Corneal Ulcer, Fungal Keratitis
Conditions
Keywords
cornea, ulcer, fungal, keratitis
Brief summary
Mycotic Antimicrobial Localized Injection (MALIN) is a randomized, masked, two-arm clinical trial investigating intrastromal voriconazole in the treatment of fungal corneal ulcers. There is currently little evidence to guide the treatment of fungal keratitis beyond topical anti-fungal drops, though intrastromal voriconazole and oral antifungal treatments are used as well. This study will provide evidence to guide the treatment of fungal keratitis in the future. The purpose of this study is to determine differences in microbiological cure for 3-day repeat cultures between different antifungal treatments. For this study, there will be 1:1 randomization to one of these two treatment groups: 1) topical natamycin plus intrastromal voriconazole injection or 2) topical natamycin alone.
Detailed description
The proposed study is a randomized controlled trial to determine whether intrastromal voriconazole improves outcomes in fungal keratitis. Patients presenting to the Aravind Eye Hospitals in Pondicherry, India for treatment of fungal keratitis will be recruited for the proposed study. Approximately 70 patients will be enrolled in the study. Subjects presenting with fungal keratitis will be randomized to receive topical natamycin plus intrastromal voriconazole or to receive topical natamycin alone. Subjects may also receive oral antifungals after day 3 at the discretion of the treating clinician. All study subjects will be followed for 3 months to evaluate response to treatment. Investigators from the University of California, San Francisco (UCSF) will assist Aravind Eye Hospital with the study design, implementation, and analysis of the research, and will help fund the study. The investigators will visit Aravind to help with the study implementation. UCSF will play an important role in this study by assisting with the study design, implementation, analysis, and funding.
Interventions
DRUGIntrastromal voriconazole
Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis.
DRUGNatamycin
Subjects will receive topical 5% natamycin drops hourly for 3 days.
Sponsors
Aravind Eye Hospitals, India
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Moderate to severe corneal ulcer that is smear positive for filamentous fungus * Pinhole visual acuity worse than 20/70 in affected eye * Basic understanding of the study as determined by the physician * Commitment to return for follow up visits
Exclusion criteria
* Gram stain positive for bacteria or evidence of other concomitant infection (i.e. herpes, acanthamoeba) * Impending or frank perforation at recruitment * Involvement of sclera at presentation * Non-infectious or autoimmune keratitis * History of corneal transplantation or recent intraocular surgery * No light perception in the affected eye * Pinhole visual acuity worse than 20/200 in the unaffected eye * Pregnant women * Participants who are decisionally and/or cognitively impaired
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Culture Positivity at Day 3 Using Potassium Hydroxide (KOH) Wet Mount to Test for Fungus | 3 days | Number of of participants with positive fungal cultures at 3 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist | 3 weeks and 3 months | Best spectacle-corrected visual acuity using calibrated Original Series Early Treatment Diabetic Retinopathy Study eye charts and recorded as number of letter read. |
| Scar Size | 3 weeks and 3 months | Scar size, geometric mean |
| Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 weeks and 3 months | Number of participants with scar depth at the anterior third (0-33% depth), middle third (\>33-67% depth), and posterior third (\>67-100% depth) of the cornea, as measured on slit lamp exam. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Corneal Neovascularization | 3 months | As measured by clinical examination and slit lamp photographs. |
| Change in Quality of Life, Measured by the Indian Vision Function Questionnaire (IND-VFQ) | 3 months | — |
| Corneal Thinning, as Measured by Pachymetry and OCT | 6 months | — |
| Corneal Topography, as Measured by a Non-contact Imaging Topographer | 6 months | — |
Countries
India, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intrastromal Voriconazole Plus Natamycin Intrastromal voriconazole plus standard of care topical treatment for fungal keratitis
Intrastromal voriconazole: Subjects will receive three intrastromal voriconazole injections over 10 days. Intrastromal voriconazole injection is a routine procedure performed by Aravind Eye Hospital for fungal keratitis.
Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days. | 35 |
| Natamycin Alone Standard of care topical treatment for fungal keratitis
Natamycin: Subjects will receive topical 5% natamycin drops hourly for 3 days. | 35 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 6 | 9 |
Baseline characteristics
| Characteristic | Total | Intrastromal Voriconazole Plus Natamycin | Natamycin Alone |
|---|---|---|---|
| Affected Eye Left | 38 Participants | 20 Participants | 18 Participants |
| Affected Eye Right | 32 Participants | 15 Participants | 17 Participants |
| Age, Continuous | 55 years | 53 years | 55 years |
| Culture Results Aspergillus species | 17 Participants | 7 Participants | 10 Participants |
| Culture Results Curvularia species | 4 Participants | 4 Participants | 0 Participants |
| Culture Results Exserohilum species | 2 Participants | 1 Participants | 1 Participants |
| Culture Results Fungal culture negative | 13 Participants | 8 Participants | 5 Participants |
| Culture Results Fusarium species | 19 Participants | 8 Participants | 11 Participants |
| Culture Results Missing | 2 Participants | 1 Participants | 1 Participants |
| Culture Results Unidentified dematiaceous | 8 Participants | 3 Participants | 5 Participants |
| Culture Results Unidentified hyaline | 5 Participants | 3 Participants | 2 Participants |
| Hypopyon size (mm) <0.5mm | 13 Participants | 6 Participants | 7 Participants |
| Hypopyon size (mm) ≥0.5mm | 28 Participants | 13 Participants | 15 Participants |
| Hypopyon size (mm) None | 29 Participants | 16 Participants | 13 Participants |
| Occupation Agriculture | 26 Participants | 11 Participants | 15 Participants |
| Occupation Non-Agriculture | 39 Participants | 22 Participants | 17 Participants |
| Occupation Unknown | 5 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 70 Participants | 35 Participants | 35 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment India | 70 participants | 35 participants | 35 participants |
| Sex: Female, Male Female | 26 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Male | 44 Participants | 26 Participants | 18 Participants |
| Trauma Dust | 7 Participants | 3 Participants | 4 Participants |
| Trauma Finger | 1 Participants | 0 Participants | 1 Participants |
| Trauma Insect | 6 Participants | 5 Participants | 1 Participants |
| Trauma Leaf | 3 Participants | 2 Participants | 1 Participants |
| Trauma Mud | 8 Participants | 4 Participants | 4 Participants |
| Trauma No trauma | 20 Participants | 10 Participants | 10 Participants |
| Trauma Other | 13 Participants | 4 Participants | 9 Participants |
| Trauma Stick | 10 Participants | 7 Participants | 3 Participants |
| Trauma Unknown object | 2 Participants | 0 Participants | 2 Participants |
| Ulcer depth, measured in % depth >0-33% | 23 Participants | 13 Participants | 10 Participants |
| Ulcer depth, measured in % depth >33-67% | 27 Participants | 11 Participants | 16 Participants |
| Ulcer depth, measured in % depth >67-100% | 20 Participants | 11 Participants | 9 Participants |
| Ulcer location Central | 62 Participants | 30 Participants | 32 Participants |
| Ulcer location Peripheral | 8 Participants | 5 Participants | 3 Participants |
| Visual Acuity, logMAR | 1.7 logMAR | 1.7 logMAR | 1.7 logMAR |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 16 / 35 | 15 / 35 |
| serious Total, serious adverse events | 0 / 35 | 0 / 35 |
Outcome results
Primary
Culture Positivity at Day 3 Using Potassium Hydroxide (KOH) Wet Mount to Test for Fungus
Number of of participants with positive fungal cultures at 3 days
Time frame: 3 days
Population: 3-day culture results missing for one participant in the Natamycin group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intrastromal Voriconazole Plus Natamycin | Culture Positivity at Day 3 Using Potassium Hydroxide (KOH) Wet Mount to Test for Fungus | 14 Participants |
| Natamycin Alone | Culture Positivity at Day 3 Using Potassium Hydroxide (KOH) Wet Mount to Test for Fungus | 11 Participants |
p-value: 0.2695% CI: [0.65, 5.23]Regression, Logistic
Secondary
Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist
Best spectacle-corrected visual acuity using calibrated Original Series Early Treatment Diabetic Retinopathy Study eye charts and recorded as number of letter read.
