Bacterial Ulcer, Corneal Ulcer, Fungal Ulcer, Infectious Keratitis
Conditions
Keywords
Cornea, Ulcer, Infectious keratitis, Bacterial, Fungal
Brief summary
The primary purpose of this study is to determine if patients randomized to corneal collagen cross-linking plus medical therapy will have a lower prevalence of positive bacterial or fungal cultures immediately after the procedure than patients who received medical therapy alone. The secondary purpose of this study is to determine if patients randomized to corneal collagen cross-linking will have a better visual acuity at 3 and 12 months than patients who receive medical therapy alone.
Detailed description
The proposed study is a randomized controlled trial to determine whether collagen cross-linking improves outcomes in microbial keratitis. Patients presenting to the Aravind Eye Hospitals in Madurai, India for treatment of microbial keratitis will be recruited for the proposed study. Approximately 266 patients will be enrolled in the study. Subjects presenting with bacterial keratitis will be randomized to receive medical therapy plus corneal collagen cross-linking at presentation or to receive medical therapy alone. All subjects with bacterial ulcers will receive standard topical antibiotic medications as required after the procedure. Subjects with fungal keratitis will be randomized into one of four groups: 1. collagen cross-linking + amphotericin; 2. collagen cross-linking + natamycin; 3. amphotericin alone; 4. natamycin alone. All study subjects will be followed for 12 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 plan to 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
PROCEDURECorneal Cross-linking
For those subjects randomized to receive collagen cross-linking, the procedure will be performed as per the routine at the hospital (UV-X machine; strict aseptic precautions; corneal epithelium debrided and 0.1% riboflavin applied for 30 minutes, then UV-A radiation applied for 30 minutes at 370nm with 3mW/cm2). Corneal cross-linking is a routine procedure performed by Aravind Eye Hospital for infectious keratitis.
DRUGAnti Fungal Drug
Topical Amphotericin B vs Topical Natamycin
Sponsors
Aravind Eye Hospitals, India
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
Patients with corneal ulcers are randomized to topical antimicrobial plus corneal crosslinking versus topical antimicrobial alone
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Corneal ulcer that is smear positive for either bacteria or filamentous fungus * Pinhole visual acuity worse than 20/70 in the affected eye * Not treated already with antimicrobial medications at presentation * Age over 18 years * Basic understanding of the study as determined by the physician * Commitment to return for follow up visits
Exclusion criteria
* Evidence of concomitant infection on exam or gram stain (i.e. herpes, both bacteria and acanthamoeba on gram stain) * 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 * Participants who are decisionally and/or cognitively impaired
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Microbiological Cure on Repeat Culture | 4 to 24 hours after enrollment | Corneal scraping of the ulcer will be performed and directly inoculated on to sheep's blood agar, chocolate agar, potato dextrose agar or Sabouraud's agar for bacterial and fungal culture. Microbiological cure is defined as no growth of bacteria or fungus on these media. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Spectacle-corrected Visual Acuity | 3 months | Best corrected visual acuity will be measured at baseline for both eyes using the standard ETDRS chart light box at the 4- and 1-meter test distances. In the case that the patient reads less than 10 letters at 4 meters, move the patient or the chart to a distance of 1 meter from the patient. |
| Scar Size | 3 months | Study clinician will measure infiltrate or scar size using a standardized protocol with the slit lamp biomicroscope. The geometric mean of the scar size will be measured by recording the horizontal and vertical diameter. |
| Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | 3 months | Adverse events include glaucoma, endophthalmitis, medication reaction, perforation including treatment by therapeutic penetrating keratoplasty. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Vision Related Quality of Life | 3 months | Mobility subscale: As measured by the Indian Visual Function Questionnaire (IVFQ) which records quality of life on a scale of 0 to 100 with 100 representing the best quality of life. |
Countries
India, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bacterial Ulcer Control Standard of care topical treatment for bacterial ulcer
Bacterial ulcer control: For those bacterial ulcer subjects randomized to the control group, they will receive the standard of care topical treatment for bacterial ulcers. This group will have their eyes irrigated with a balanced salt solution. | 19 |
| Bacterial Ulcer Cross-linking Standard of care topical treatment for bacterial ulcer plus cross-linking
Bacterial ulcer cross-linking: For those subjects randomized to receive collagen cross-linking, the procedure will be performed as per the routine at the hospital (UV-X machine; strict aseptic precautions; corneal epithelium debrided and 0.1% riboflavin applied for 30 minutes, then UV-A radiation applied for 30 minutes at 370nm with 3mW/cm2). Corneal cross-linking is a routine procedure performed by Aravind Eye Hospital for infectious keratitis. | 17 |
| Fungal Ulcer Control With Natamycin Standard of care topical treatment for fungal ulcer with natamycin
Fungal ulcer control: Prior to receiving sham cross-linking, topical amphotericin B or topical natamycin antifungal therapy will be started as per routine at the hospital; a loading dose of amphotericin B or natamycin every 5 minutes x 6 will be followed by dosing every 30 minutes. Amphotericin B and natamycin are routinely used therapies for fungal keratitis at Aravind Eye Hospital.
