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 the addition of oral voriconazole to topical treatment regimens results in lower rates of perforation in severe fungal corneal ulcers.
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 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.
Interventions
DRUGVoriconazole
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.
DRUGPlacebo
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.
Sponsors
Aravind Eye Hospitals, India
Dartmouth-Hitchcock Medical Center
Lumbini Eye Institute and Research Centre
Bharatpur Eye Hospital
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 worse than 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
* 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) * Known liver disease, including hepatitis or cirrhosis (Child-Pugh A-C) * 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 better than 6/120 (20/400) in the study eye (note that any acuity, uncorrected, corrected, pinhole, or BSCVA can be used for enrollment) * Currently on rifampin, rifabutin, ritonavir, long acting barbiturates, phenytoin, carbamazepine, or other drugs known to interact with voriconazole * 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 |
|---|---|---|
| Incidence of Perforation or Therapeutic Penetrating Keratoplasty | 3 months from enrollment | Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Spectacle-corrected logMAR Visual Acuity at 3-weeks | 3 weeks after enrollment | Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear |
| Size of Infiltrate/Scar - 3 Months | 3 months after enrollment | Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate |
| Size of Infiltrate/Scar | 3 weeks after enrollment | Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate |
| Hazard Ratio for Re-epithelialization | Up to 21 days | Hazard Ratio of re-epithelialization comparing the treatment groups |
| Best Spectacle-corrected logMAR Visual Acuity | 3 months after enrollment | Best spectacle-corrected logMAR visual acuity at 3 months after enrollment, adjusting for enrollment BSCVA and treatment arm in a multiple linear |
| Number of Adverse Events | 3-months from enrollment | Comparing the number of serious and non-serious adverse events by treatment arm. |
| Minimum Inhibitory Concentration of Isolates - Natamycin | 7 days | Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm |
| Minimum Inhibitory Concentration of Isolates - Voriconazole | 7 days | Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm |
| Microbiological Cure at 7 Days | 7 days | Fungal Culture negative at 7 days post treatment |
Countries
India, Nepal, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 121 |
| 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. | 119 |
| Total | 240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 3-month Follow-up Visit | Lost to Follow-up | 12 | 6 |
| 3-week Followup Visit | Lost to Follow-up | 9 | 6 |
Baseline characteristics
| Characteristic | Oral Voriconazole | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 49 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 93 Participants | 191 Participants | 98 Participants |
| Age, Continuous | 54 years | 54 years | 50 years |
| Region of Enrollment India | 21 participants | 44 participants | 23 participants |
| Region of Enrollment Nepal | 98 participants | 196 participants | 98 participants |
| Sex: Female, Male Female | 54 Participants | 104 Participants | 50 Participants |
| Sex: Female, Male Male | 65 Participants | 136 Participants | 71 Participants |
| Weight (lbs) | 105 lbs | 108 lbs | 108 lbs |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 121 | 52 / 119 |
| serious Total, serious adverse events | 1 / 121 | 7 / 119 |
Outcome results
Primary
Incidence of Perforation or Therapeutic Penetrating Keratoplasty
Hazard ratio of perforation or therapeutic penetrating keratoplasty (TPK) comparing voriconazole to placebo
Time frame: 3 months from enrollment
Population: Comparison of rate of perforation or TPK between the treatment groups (topical voriconazole with oral voriconazole vs. topical voriconazole with oral placebo)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Voriconazole | Incidence of Perforation or Therapeutic Penetrating Keratoplasty | 0.0095562 New perforations or TPK/person-days |
| Oral Placebo | Incidence of Perforation or Therapeutic Penetrating Keratoplasty | 0.011204 New perforations or TPK/person-days |