Time frame: 3 weeks and 3 months
Population: 3-week visual acuity data was available for 65 people: 33 in the ISV group (2 lost to follow-up) and 32 in the Natamycin only group (3 lost of follow-up). 3-month visual acuity data was available for 58 people: 30 in the ISV group (5 lost to follow-up) and 28 in the Natamycin only group (7 lost to follow-up).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intrastromal Voriconazole Plus Natamycin | Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist | 3 weeks | 1.39 logarithm of the minimum angle (logMAR) | Standard Deviation 0.59 |
| Intrastromal Voriconazole Plus Natamycin | Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist | 3 months | 1.30 logarithm of the minimum angle (logMAR) | Standard Deviation 0.6 |
| Natamycin Alone | Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist | 3 weeks | 1.23 logarithm of the minimum angle (logMAR) | Standard Deviation 0.65 |
| Natamycin Alone | Best Spectacle-corrected Visual Acuity, as Measured by a Refractionist | 3 months | 1.28 logarithm of the minimum angle (logMAR) | Standard Deviation 0.66 |
p-value: 0.2595% CI: [-1.2, 4.4]Regression, Linear
p-value: 0.7595% CI: [-2.6, 3.6]Regression, Linear
Secondary
Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea
Number of participants with scar depth at the anterior third (0-33% depth), middle third (\>33-67% depth), and posterior third (\>67-100% depth) of the cornea, as measured on slit lamp exam.
Time frame: 3 weeks and 3 months
Population: 3-week scar depth data was available for 40 people: 24 in the ISV group (2 lost to follow-up \[LTF\], 9 unable to assess) and 16 in the Natamycin only group (3 LTF, 16 unable to assess). 3-month scar depth was available for 29 people: 16 in the ISV group (5 LTF, 14 unable to assess) and 13 in the Natamycin only group (7 LTF, 15 unable to assess).
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Intrastromal Voriconazole Plus Natamycin | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Weeks | Anterior third | 9 Participants |
| Intrastromal Voriconazole Plus Natamycin | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Weeks | Middle third | 8 Participants |
| Intrastromal Voriconazole Plus Natamycin | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Weeks | Posterior third | 7 Participants |
| Intrastromal Voriconazole Plus Natamycin | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Months | Anterior third | 6 Participants |
| Intrastromal Voriconazole Plus Natamycin | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Months | Middle third | 5 Participants |
| Intrastromal Voriconazole Plus Natamycin | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Months | Posterior third | 5 Participants |
| Natamycin Alone | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Months | Middle third | 2 Participants |
| Natamycin Alone | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Weeks | Anterior third | 13 Participants |
| Natamycin Alone | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Months | Anterior third | 7 Participants |
| Natamycin Alone | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Weeks | Middle third | 2 Participants |
| Natamycin Alone | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Months | Posterior third | 4 Participants |
| Natamycin Alone | Number of Participants With Scar Depth at the Anterior Third, Middle Third, and Posterior Third of the Cornea | 3 Weeks | Posterior third | 1 Participants |
Secondary
Scar Size
Scar size, geometric mean
Time frame: 3 weeks and 3 months
Population: 3-week scar size data was available for 42 people: 24 in the ISV group (2 lost to follow-up \[LTF\], 9 unable to assess) and 18 in the Natamycin only group (3 LTF, 14 unable to assess). 3-month scar size data was available for 29 people: 16 in the ISV group (5 LTF, 14 unable to assess) and 13 in the Natamycin only group (7 LTF, 15 unable to assess).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intrastromal Voriconazole Plus Natamycin | Scar Size | 3 Weeks | 4.8 millimeters squared | Standard Deviation 1.2 |
| Intrastromal Voriconazole Plus Natamycin | Scar Size | 3 Months | 4.9 millimeters squared | Standard Deviation 1.2 |
| Natamycin Alone | Scar Size | 3 Weeks | 4.1 millimeters squared | Standard Deviation 1.3 |
| Natamycin Alone | Scar Size | 3 Months | 4.5 millimeters squared | Standard Deviation 1.1 |
Other Pre-specified
Change in Quality of Life, Measured by the Indian Vision Function Questionnaire (IND-VFQ)
Time frame: 3 months
Other Pre-specified
Corneal Neovascularization
As measured by clinical examination and slit lamp photographs.
Time frame: 3 months
Other Pre-specified
Corneal Thinning, as Measured by Pachymetry and OCT
Time frame: 6 months
Other Pre-specified
Corneal Topography, as Measured by a Non-contact Imaging Topographer
Time frame: 6 months