For those fungal ulcer subjects randomized to the control group, they will receive the standard of care topical treatment for fungal ulcers. This group will have their eyes irrigated with a balanced salt solution. | 26 |
| Fungal Ulcer Cross-linking Plus Natamycin Standard of care topical treatment for fungal ulcer with natamycin plus cross-linking
Fungal ulcer cross-linking: Prior to receiving cross-linking, topical amphotericin B or topical natamycin antifungal therapy will be started as per routine at the hospital; a loading dose of amphotericin B or natamycin every 5 minutes x 6 will be followed by dosing every 30 minutes. Amphotericin B and natamycin are routinely used therapies for fungal keratitis at Aravind Eye Hospital.
For those subjects randomized to receive collagen cross-linking, the procedure will be performed as per the routine at the hospital (UV-X machine; strict aseptic precautions; corneal epithelium debrided and 0.1% riboflavin applied for 30 minutes, then UV-A radiation applied for 30 minutes at 370nm with 3mW/cm2). Corneal cross-linking is a routine procedure performed by Aravind Eye Hospital for infectious keratitis. | 27 |
| Fungal Ulcer Control With Amphotericin Standard of care topical treatment for fungal ulcer with amphotericin
Fungal ulcer control: Prior to receiving sham cross-linking, topical amphotericin B or topical natamycin antifungal therapy will be started as per routine at the hospital; a loading dose of amphotericin B or natamycin every 5 minutes x 6 will be followed by dosing every 30 minutes. Amphotericin B and natamycin are routinely used therapies for fungal keratitis at Aravind Eye Hospital.
For those fungal ulcer subjects randomized to the control group, they will receive the standard of care topical treatment for fungal ulcers. This group will have their eyes irrigated with a balanced salt solution. | 30 |
| Fungal Ulcer Cross-linking Plus Amphotericin Standard of care topical treatment for fungal ulcer with amphotericin plus cross-linking
Fungal ulcer cross-linking: Prior to receiving cross-linking, topical amphotericin B or topical natamycin antifungal therapy will be started as per routine at the hospital; a loading dose of amphotericin B or natamycin every 5 minutes x 6 will be followed by dosing every 30 minutes. Amphotericin B and natamycin are routinely used therapies for fungal keratitis at Aravind Eye Hospital.
For those subjects randomized to receive collagen cross-linking, the procedure will be performed as per the routine at the hospital (UV-X machine; strict aseptic precautions; corneal epithelium debrided and 0.1% riboflavin applied for 30 minutes, then UV-A radiation applied for 30 minutes at 370nm with 3mW/cm2). Corneal cross-linking is a routine procedure performed by Aravind Eye Hospital for infectious keratitis. | 28 |
| Total | 147 |
Baseline characteristics
| Characteristic | Bacterial Ulcer Control | Fungal Ulcer Cross-linking Plus Amphotericin | Total | Fungal Ulcer Control With Amphotericin | Fungal Ulcer Cross-linking Plus Natamycin | Fungal Ulcer Control With Natamycin | Bacterial Ulcer Cross-linking |
|---|---|---|---|---|---|---|---|
| Affected Eye Left | 8 Participants | 13 Participants | 70 Participants | 18 Participants | 12 Participants | 11 Participants | 8 Participants |
| Affected Eye Right | 11 Participants | 15 Participants | 77 Participants | 12 Participants | 15 Participants | 15 Participants | 9 Participants |
| Age, Continuous | 60 years | 56 years | 54.5 years | 45 years | 55 years | 50 years | 59 years |
| % Depth >0-33% | 5 Participants | 9 Participants | 60 Participants | 13 Participants | 13 Participants | 14 Participants | 6 Participants |
| % Depth >33-67% | 10 Participants | 19 Participants | 79 Participants | 17 Participants | 12 Participants | 11 Participants | 10 Participants |
| % Depth >67-100% | 4 Participants | 0 Participants | 6 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| % Depth NA | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Duration of symptoms | 3 days | 4 days | 5 days | 5 days | 7 days | 5 days | 4 days |
| Epithelial defect | 3.2 mm | 3.4 mm | 3.2 mm | 3.5 mm | 3.9 mm | 3.0 mm | 3 mm |
| Hypopyon <0.5 mm | 2 Participants | 1 Participants | 15 Participants | 5 Participants | 5 Participants | 1 Participants | 1 Participants |