Comparison: The sample size was determined based on the primary end point: perforation or the need for TPK within 3 months. Simulation-based analyses estimated that a sample sizeof 240 study participants (120 per arm) would provide 80% power to detect a 15% difference in the 3-month perforation or need for TPK rate between topical antifungal plus oral voriconazole vs topical antifungal alone,with a 2-tailed α value of .05 and approximately 15%loss to follow-up.p-value: 0.2995% CI: [0.57, 1.18]Regression, Cox
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
Time frame: 3 months after enrollment
Population: Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and study site
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Voriconazole | Best Spectacle-corrected logMAR Visual Acuity | .7852594 logMAR | Standard Error 0.1083858 |
| Oral Placebo | Best Spectacle-corrected logMAR Visual Acuity | .787141 logMAR | Standard Error 0.1646131 |
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
Time frame: 3 weeks after enrollment
Population: Best spectacle-corrected logMAR visual acuity at 3 weeks after enrollment, adjusting for enrollment BSCVA and study site.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Voriconazole | Best Spectacle-corrected logMAR Visual Acuity at 3-weeks | .8745454 logMAR | Standard Error 0.1080198 |
| Oral Placebo | Best Spectacle-corrected logMAR Visual Acuity at 3-weeks | .744252 logMAR | Standard Error 0.0964871 |
Secondary
Hazard Ratio for Re-epithelialization
Hazard Ratio of re-epithelialization comparing the treatment groups
Time frame: Up to 21 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Voriconazole | Hazard Ratio for Re-epithelialization | .0141123 Number re-epthelialized/person-days |
| Oral Placebo | Hazard Ratio for Re-epithelialization | .0130862 Number re-epthelialized/person-days |
p-value: 0.6595% CI: [0.49, 1.57]Regression, Cox
Secondary
Microbiological Cure at 7 Days
Fungal Culture negative at 7 days post treatment
Time frame: 7 days
Population: Fungal Culture negative at 7 days post treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Voriconazole | Microbiological Cure at 7 Days | 50 Participants |
| Oral Placebo | Microbiological Cure at 7 Days | 50 Participants |
Secondary
Minimum Inhibitory Concentration of Isolates - Natamycin
Minimum Inhibitory Concentration (MIC) of isolates to natamycin by treatment arm
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oral Voriconazole | Minimum Inhibitory Concentration of Isolates - Natamycin | 12 mg/L |
| Oral Placebo | Minimum Inhibitory Concentration of Isolates - Natamycin | 4 mg/L |
Secondary
Minimum Inhibitory Concentration of Isolates - Voriconazole
Minimum Inhibitory Concentration (MIC) of isolates to voriconazole by treatment arm
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oral Voriconazole | Minimum Inhibitory Concentration of Isolates - Voriconazole | 1 mg/L |
| Oral Placebo | Minimum Inhibitory Concentration of Isolates - Voriconazole | 2 mg/L |
Secondary
Number of Adverse Events
Comparing the number of serious and non-serious adverse events by treatment arm.
Time frame: 3-months from enrollment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Oral Voriconazole | Number of Adverse Events | 58 adverse events |
| Oral Placebo | Number of Adverse Events | 28 adverse events |
p-value: <0.001Fisher Exact
Secondary
Size of Infiltrate/Scar
Size of infiltrate/scar at 3 weeks after enrollment, using enrollment infiltrate scar/size as a covariate
Time frame: 3 weeks after enrollment
Population: Mean infiltrate scar size at three weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Voriconazole | Size of Infiltrate/Scar | .2192398 mm^2 | Standard Error 0.1663 |
| Oral Placebo | Size of Infiltrate/Scar | .7973467 mm^2 | Standard Error 0.073885 |
Secondary
Size of Infiltrate/Scar - 3 Months
Size of infiltrate/scar at 3 months after enrollment, using enrollment infiltrate scar/size as a covariate
Time frame: 3 months after enrollment
Population: Mean infiltrate scar size at three months correcting for baseline scar size and site
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oral Voriconazole | Size of Infiltrate/Scar - 3 Months | .9319315 mm^2 | Standard Error 0.06508 |
| Oral Placebo | Size of Infiltrate/Scar - 3 Months | .697005 mm^2 | Standard Error 0.0927 |