriconazole | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Perforation or Therapeutic Penetrating Keratoplasty | Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo | 3 months from enrollment |
| Measure | Description | Time Frame |
|---|---|---|
| Best Spectacle-corrected logMAR Visual Acuity | Best spectacle-corrected logMAR visual acuity at 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear | 3 months after enrollment |
| Best Spectacle-corrected logMAR Visual Acuity at 3-weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| NV Prajna, DNB, FRC Ophth | Aravind Eye Hospitals | Principal Investigator |
| Nisha Acharya, MD, MS | Proctor Foundation, UCSF | Principal Investigator |
| Tom Lietman, MD | Proctor Foundation, UCSF | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Proctor Foundation, UCSF | San Francisco | California | 94143 | United States | ||
| Aravind Eye Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40372030 | Derived | Zegans ME, Kamath MM, Jones JT, Bao R, Ross BS, Gutierrez-Perez C, Adams EM, Lightfoot JD, Poimenidou G, Pavuluri C, Prajna V, Cramer RA, Fuller KK. Propranolol is efficacious against Aspergillus and Fusarium corneal isolates in vitro and in a murine model of Aspergillus keratitis. Antimicrob Agents Chemother. 2025 Jun 4;69(6):e0166424. doi: 10.1128/aac.01664-24. Epub 2025 May 15. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 3-week Followup Visit |
|
| ||||||||||||||||||
| 3-month Follow-up Visit |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Incidence of Perforation or Therapeutic Penetrating Keratoplasty | Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo | Comparison of rate of perforation or TPK between the treatment groups (topical voriconazole with oral voriconazole vs. topical voriconazole with oral placebo) | Posted | Number | New perforations or TPK/person-days | 3 months from enrollment |
|
Over the entire course of the trial. (June, 2010-December 2015)
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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 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Endophthalmitis | Eye disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ulcer not healing after 6 weeks of therapy | Eye disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kathryn Ray | University of California, San Francisco | 415-514-3227 | kathryn.ray@ucsf.edu |
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| ID | Term |
|---|---|
| D003320 | Corneal Ulcer |
| D015821 | Eye Infections, Fungal |
| D009181 | Mycoses |
| D005128 | Eye Diseases |
| ID | Term |
|---|---|
| D015817 | Eye Infections |
| D007239 | Infections |
| D007634 | Keratitis |
| D003316 | Corneal Diseases |
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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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| OTHER |
| National Eye Institute (NEI) | NIH |
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|
| Placebo | Drug | 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. |
|
Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear |
| 3 weeks after enrollment |
| Size of Infiltrate/Scar - 3 Months | Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate | 3 months after enrollment |
| Size of Infiltrate/Scar | Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate | 3 weeks after enrollment |
| Hazard Ratio for Re-epithelialization | Hazard Ratio of re-epithelialization comparing the treatment groups | Up to 21 days |
| Microbiological Cure at 7 Days | Fungal Culture negative at 7 days post treatment | 7 days |
| Number of Adverse Events | Comparing the number of serious and non-serious adverse events by treatment arm. | 3-months from enrollment |
| Minimum Inhibitory Concentration of Isolates - Natamycin | Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm | 7 days |
| Minimum Inhibitory Concentration of Isolates - Voriconazole | Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm | 7 days |
| Coimbatore |
| Tamil Nadu |
| India |
| Aravind Eye Hospitals | Madurai | Tamil Nadu | India |
| Aravind Eye Hospital | Pondicherry | Tamil Nadu | India |
| Aravind Eye Hospital | Tirunelveli | Tamil Nadu | India |
| Bharatpur Eye Hospital | Bharatpur | Chitwan | Nepal |
| Lumbini Eye Institute | Siddharthanagar | Lumbini | Nepal |
| NOT COMPLETED |
|
|
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Inter-Quartile Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Weight (lbs) | Median | Inter-Quartile Range | lbs |
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Secondary | Best Spectacle-corrected logMAR Visual Acuity | Best spectacle-corrected logMAR visual acuity at 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear | Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and study site | Posted | Mean | Standard Error | logMAR | 3 months after enrollment |
|
|
|
| Secondary | Best Spectacle-corrected logMAR Visual Acuity at 3-weeks | Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear | Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and study site. | Posted | Mean | Standard Error | logMAR | 3 weeks after enrollment |
|
|
|
| Secondary | Size of Infiltrate/Scar - 3 Months | Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate | Mean infiltrate scar size at three months correcting for baseline scar size and site | Posted | Mean | Standard Error | mm^2 | 3 months after enrollment |
|
|
|
| Secondary | Size of Infiltrate/Scar | Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate | Mean infiltrate scar size at three weeks. | Posted | Mean | Standard Error | mm^2 | 3 weeks after enrollment |
|
|
|
| Secondary | Hazard Ratio for Re-epithelialization | Hazard Ratio of re-epithelialization comparing the treatment groups | Posted | Number | Number re-epthelialized/person-days | Up to 21 days |
|
|
|
|
| Secondary | Microbiological Cure at 7 Days | Fungal Culture negative at 7 days post treatment | Fungal Culture negative at 7 days post treatment | Posted | Count of Participants | Participants | 7 days |
|
|
|
| Secondary | Number of Adverse Events | Comparing the number of serious and non-serious adverse events by treatment arm. | Posted | Number | adverse events | 3-months from enrollment |
|
|
|
|
| Secondary | Minimum Inhibitory Concentration of Isolates - Natamycin | Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm | Posted | Median | Inter-Quartile Range | mg/L | 7 days |
|
|
|
| Secondary | Minimum Inhibitory Concentration of Isolates - Voriconazole | Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm | Posted | Median | Inter-Quartile Range | mg/L | 7 days |
|
|
|
| 1 |
| 121 |
| 27 |
| 121 |
| EG001 | 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. | 7 | 119 | 52 | 119 |
| Evisceration | Eye disorders | Systematic Assessment |
|
| Myocardial infarction or stroke | Cardiac disorders | Systematic Assessment |
|
| AST or ALT elevated to five times the upper limit of normal | Hepatobiliary disorders | Systematic Assessment |
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| Increase in hypopyon (increase>2mm) | Eye disorders | Systematic Assessment |
|
| Headache | General disorders | Systematic Assessment |
|
| AST or ALT elevated to twice upper limit of normal | Hepatobiliary disorders | Systematic Assessment |
|
| Dizziness | General disorders | Systematic Assessment |
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| Vomiting | General disorders | Systematic Assessment |
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| Visual disturbances | Psychiatric disorders | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Fever | General disorders | Systematic Assessment |
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| Lethargy | General disorders | Systematic Assessment |
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| Nausea | General disorders | Systematic Assessment |
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| Local allergic reaction | General disorders | Systematic Assessment |
|
| Other systemic event thought to be related to study drug | General disorders | Systematic Assessment |
|
| Dermatologic reaction | General disorders | Systematic Assessment |
|
| Stomach pain | Gastrointestinal disorders | Systematic Assessment |
|
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| D001423 |
| Bacterial Infections and Mycoses |