| Hypopyon >=0.5 mm | 11 Participants | 13 Participants | 56 Participants | 10 Participants | 6 Participants | 6 Participants | 10 Participants |
| Hypopyon No | 6 Participants | 14 Participants | 76 Participants | 15 Participants | 16 Participants | 19 Participants | 6 Participants |
| Infiltrate and/or scar | 3.5 mm | 3.1 mm | 3.3 mm | 3.5 mm | 3.9 mm | 3.0 mm | 3 mm |
| Medication use at enrollment | 8 Participants | 24 Participants | 100 Participants | 19 Participants | 21 Participants | 18 Participants | 10 Participants |
| Occupation Agriculture | 12 Participants | 13 Participants | 80 Participants | 18 Participants | 13 Participants | 16 Participants | 8 Participants |
| Occupation NA | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Occupation Nonagriculture | 6 Participants | 15 Participants | 66 Participants | 12 Participants | 14 Participants | 10 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 28 Participants | 147 Participants | 30 Participants | 27 Participants | 26 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment India | 19 Participants | 28 Participants | 147 Participants | 30 Participants | 27 Participants | 26 Participants | 17 Participants |
| Sex: Female, Male Female | 6 Participants | 11 Participants | 63 Participants | 16 Participants | 12 Participants | 9 Participants | 9 Participants |
| Sex: Female, Male Male | 13 Participants | 17 Participants | 84 Participants | 14 Participants | 15 Participants | 17 Participants | 8 Participants |
| Ulcer location Central | 14 Participants | 22 Participants | 119 Participants | 26 Participants | 23 Participants | 21 Participants | 13 Participants |
| Ulcer location NA | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ulcer location Peripheral | 4 Participants | 6 Participants | 27 Participants | 4 Participants | 4 Participants | 5 Participants | 4 Participants |
| Visual acuity | 1.7 LogMar | 1.22 LogMar | 1.1 LogMar | 1.05 LogMar | 1.1 LogMar | 1.05 LogMar | 1.7 LogMar |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 17 | 0 / 26 | 0 / 27 | 0 / 30 | 0 / 28 |
| other Total, other adverse events | 0 / 19 | 0 / 17 | 0 / 26 | 0 / 27 | 0 / 30 | 1 / 28 |
| serious Total, serious adverse events | 4 / 19 | 1 / 17 | 7 / 26 | 6 / 27 | 10 / 30 | 6 / 28 |
Outcome results
Primary
Microbiological Cure on Repeat Culture
Corneal scraping of the ulcer will be performed and directly inoculated on to sheep's blood agar, chocolate agar, potato dextrose agar or Sabouraud's agar for bacterial and fungal culture. Microbiological cure is defined as no growth of bacteria or fungus on these media.
Time frame: 4 to 24 hours after enrollment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bacterial Ulcer Control | Microbiological Cure on Repeat Culture | Culture negative | 5 Participants |
| Bacterial Ulcer Control | Microbiological Cure on Repeat Culture | Culture positive | 14 Participants |
| Bacterial Ulcer Cross-linking | Microbiological Cure on Repeat Culture | Culture negative | 5 Participants |
| Bacterial Ulcer Cross-linking | Microbiological Cure on Repeat Culture | Culture positive | 11 Participants |
| Fungal Ulcer Control With Natamycin | Microbiological Cure on Repeat Culture | Culture negative | 17 Participants |
| Fungal Ulcer Control With Natamycin | Microbiological Cure on Repeat Culture | Culture positive | 9 Participants |
| Fungal Ulcer Cross-linking Plus Natamycin | Microbiological Cure on Repeat Culture | Culture negative | 14 Participants |
| Fungal Ulcer Cross-linking Plus Natamycin | Microbiological Cure on Repeat Culture | Culture positive | 12 Participants |
| Fungal Ulcer Control With Amphotericin | Microbiological Cure on Repeat Culture | Culture negative | 15 Participants |
| Fungal Ulcer Control With Amphotericin | Microbiological Cure on Repeat Culture | Culture positive | 12 Participants |
| Fungal Ulcer Cross-linking Plus Amphotericin | Microbiological Cure on Repeat Culture | Culture negative | 13 Participants |
| Fungal Ulcer Cross-linking Plus Amphotericin | Microbiological Cure on Repeat Culture | Culture positive | 13 Participants |
Secondary
Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty
Adverse events include glaucoma, endophthalmitis, medication reaction, perforation including treatment by therapeutic penetrating keratoplasty.
Time frame: 3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bacterial Ulcer Control | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Perforation | 1 participants |
| Bacterial Ulcer Control | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Therapeutic penetrating keratoplasty | 3 participants |
| Bacterial Ulcer Control | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Endophthalmitis | 0 participants |
| Bacterial Ulcer Control | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Median tarsorrhaphy | 0 participants |
| Bacterial Ulcer Cross-linking | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Endophthalmitis | 0 participants |
| Bacterial Ulcer Cross-linking | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Therapeutic penetrating keratoplasty | 1 participants |
| Bacterial Ulcer Cross-linking | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Perforation | 0 participants |
| Bacterial Ulcer Cross-linking | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Median tarsorrhaphy | 0 participants |
| Fungal Ulcer Control With Natamycin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Median tarsorrhaphy | 0 participants |
| Fungal Ulcer Control With Natamycin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Endophthalmitis | 0 participants |
| Fungal Ulcer Control With Natamycin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Therapeutic penetrating keratoplasty | 5 participants |
| Fungal Ulcer Control With Natamycin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Perforation | 2 participants |
| Fungal Ulcer Cross-linking Plus Natamycin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Perforation | 1 participants |
| Fungal Ulcer Cross-linking Plus Natamycin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Median tarsorrhaphy | 0 participants |
| Fungal Ulcer Cross-linking Plus Natamycin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Therapeutic penetrating keratoplasty | 5 participants |
| Fungal Ulcer Cross-linking Plus Natamycin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Endophthalmitis | 0 participants |
| Fungal Ulcer Control With Amphotericin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Endophthalmitis | 1 participants |
| Fungal Ulcer Control With Amphotericin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Median tarsorrhaphy | 0 participants |
| Fungal Ulcer Control With Amphotericin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Therapeutic penetrating keratoplasty | 5 participants |
| Fungal Ulcer Control With Amphotericin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Perforation | 4 participants |
| Fungal Ulcer Cross-linking Plus Amphotericin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Therapeutic penetrating keratoplasty | 3 participants |
| Fungal Ulcer Cross-linking Plus Amphotericin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Endophthalmitis | 0 participants |
| Fungal Ulcer Cross-linking Plus Amphotericin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Median tarsorrhaphy | 1 participants |
| Fungal Ulcer Cross-linking Plus Amphotericin | Adverse Events Including Rate of Perforation/Need for Therapeutic Penetrating Keratoplasty | Perforation | 3 participants |
Secondary
Best Spectacle-corrected Visual Acuity
Best corrected visual acuity will be measured at baseline for both eyes using the standard ETDRS chart light box at the 4- and 1-meter test distances. In the case that the patient reads less than 10 letters at 4 meters, move the patient or the chart to a distance of 1 meter from the patient.
Time frame: 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bacterial Ulcer Control | Best Spectacle-corrected Visual Acuity | 0.82 logMar |
| Bacterial Ulcer Cross-linking | Best Spectacle-corrected Visual Acuity | 1.32 logMar |
| Fungal Ulcer Control With Natamycin | Best Spectacle-corrected Visual Acuity | 0.43 logMar |
| Fungal Ulcer Cross-linking Plus Natamycin | Best Spectacle-corrected Visual Acuity | 1 logMar |
| Fungal Ulcer Control With Amphotericin | Best Spectacle-corrected Visual Acuity | 0.48 logMar |
| Fungal Ulcer Cross-linking Plus Amphotericin | Best Spectacle-corrected Visual Acuity | 0.8 logMar |
Secondary
Scar Size
Study clinician will measure infiltrate or scar size using a standardized protocol with the slit lamp biomicroscope. The geometric mean of the scar size will be measured by recording the horizontal and vertical diameter.
Time frame: 3 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bacterial Ulcer Control | Scar Size | 3.5 mm |
| Bacterial Ulcer Cross-linking | Scar Size | 3.0 mm |
| Fungal Ulcer Control With Natamycin | Scar Size | 3.0 mm |
| Fungal Ulcer Cross-linking Plus Natamycin | Scar Size | 3.9 mm |
| Fungal Ulcer Control With Amphotericin | Scar Size | 3.5 mm |
| Fungal Ulcer Cross-linking Plus Amphotericin | Scar Size | 3.1 mm |
Other Pre-specified
Vision Related Quality of Life
Mobility subscale: As measured by the Indian Visual Function Questionnaire (IVFQ) which records quality of life on a scale of 0 to 100 with 100 representing the best quality of life.
Time frame: 3 months
Population: These data were exploratory in nature, we did not collect the data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fungal Ulcer Control With Natamycin | Vision Related Quality of Life | 89.6 score on a scale |
| Fungal Ulcer Cross-linking Plus Natamycin | Vision Related Quality of Life | 91.7 score on a scale |
| Fungal Ulcer Control With Amphotericin | Vision Related Quality of Life | 95.8 score on a scale |
| Fungal Ulcer Cross-linking Plus Amphotericin | Vision Related Quality of Life | 89.6 score on a scale |